Liver volume as a predictor of functional improvement post DAA treatment

Background New direct antiviral agents (DAA) for HCV treatment result in sustained viral response (SVR) in most patients. However, predicting the point of no-return is still an unmet need for those with advanced liver disease. Aim to assess if baseline liver volume is a predictor of post-SVR liver function. Methods Cirrhotic patients assessed for liver transplantation (LT) and consecutively treated with DAA between September 2014 and 2015 who achieved an SVR were included. Pretreatment liver (LV) and spleen (SV) volumes adjusted by Body Surface Area (BSA) were calculated from CT/MR images. Liver function was assessed by Child-Turcotte-Pugh (CTP) and MELD scores and a multivariate mixed regression model was used to identify baseline factors associated with improvement of liver function overtime. Results We included 42 patients with a median age of 58.6 years (Q1-Q3: 52.7 - 68.8); MELD, 14 (11-17); CTP, 9 (8-10); LV, 1400.9 mL (1183.2-1601.4); SV, 782.9 mL (490.6-1118.8). MELD scores at baseline and at last control were 14 (11-17) and 10 (8-12), respectively (p

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Brain Integrity Changes underlying Cognitive and Functional Recovery Postliver Transplant Continue to Evolve Over 1 Year

Abstract: Background There is evidence of brain recovery on brain MRI early postliver transplant(LT) but the longer-term impact is unclear. Aim of this study was to determine the change in brain MRI parameters, cognition and health-related quality of life (HRQOL) between 6 and 12 months post-LT. Methods Listed cirrhotics underwent cognitive, HRQOL and brain MRI pre, 6 months (post-LT1) and 1-year (post-LT2) post-LT. Assessment of MRI changes between visits was performed for ammonia-associated metabolite changes using spectroscopy (MRS), white matter changes using Tract-based Spatial Statistics (TBSS) analysis on Diffusion Tensor Imaging (DTI) data and grey matter changes using Voxel-based morphometry (VBM) analysis on 3D high resolution T1-weighted images. Results Forty-five patients were included of which, twenty-three were tested at all visits. Cognitive and HRQOL scores improved between all visits compared to pre-LT values. This trend continued on MRS with reduced glutamine+glutamate(Glx) and higher myoinositol(mI), Choline(Cho) between pre-LT/post-LT1 but lower degrees of improvement between post-LT1/post-LT2. On DTI, mean-diffusivity(MD), linear-diffusivity(LD) and mode of anisotropy(MO) continued to increase in the posterior internal capsule at both post-LT visits. On VBM, a continued increase was seen in basal ganglia grey matter between both post-LT visits was seen. Conclusions HRQOL and cognition continue to improve compared to pre-LT values up to 1 year post-LT, although the rate of improvement slows down after 6 months. Grey matter increase is steady over time at 1 year although changes in ammonia-related metabolites and white matter integrity improve at a slower pace at 1 year post-LT. Corresponding Author: Jasmohan S Bajaj, MD, MS, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, VA, 23221, USA, Phone: (804) 675-5802, Fax: (804) 675 5816. Email: jasmohan.bajaj@vcuhealth.org Author contributions: JSB, VA, JS, FGM, JBW were involved in research design, performance of the research and data analysis, MBW, HSG, DMH, MF, EAG, AF, RKS, RTS, PP, AJS, MSS, SM, VL were involved in performance of the research, LRT was involved in data analysis, All authors participated in the writing of the paper. Funding: Partly supported by NIH RO1DK089713 and VA Merit Review 1I0CX001076 to JSB Disclosure: The authors declare no conflicts of interest Presentation: Portions of this study were presented as an oral presentation at the EASL conference in Amsterdam 2017. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Pomalidomide with Dexamethasone for Treating Relapsed and Refractory Multiple Myeloma Previously Treated with Lenalidomide and Bortezomib: An Evidence Review Group Perspective of an NICE Single Technology Appraisal

Abstract

The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the manufacturer of pomalidomide (POM; Imnovid^®, Celgene) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with dexamethasone (POM + LoDEX) for the treatment of relapsed and refractory multiple myeloma (RRMM) after at least two regimens including lenalidomide (LEN) and bortezomib (BOR). Kleijnen Systematic Reviews Ltd (KSR) and Erasmus University Rotterdam were commissioned as the Evidence Review Group (ERG) for this submission. The ERG reviewed the evidence submitted by the manufacturer, validated the manufacturer's decision analytic model, and conducted exploratory analyses in order to assess the robustness and validity of the presented clinical and cost-effectiveness results. This paper describes the company submission, the ERG assessment, and NICE's subsequent decisions. The company conducted a systematic review to identify studies comparing POM with comparators outlined in the NICE scope: panobinostat with bortezomib and dexamethasone (PANO + BOR + DEX), bendamustine with thalidomide and dexamethasone (BTD) and conventional chemotherapy (CC). The main clinical effectiveness evidence was obtained from MM-003, a randomized controlled trial (RCT) comparing POM + LoDEX with high-dose dexamethasone (HiDEX; used as a proxy for CC). Additional data from other studies were also used as nonrandomized observational data sources for the indirect treatment comparison of POM + LoDEX with BTD and PANO + BOR + DEX. Covariate or treatment switching adjustment methods were used for each comparison. The model developed in Microsoft^® Excel 2010 using a semi-Markov partitioned survival structure, submitted in the original submission to NICE for TA338, was adapted for the present assessment of the cost effectiveness of POM + LoDEX. Updated evidence from the clinical-effectiveness part was used for the survival modelling of progression-free survival and overall survival. For POM + LoDEX, the patient access scheme (PAS) discount was applied to the POM price. Three separate comparisons were conducted for each comparator, each comparison using a different dataset and adjustment methods. The ERG identified and corrected some errors, and the corrected incremental cost-effectiveness ratios (ICERs) for POM + LoDEX versus each comparator were presented: approximately £45,000 per quality-adjusted life-year (QALY) gained versus BTD, savings of approximately £143,000 per QALY lost versus PANO + BOR + DEX, and approximately £49,000 per QALY gained versus CC. The ERG also conducted full incremental analyses, which revealed that CC, POM + LoDEX and PANO + BOR + DEX were on the cost-effectiveness frontier. The committee's decision on the technology under analysis deemed that POM + LoDEX should be recommended as an option for treating multiple myeloma in adults at third or subsequent relapse of treatments including both LEN and BOR, contingent on the company providing POM with the discount agreed in the PAS.

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A Prospective International Multicentre Cohort Study of Intraoperative Heart Rate and Systolic Blood Pressure and Myocardial Injury After Noncardiac Surgery: Results of the VISION Study

BACKGROUND: The association between intraoperative cardiovascular changes and perioperative myocardial injury has chiefly focused on hypotension during noncardiac surgery. However, the relative influence of blood pressure and heart rate (HR) remains unclear. We investigated both individual and codependent relationships among intraoperative HR, systolic blood pressure (SBP), and myocardial injury after noncardiac surgery (MINS). METHODS: Secondary analysis of the Vascular Events in Noncardiac Surgery Cohort Evaluation (VISION) study, a prospective international cohort study of noncardiac surgical patients. Multivariable logistic regression analysis tested for associations between intraoperative HR and/or SBP and MINS, defined by an elevated serum troponin T adjudicated as due to an ischemic etiology, within 30 days after surgery. Predefined thresholds for intraoperative HR and SBP were: maximum HR >100 beats or minimum HR 160 mm Hg or minimum SBP 100 bpm was associated with MINS (odds ratio [OR], 1.27 [1.07–1.50]; P 160 mm Hg was associated with MINS (OR, 1.16 [1.01–1.34]; P = .04) and myocardial infarction (OR, 1.34 [1.09–1.64]; P = .01) but, paradoxically, reduced mortality (OR, 0.76 [0.58–0.99]; P = .04). Minimum HR 100 bpm was more strongly associated with MINS (OR, 1.42 [1.15–1.76]; P

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Impact of Anesthetic Regimen on Remote Ischemic Preconditioning in the Rat Heart In Vivo

Remote ischemic preconditioning (RIPC) seems to be a promising cardioprotective strategy with contradictive clinical data suggesting the anesthetic regimen influencing the favorable impact of RIPC. This study aimed to investigate whether cardio protection by RIPC is abolished by anesthetic regimens. Male Wistar rats were randomized to 6 groups. Anesthesia was either maintained by pentobarbital (Pento) alone or a combination of sevoflurane (Sevo) and remifentanil or propofol (Prop) and remifentanil in combination with and without RIPC. RIPC reduced infarct size in Pento- and Sevo-anesthetized rats (Pento-RIPC: 30% ± 9% versus Pento-control [Con]: 65% ± 6%, P

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Healthcare Simulation Education: Evidence, Theory and Practice, 1st ed.

No abstract available

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The Local, Global Perspective

No abstract available

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A Left Ventricle to Left Atrial Appendage Fistula After Mitral Valve Replacement

No abstract available

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Pressure Waveform Analysis

Monitoring cardiac output is of special interest for detecting early hemodynamic impairment and for guiding its treatment. Among the techniques that are available to monitor cardiac output, pressure waveform analysis estimates cardiac output from the shape of the arterial pressure curve. It is based on the general principle that the amplitude of the systolic part of the arterial curve is proportional to cardiac output and arterial compliance. Such an estimation of cardiac output has the advantage of being continuous and in real time. With "calibrated" devices, the initial estimation of cardiac output by pressure waveform analysis is calibrated by measurements of cardiac output made by transpulmonary thermal or lithium dilution. Later, at each time transpulmonary dilution is performed, the estimation by pressure waveform analysis, which may drift over time, is calibrated again. By contrast, uncalibrated devices do not use any independent measurement of cardiac output. Unlike calibrated devices, they can be plugged to any arterial catheter. Nevertheless, uncalibrated devices are not reliable in cases of significant short-term changes in arterial resistance, as for instance in patients undergoing liver surgery or those with vasodilatory shock receiving vasopressors. Perioperative hemodynamic monitoring is recommended for high-risk surgical patients since it reduces the number of complications in these patients. The pressure waveform analysis monitoring, especially with uncalibrated devices, is suitable for this purpose. In the intensive care setting, hemodynamic monitoring is recommended for patients with acute circulatory failure, who do not respond to initial therapy. Since these patients often experience large changes in arterial resistance, either spontaneously or due to vasoactive drugs, calibrated devices are more suitable in this context. Not only are they more reliable than uncalibrated devices but also they provide a comprehensive hemodynamic assessment through measurements of a variety of transpulmonary thermodilution-related variables. In this review, we summarize the characteristics of the monitoring devices using the pressure waveform analysis and discuss the appropriate use of different devices in the perioperative and intensive care unit settings. Accepted for publication August 30, 2017. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Jean-Louis Teboul, MD, PhD, Service de réanimation médicale, Hôpitaux universitaires Paris-Sud, Hôpital de Bicêtre, 78 rue du Général Leclerc, Le Kremlin-Bicêtre F-94270, France. Address e-mail to jean-louis.teboul@aphp.fr. © 2017 International Anesthesia Research Society

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Anaesthesia for the Elderly Patient, 2nd ed.

No abstract available

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The Effect of Adding Subarachnoid Epinephrine to Hyperbaric Bupivacaine and Morphine for Repeat Cesarean Delivery: A Double-Blind Prospective Randomized Control Trial

BACKGROUND: Spinal anesthesia has become the most common type of anesthetic for cesarean delivery. The major limitation to spinal anesthesia is that the duration of the anesthetic may not be adequate in the event of a prolonged surgery. Some practitioners add epinephrine to hyperbaric bupivacaine to increase the duration, although its effect has not been fully studied. We therefore aimed to evaluate whether adding epinephrine to the spinal medication prolongs the duration of action of the resultant block in women presenting for repeat cesarean delivery. METHODS: Sixty-eight patients were randomized to receive no epinephrine (NE group), epinephrine 100 µg (low-dose [LD] group), or epinephrine 200 µg (high-dose [HD] group) with a standardized spinal mixture (1.5 mL 0.75% hyperbaric bupivacaine with 0.25 mg morphine). Sixty-five patients were included for primary analysis. Our primary outcome was time to intraoperative activation of the epidural catheter or postoperative regression of sensory blockade to T-10 dermatome level as measured by pinprick sensation; motor recovery was a secondary outcome, and graded via a Modified Bromage scale. RESULTS: Block onset time, vital sign changes, and the incidence of hypotension; nausea, and vomiting were similar among groups. Median difference in time to T-10 regression was greatest in the HD group compared to the NE group (median difference [min] [95% confidence interval]: 40 [15–60]; P = .007), followed by the HD group to the LD group (30 [15–45]; P = .007). Comparisons of LD to NE were not significant, but trended to an increase in T-10 regression time (10 [−15 to 30]; P = .76). Median difference in time to knee extension (Bromage 3) was also greatest in the HD group when compared to both the LD and NE group (median difference [min] [95% confidence interval]: 30 [0–60]; P = .034, 60 [0–93]; P = .007). Median difference time to knee extension (min) between the LD and NE group was also significant (37.5 [15–60]; P = .001]. Pain scores during the procedure were higher in the NE group (median [interquartile range] HD: 0 [0–0], LD: 0 [0–0], NE: 0 [0–3]; P = .02) during uterine closure and were otherwise not significantly different from the other groups. CONCLUSIONS: In this single center, prospective, double-blind, randomized control trial, the addition of epinephrine 200 µg to hyperbaric bupivacaine and preservative-free morphine for repeat cesarean delivery prolonged the duration of the sensory blockade. Motor blockade was similarly prolonged and block quality may have been enhanced. Accepted for publication August 30, 2017. Funding: Funding for this study was procured though the Icahn School of Medicine at Mount Sinai. Clinical Trial # (ClinicalTrials.gov): NCT02369510. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Daniel Katz, MD, Department of Anesthesiology, Pain, and Perioperative Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Pl, KCC 8th Floor Box 1010, New York, NY 10029. Address e-mail to Daniel.Katz@MountSinai.org. © 2017 International Anesthesia Research Society

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Use of 3D Transesophageal Echocardiography and the Clock-Face Model to Localize and Facilitate Closure of a Mitral Paravalvular Defect

No abstract available

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Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids

Abstract

Background

Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production.

Methods

A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases. An "autonomous" mass spectrometry-based untargeted metabolomic workflow with integrative metabolic pathway analysis revealed a number of differentially regulated metabolites in primary mammary fat pad (MFP) tumors compared to microdissected paired lung metastases. The study was further extended to analyze metabolites in paired normal tissues which determined the potential influence of metabolites from the microenvironment.

Results

Metabolomic analysis revealed that multiple metabolites were increased in metastases, including cholesterol sulfate and phospholipids (phosphatidylglycerols and phosphatidylethanolamine). Metabolite analysis of normal lung tissue in the mouse model also revealed increased levels of these metabolites compared to tissues from normal MFP and primary MFP tumors, indicating potential extracellular uptake by cancer cells in lung metastases. These results indicate a potential functional importance of cholesterol sulfate and phospholipids in propagating metastasis. In addition, metabolites involved in DNA/RNA synthesis and the TCA cycle were decreased in lung metastases compared to primary MFP tumors.

Conclusions

Using an integrated metabolomic workflow, this study identified a link between cholesterol sulfate and phospholipids, metabolic characteristics of the metastatic niche, and the capacity of tumor cells to colonize distant sites.

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Near field effect on elasticity measurement for cartilage-bone structure using Lamb wave method

Cartilage elasticity changes with cartilage degeneration. Hence, cartilage elasticity detection might be an alternative to traditional imaging methods for the early diagnosis of osteoarthritis. Based on the wa...

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Announcements

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Table of Contents

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Subscriptions Page

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EvSex16: Evolutionary Genomics of Sex

dosage compensationevolutionmeiosispopulation geneticssex chromosomesex determination

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Roles of Female and Male Genotype in Post-Mating Responses in Drosophila melanogaster

Abstract

Mating induces a multitude of changes in female behavior, physiology, and gene expression. Interactions between female and male genotype lead to variation in post-mating phenotypes and reproductive success. So far, few female molecules responsible for these interactions have been identified. Here, we used Drosophila melanogaster from 5 geographically dispersed populations to investigate such female × male genotypic interactions at the female transcriptomic and phenotypic levels. Females from each line were singly-mated to males from the same 5 lines, for a total of 25 combinations. Reproductive output and refractoriness to re-mating were assayed in females from the 25 mating combinations. Female × male genotypic interactions resulted in significant differences in these post-mating phenotypes. To assess whether female × male genotypic interactions affect the female post-mating transcriptome, next-generation RNA sequencing was performed on virgin and mated females at 5 to 6 h post-mating. Seventy-seven genes showed strong variation in mating-induced expression changes in a female × male genotype-dependent manner. These genes were enriched for immune response and odorant-binding functions, and for expression exclusively in the head. Strikingly, variation in post-mating transcript levels of a gene encoding a spermathecal endopeptidase was correlated with short-term egg production. The transcriptional variation found in specific functional classes of genes might be a read-out of female × male compatibility at a molecular level. Understanding the roles these genes play in the female post-mating response will be crucial to better understand the evolution of post-mating responses and related conflicts between the sexes.

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Environmental Plasticity in the Intersexual Correlation and Sex Bias of Gene Expression

Abstract

Intersexual genetic correlations are expected to constrain the evolution of sexual dimorphic traits, including the degree of sex-biased gene expression. Consistent with that expectation, studies in fruit flies and birds have reported that genes whose expression has a strong intersexual genetic correlation (r_MF) show a lower level of sex-biased expression (SBE). However, it is known that both r_MF and SBE can be affected by the environment. It is therefore unclear whether there is a consistent relationship between these 2 quantities across multiple environments. In this paper, we study this relationship in the African malaria mosquito Anopheles gambiae. We show that both r_MF and SBE change between environments. The change in SBE across environments is significantly correlated with d_N/d_S: greater changes in SBE are associated with higher values of d_N/d_S. Furthermore, the relationship between r_MF and SBE is sensitive to the environment. We conclude that this relationship is sufficiently plastic that environmental effects should be considered in future studies.

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Genomic Signatures of Sexual Conflict

Abstract

Sexual conflict is a specific class of intergenomic conflict that describes the reciprocal sex-specific fitness costs generated by antagonistic reproductive interactions. The potential for sexual conflict is an inherent property of having a shared genome between the sexes and, therefore, is an extreme form of an environment-dependent fitness effect. In this way, many of the predictions from environment-dependent selection can be used to formulate expected patterns of genome evolution under sexual conflict. However, the pleiotropic and transmission constraints inherent to having alleles move across sex-specific backgrounds from generation to generation further modulate the anticipated signatures of selection. We outline methods for detecting candidate sexual conflict loci both across and within populations. Additionally, we consider the ability of genome scans to identify sexually antagonistic loci by modeling allele frequency changes within males and females due to a single generation of selection. In particular, we highlight the need to integrate genotype, phenotype, and functional information to truly distinguish sexual conflict from other forms of sexual differentiation.

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Genetic Mapping and Phylogenetic Analysis Reveal Intraspecific Variation in Sex Chromosomes of the Virginian Strawberry

Abstract

With their extraordinary diversity in sexual systems, flowering plants offer unparalleled opportunities to understand sex determination and to reveal generalities in the evolution of sex chromosomes. Comparative genetic mapping of related taxa with good phylogenetic resolution can delineate the extent of sex chromosome diversity within plant groups, and lead the way to understanding the evolutionary drivers of such diversity. The North American octoploid wild strawberries provide such an opportunity. We performed linkage mapping using targeted sequence capture for the subdioecious western Fragaria virginiana ssp. platypetala and compared the location of its sex-determining region (SDR) to those of 2 other (sub)dioecious species, the eastern subspecies, F. virginiana ssp. virginiana (whose SDR is at 0–5.5 Mb on chromosome VI of the B2 subgenome), and the sister species F. chiloensis (whose SDR is at 37 Mb on chromosome VI of the Av subgenome). Male sterility was dominant in F. virginiana ssp. platypetala and mapped to a chromosome also in homeologous group VI. Likewise, one major quantitative trait locus (QTL) for female fertility overlapped the male sterility region. However, the SDR mapped to yet another subgenome (B1), and to a different location (13 Mb), but similar to the location inferred in one population of the naturally occurring hybrid between F. chiloensis and F. virginiana (F. ×ananassa ssp. cuneifolia). Phylogenetic analysis of chromosomes across the octoploid taxa showed consistent subgenomic composition reflecting shared evolutionary history but also reinforced within-species variation in the SDR-carrying chromosome, suggesting either repeated evolution, or recent turnovers in SDR.

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Chromosomal Context Affects the Molecular Evolution of Sex-linked Genes and Their Autosomal Counterparts in Turtles and Other Vertebrates

Abstract

Sex chromosomes evolve differently from autosomes because natural selection acts distinctly on them given their reduced recombination and smaller population size. Various studies of sex-linked genes compared with different autosomal genes within species support these predictions. Here, we take a novel alternative approach by comparing the rate of evolution between subsets of genes that are sex-linked in selected reptiles/vertebrates and the same genes located in autosomes in other amniotes. We report for the first time the faster evolution of Z-linked genes in a turtle (the Chinese softshell turtle Pelodiscus sinensis) relative to autosomal orthologs in other taxa, including turtles with temperature-dependent sex determination (TSD). This faster rate was absent in its close relative, the spiny softshell turtle (Apalone spinifera), thus revealing important lineage effects, and was only surpassed by mammalian-X linked genes. In contrast, we found slower evolution of X-linked genes in the musk turtle Staurotypus triporcatus (XX/XY) and homologous Z-linked chicken genes. TSD lineages displayed overall faster sequence evolution than taxa with genotypic sex determination (GSD), ruling out global effects of GSD on molecular evolution beyond those by sex-linkage. Notably, results revealed a putative selective sweep around two turtle genes involved in vertebrate gonadogenesis (Pelodiscus-Z-linked Nf2 and Chrysemys-autosomal Tspan7). Our observations reveal important evolutionary changes at the gene level mediated by chromosomal context in turtles despite their low overall evolutionary rate and illuminate sex chromosome evolution by empirically testing expectations from theoretical models. Genome-wide analyses are warranted to test the generality and prevalence of the observed patterns.

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Genetic Evidence for Sexuality in Cochliopodium (Amoebozoa)

Abstract

Microbial eukaryotes, including amoeboids, display diverse and complex life cycles that may or may not involve sexual reproduction. A recent comprehensive gene inventory study concluded that the Amoebozoa are ancestrally sexual. However, the detection of sex genes in some lineages known for their potentially sexual life cycle was very low. Particularly, the genus Cochliopodium, known to undergo a process of cell fusion, karyogamy, and subsequent fission previously described as parasexual, had no meiosis genes detected. This is likely due to low data representation, given the extensive nuclear fusion observed in the genus. In this study, we generate large amounts of transcriptome data for 2 species of Cochliopodium, known for their high frequency of cellular and nuclear fusion, in order to study the genetic basis of the complex life cycle observed in the genus. We inventory 60 sex-related genes, including 11 meiosis-specific genes, and 31 genes involved in fusion and karyogamy. We find a much higher detection of sex-related genes, including 5 meiosis-specific genes not previously detected in Cochliopodium, in this large transcriptome data. The expressed genes form a near-complete recombination machinery, indicating that Cochliopodium is an actively recombining sexual lineage. We also find 9 fusion-related genes in Cochliopodium, although no conserved fusion-specific genes were detected in the transcriptomes. Cochliopodium thus likely uses lineage specific genes for the fusion and depolyploidization processes. Our results demonstrate that Cochliopodium possess the genetic toolkit for recombination, while the mechanism involving fusion and genome reduction remains to be elucidated.

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New Insights into the Evolution of the W Chromosome in Lepidoptera

Abstract

Moths and butterflies (Lepidoptera) represent the most diverse group of animals with heterogametic females. Although the vast majority of species has a WZ/ZZ (female/male) sex chromosome system, it is generally accepted that the ancestral system was Z/ZZ and the W chromosome has evolved in a common ancestor of Tischeriidae and Ditrysia. However, the lack of data on sex chromosomes in lower Lepidoptera has prevented a formal test of this hypothesis. Here, we performed a detailed analysis of sex chromosomes in Tischeria ekebladella (Tischeriidae) and 3 species representing lower Ditrysia, Cameraria ohridella (Gracillariidae), Plutella xylostella (Plutellidae), and Tineola bisselliella (Tineidae). Using comparative genomic hybridization we show that the first 3 species have well-differentiated W chromosomes, which vary considerably in their molecular composition, whereas T. bisselliella has no W chromosome. Furthermore, our results suggest the presence of neo-sex chromosomes in C. ohridella. For Z chromosomes, we selected 5 genes evenly distributed along the Z chromosome in ditrysian model species and tested their Z-linkage using qPCR. The tested genes (Henna, laminin A, Paramyosin, Tyrosine hydroxylase, and 6-Phosphogluconate dehydrogenase) proved to be Z-linked in all species examined. The conserved synteny of the Z chromosome across Tischeriidae and Ditrysia, along with the W chromosome absence in the lower ditrysian families Psychidae and Tineidae, suggests a possible independent origin of the W chromosomes in these 2 lineages.

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Retention of Core Meiotic Genes Across Diverse Hymenoptera

Abstract

The cellular mechanisms of meiosis are critical for proper gamete formation in sexual organisms. Functional studies in model organisms have identified genes essential for meiosis, yet the extent to which this core meiotic machinery is conserved across non-model systems is not fully understood. Moreover, it is unclear whether deviation from canonical modes of sexual reproduction is accompanied by modifications in the genetic components involved in meiosis. We used a robust approach to identify and catalogue meiosis genes in Hymenoptera, an insect order typically characterized by haplodiploid reproduction. Using newly available genome data, we searched for 43 genes involved in meiosis in 18 diverse hymenopterans. Seven of eight genes with roles specific to meiosis were found across a majority of surveyed species, suggesting the preservation of core meiotic machinery in haplodiploid hymenopterans. Phylogenomic analyses of the inventory of meiosis genes and the identification of shared gene duplications and losses provided support for the grouping of species within Proctotrupomorpha, Ichneumonomorpha, and Aculeata clades, along with a paraphyletic Symphyta. The conservation of meiosis genes across Hymenoptera provides a framework for studying transitions between reproductive modes in this insect group.

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Genetic Variation for Mitochondrial Function in the New Zealand Freshwater Snail Potamopyrgus antipodarum

Abstract

The proteins responsible for mitochondrial function are encoded by 2 different genomes with distinct inheritance regimes, rendering rigorous inference of genotype–phenotype connections intractable for all but a few model systems. Asexual organisms provide a powerful means to address these challenges because offspring produced without recombination inherit both nuclear and mitochondrial genomes from a single parent. As such, these offspring inherit mitonuclear genotypes that are identical to the mitonuclear genotypes of their parents and siblings but different from those of other asexual lineages. Here, we compared mitochondrial function across distinct asexual lineages of Potamopyrgus antipodarum, a New Zealand freshwater snail model for understanding the evolutionary consequences of asexuality. Our analyses revealed substantial phenotypic variation across asexual lineages at 3 levels of biological organization: mitogenomic, organellar, and organismal. These data demonstrate that different asexual lineages have different mitochondrial function phenotypes, likely reflecting heritable variation (i.e., the raw material for evolution) for mitochondrial function in P. antipodarum. The discovery of this variation combined with the methods developed here sets the stage to use P. antipodarum to study central evolutionary questions involving mitochondrial function, including whether mitochondrial mutation accumulation influences the maintenance of sexual reproduction in natural populations.

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rSalvador: An R Package for the Fluctuation Experiment

The past few years saw a surge of novel applications of the Luria-Delbruck fluctuation assay protocol in bacterial research.  Appropriate analysis of fluctuation assay data often requires computational methods that are unavailable in the popular web tool FALCOR. This paper introduces an R packages named rSalvador to bring improvements to the field. The paper focuses on rSalvador's capabilities to alleviate three kinds of problems found in recent investigations: (i) resorting to partial plating without properly accounting for the effects of partial plating; (ii) conducting attendant fitness assays without incorporating mutants' relative fitness in subsequent data analysis; and (iii) comparing mutation rates using methods that are in general inapplicable to fluctuation assay data. In addition, the paper touches on rSalvador's capabilities to estimate sample size and the difficulties related to parameter non-identifiability.

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A twenty-four-hour observational study of hand hygiene compliance among health-care workers in Debre Berhan referral hospital, Ethiopia

Hand hygiene (HH) is recognized as the single most effective strategy for preventing health care–associated infections. In developing countries, data on hand hygiene compliance is available only for few health...

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CD31 Expression Determines Redox Status and Chemoresistance in Human Angiosarcomas

Purpose: Angiosarcomas (AS) are soft tissue sarcomas with endothelial differentiation and vasoformative capacity. Most AS show strong constitutive expression of the endothelial adhesion receptor CD31/PECAM-1 pointing to an important role of this molecule. However, the biological function of CD31 in AS is unknown. Experimental Design: The expression levels of CD31 in AS cells and its effects on cell viability, colony formation and chemoresistance was evaluated in human AS clinical samples and in cell lines through isolation of CD31^high and CD31^low cell subsets. The redox-regulatory CD31 function linked to YAP signaling was determined using a CD31 blocking antibody and siRNA approach and was further validated in CD31-knockout endothelial cells. Results: We found that most AS contain a small CD31^low cell population. CD31^low cells had lost part of their endothelial properties, were more tumorigenic and chemoresistant than CD31^high cells due to more efficient reactive oxygen species (ROS) detoxification. Active downregulation of CD31 resulted in loss of endothelial tube formation, nuclear accumulation of YAP, and YAP-dependent induction of antioxidative enzymes. Addition of pazopanib, a known enhancer of proteasomal YAP degradation re-sensitized CD31^low cells for doxorubicin resulting in growth suppression and induction of apoptosis. Conclusions: Human AS contain a small aggressive CD31^low population that have lost part of their endothelial differentiation programs and are more resistant against oxidative stress and DNA damage due to intensified YAP signaling. Our finding that the addition of YAP inhibitors can re-sensitize CD31^low cells towards doxorubicin may aid in the rational development of novel combination therapies to treat AS.

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Clinical and Immunological Biomarkers for Histologic Regression of High Grade Cervical Dysplasia and Clearance of HPV16 and HPV18 after Immunotherapy

Purpose: As previously reported, treatment of high grade cervical dysplasia with VGX-3100 resulted in complete histopathologic regression (CR) concomitant with elimination of HPV16/18 infection in 40.0% of VGX-3100-treated patients compared to only 14.3% in placebo recipients in a randomized PhaseIIb study.  Here, we identify clinical and immunological characteristics that either predicted or correlated with therapeutic benefit from VGX-3100 to identify parameters that might guide clinical decision-making for this disease. Experimental Design: We analyzed samples taken from cervical swabs, whole blood and tissue biopsies/resections to determine correlates and predictors of treatment success.  Results. At study entry, the presence of pre-existing immunosuppressive factors such as FoxP3 and PD-L1 in cervical lesions showed no association with treatment outcome. The combination of HPV typing and cervical cytology following dosing was predictive for both histologic regression and elimination of detectable virus at the efficacy assessment twenty two weeks later (negative predictive value 94%). Patients treated with VGX-3100 who had lesion regression had a statistically significant >2-fold increase in CD137+perforin+CD8+ Tcells specific for the HPV genotype causing disease.  Increases in cervical mucosal CD137+ and CD103+ infiltrates were observed only in treated patients.  Perforin+ cell infiltrates were significantly increased >2-fold in cervical tissue only in treated patients who had histologic CR. Conclusion. Quantitative measures associated with an effector immune response to VGX-3100 antigens were associated with lesion regression. Consequently, these analyses indicate that certain immunologic responses associate with successful resolution of HPV-induced pre-malignancy, with particular emphasis on the upregulation of perforin in the immunotherapy induced immune response.

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A Randomized, Double-blind, Placebo-controlled Phase 2 Study of Ontuxizumab (MORAb-004) in Patients with Chemorefractory Metastatic Colorectal Cancer

Purpose: The purpose of this study was to evaluate the safety and efficacy of ontuxizumab (MORAb-004), a monoclonal antibody that interferes with endosialin (tumor endothelial marker-1 [TEM-1]) function, in patients with chemorefractory metastatic colorectal cancer and to identify a responsive patient population based on biomarkers. Design: This was a randomized, double-blind, placebo-controlled, Phase 2 study. Patients were randomly assigned in a 2:1 ratio to receive weekly intravenous ontuxizumab (8 mg/kg) or placebo plus best supportive care (BSC) until progression or unacceptable toxicity. Tissue and blood biomarkers were evaluated for their ability to identify a patient population that was responsive to ontuxizumab. Results: A total of 126 patients were enrolled. No significant difference between the ontuxizumab and placebo groups was evident for the primary endpoint of progression-free survival (PFS), with a median PFS of 8.1 weeks in each group (hazard ratio of 1.13; 95% confidence interval: 0.76, 1.67; P=0.53). There were no significant differences between groups for overall survival (OS) or overall response rate (ORR). The most common treatment-emergent adverse events (TEAEs) in the ontuxizumab group (vs the placebo group, respectively) were fatigue (53.7% vs 47.5%), nausea (39.0% vs 35.0%), decreased appetite (34.1% vs 27.5%), and constipation (28.0% vs 32.5%). The most common Grade 3/4 TEAE in the ontuxizumab group vs placebo was back pain (11.0% vs 0%). No single biomarker clearly identified patients responsive to ontuxizumab. Conclusion: No benefit with ontuxizumab monotherapy compared with placebo for clinical response parameters of PFS, OS, or ORR was demonstrated. Ontuxizumab was well tolerated.

http://ift.tt/2lvYutA

Location of mutation in BRCA2 gene and survival in patients with ovarian cancer

Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene impacts the clinical outcome of OC patients. Experimental Design: A study cohort of 353 women with OC who underwent genetic germline testing for BRCA1 and BRCA2 genes were identified. Progression-free survival (PFS), platinum-free interval (PFI) and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of OC (n=316) was used as a validation cohort. Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2. After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS (58%; adjusted Hazard ratio [HR], 0.36; 95% CI, 0.20-0.64; p=0.001) and prolonged PFI (29.7 vs 15.5 months, p=0.011), compared to non-carriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42-1.07; p=0.094) or PFI (19 vs 15.5 months, p=0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13-0.68; p=0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02-0.38; p=0.001). Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged progression-free survival, platinum-free interval and overall survival.

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Global metabolic profiling identifies a pivotal role of proline and hydroxyproline metabolism in supporting hypoxic response in hepatocellular carcinoma.

Purpose: Metabolic reprogramming is frequently identified in hepatocellular carcinoma, which is the most common type of liver malignancy. The reprogrammed cellular metabolisms promote tumor cell survival, proliferation, angiogenesis and metastasis. However, the mechanisms of this process remain unclear in hepatocellular carcinoma. Experimental Design: Theglobal non-targeted metabolic studyin 69 paired hepatic carcinomas and adjacent tissue specimens were performed using capillary electrophoresis-time of flight mass spectrometry (CE-TOF/MS)-based approach. Key findings were validated by targeted metabolomic approach. Biological studies were also performed to investigate the role of proline biosynthesis in HCC pathogenesis. Results: Proline metabolism wasmarkedly changed in HCC tumor tissue, characterized withaccelerated consumption of proline and accumulation of hydroxyproline, which significantly correlated with α-fetoproteinlevels and poor prognosisin HCC.In addition, we found that hydroxyproline promoted hypoxia- and HIF-dependent phenotype in HCC. Moreover, we demonstrated that hypoxia activated proline biosynthesis via upregulation of ALDH18A, subsequently leading to accumulation of hydroxyproline via attenuated PRODH2 activity. More importantly, we showed that glutamine, proline and hydroxyproline metabolic axis supported HCC cell survival through modulating HIF1α stability in response to hypoxia. Finally, Inhibition of proline biosynthesis significantly enhanced cytotoxicity of sorafenib in vitro and in vivo. Conclusions: Our results demonstrate that hypoxic microenvironment activates proline metabolism, resulting in accumulation of hydroxyproline that promotes HCC tumor progression and sorafenib resistance through modulating HIF1α. These findings provide the proof of concept for targeting proline metabolism as a potential therapeutic strategy for hepatocellular carcinoma.

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Hypoxia-inducible PIM kinase expression promotes resistance to anti-angiogenic agents

Purpose: Patients develop resistance to anti-angiogenic drugs, secondary to changes in the tumor microenvironment, including hypoxia. PIM kinases are pro-survival kinases and their expression increases in hypoxia. The goal of this study was to determine whether targeting hypoxia-induced PIM kinase expression is effective in combination with VEGF-targeting agents. The rationale for this therapeutic approach is based on the fact that anti-angiogenic drugs can make tumors hypoxic, and thus more sensitive to PIM inhibitors. Experimental Design: Xenograft and orthotopic models of prostate and colon cancer were used to assess the effect of PIM activation on the efficacy of VEGF-targeting agents. Immunohistochemistry and in vivo imaging were used to analyze angiogenesis, apoptosis, proliferation, and metastasis. Biochemical studies were performed to characterize the novel signaling pathway linking PIM and HIF-1. Results: PIM was upregulated following treatment with anti-VEGF therapies, and PIM1 overexpression reduced the ability of these drugs to disrupt vasculature and block tumor growth. PIM inhibitors reduced HIF-1 activity, opposing the shift to a pro-angiogenic gene signature associated with hypoxia. Combined inhibition of PIM and VEGF produced a synergistic anti-tumor response characterized by decreased proliferation, reduced tumor vasculature, and decreased metastasis. Conclusions: This study describes PIM kinase expression as a novel mechanism of resistance to anti-angiogenic agents. Our data provide justification for combining PIM and VEGF inhibitors to treat solid tumors. The unique ability of PIM inhibitors to concomitantly target HIF-1 and selectively kill hypoxic tumor cells addresses two major components of tumor progression and therapeutic resistance.

http://ift.tt/2yigf5t

Inhibition of REDD1 sensitizes bladder urothelial carcinoma to paclitaxel by inhibiting autophagy

Purpose: Regulated in development and DNA damage response-1 (REDD1) is a stress related protein and is involved in the progression of cancer. The role and regulatory mechanism of REDD1 in bladder urothelial carcinoma (BUC), however, is yet unidentified. Experimental Design: The expression of REDD1 in BUC was detected by western blot and immunohistochemistry. The correlation between REDD1 expression and clinical features in BUC patients were assessed. The effects of REDD1 on cellular proliferation, apoptosis, autophagy, and paclitaxel sensitivity were determined both in vitro and in vivo. Then the targeted-regulating mechanism of REDD1 by microRNAs was explored. Results: Here the significant increase of REDD1 expression is detected in BUC tissue, and REDD1 is firstly reported as an independent prognostic factor in BUC patients. Silencing REDD1 expression in T24 and EJ cells decreased cell proliferation, increased apoptosis, and decreased autophagy, whereas the ectopic expression of REDD1 in RT4 and BIU87 cells had the opposite effect. Additionally, the REDD1-mediated proliferation, apoptosis, and autophagy are found to be negatively regulated by miR-22 in vitro, which intensify the paclitaxel sensitivity via inhibition of the well-acknowledged REDD1-EEF2K-autophagy axis. AKT/mTOR signaling initially activated or inhibited in response to silencing or enhancing REDD1 expression and then recovered rapidly. Lastly, the inhibited REDD1 expression by either RNAi or miR-22 sensitizes BUC tumor cells to paclitaxel in a subcutaneous transplant sarcoma model in vivo. Conclusion: REDD1 is confirmed as an oncogene in BUC, and antagonizing REDD1 could be a potential therapeutic strategy to sensitize BUC cells to paclitaxel.

http://ift.tt/2luw3fr

Targeting CDH17 in cancer: when blocking the ligand beats blocking the receptor?

Cadherin-17 (CDH17) has been implicated as pro-tumorigenic for many years but mechanisms have been unclear. A Spanish team have generated antibodies to an RGD-motif in CDH17 that inhibits integrin α2β1 binding to CDH17 and thereby inhibits integrin activation, tumorigenesis and metastasis. These reagents may have therapeutic potential.

http://ift.tt/2yfC0CR

Hypo-osmolar formulation of TFV enema promotes uptake and metabolism of TFV in tissues and leading to prevention of SHIV/SIV infection [PublishAheadOfPrint]

Oral PrEP has been approved for prophylaxis of HIV-1 transmission, but is associated with high costs and issues of adherence. Protection from anal transmission of HIV using topical microbicides using methods congruent with sexual behavior offers the promise of improved adherence. We compared the PK and ex vivo efficacy of iso-osmolar (IOsm) and hypo-osmolar (HOsm) rectal enema formulations of tenofovir (TFV) in rhesus macaques. Single-dose PK of IOsm or HOsm high (5.28mg/mL) and low (1.76mg/mL) dose formulations of TFV enemas were evaluated for systemic uptake in blood, colorectal biopsies and rectal CD4+ T cells. Markedly higher TFV concentrations were observed in plasma and tissues after administration of the HOsm high dose formulation than all others tested. TFV and TFV diphosphate (TFV-DP) concentrations in tissue correlated for the HOsm high dose formulation, demonstrating rapid uptake and transformation of TFV to TFV-DP in tissues. TFV-DP in tissues collected at 1 and 24 hours were 7x and 5x higher, respectively (p<0.01) compared to the IOsm formulation. HOsm high dose formulation was prevented infection in ex vivo challenges of rectal tissues collected at 1, 24 and 72 hours after the intrarectal dosing, whereas the same TFV dose formulated as IOsm enema was less effective.

http://ift.tt/2A2IsL4

Development of a novel multi-penicillin assay and assessment of the impact of analyte degradation: lessons for scavenged sampling in antimicrobial pharmacokinetic study design [PublishAheadOfPrint]

Penicillins are widely used to treat infections in children, however the evidence is continuing to evolve in defining optimal dosing. Modern paediatric pharmacokinetic study protocols frequently favour opportunistic, "scavenged" sampling. This study aimed to develop a small volume single assay for five major penicillins and to assess the influence of sample degradation on inferences made using pharmacokinetic modelling, to investigate the suitability of scavenged sampling strategies.

Using a rapid ultra-high performance liquid chromatographic-tandem mass spectrometric method, an assay for five penicillins (amoxicillin, ampicillin, benzylpenicillin, piperacillin and flucloxacillin) in blood plasma was developed and validated. Penicillin stabilities were evaluated under different conditions. Using these data, the impact of drug degradation on inferences made during pharmacokinetic modelling was evaluated.

All evaluated penicillins indicated good stability at room temperature (23 ± 2°C) over 1 hour remaining in the range of 98-103% of the original concentration. More rapid analyte degradation had already occurred after 4 hours with stability ranging from 68% to 99%. Stability over longer periods declined: degradation of up to 60% was observed with delayed sample processing of up to 24 hours. Modelling showed that analyte degradation can lead to a 30% and 28% bias in clearance and volume of distribution, respectively, and falsely show nonlinearity in clearance.

Five common penicillins can now be measured in a single low volume blood sample. Beta-lactam chemical instability in plasma can cause misleading pharmacokinetic modelling results, which could impact upon model-based dosing recommendations and the forthcoming era of beta-lactam therapeutic drug monitoring.

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Evaluation of the In Vitro Activity of Meropenem-Vaborbactam against Clinical Isolates of KPC-Positive Enterobacteriaceae [PublishAheadOfPrint]

Vaborbactam (formerly RPX7009) is a novel inhibitor of serine β-lactamases, including Ambler class A carbapenemases such as KPCs. The current study evaluated the in vitro activity of the combination agent meropenem-vaborbactam against a 2014-2015 global collection of 991 isolates of KPC-positive Enterobacteriaceae using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method. The concentration of meropenem (when tested with a fixed concentration of 8 μg/ml of vaborbactam) that inhibited 90% of isolates of KPC-positive Enterobacteriaceae (MIC₉₀) was 1 μg/ml, and MIC values ranged from ≤0.03->32 μg/ml; 99.0% (981/991) of isolates had meropenem-vaborbactam MICs ≤4 μg/ml, the FDA-approved susceptible MIC breakpoint for meropenem-vaborbactam (Vabomere^™). Vaborbactam lowered the meropenem MIC₅₀ from 32 to 0.06 μg/ml and the MIC₉₀ from >32 to 1 μg/ml, respectively. There were no differences in the activity of meropenem-vaborbactam stratifying isolates by KPC variant type. We conclude that meropenem-vaborbactam demonstrated potent in vitro activity against a 2014-2015, worldwide collection of clinical isolates of KPC-positive Enterobacteriaceae.

http://ift.tt/2A0Nesi

Association between a suppressor combined antiretroviral therapy containing Maraviroc and the hepatitis B virus vaccine response. [PublishAheadOfPrint]

Introduction: The response to the HBV vaccine in HIV-infected patients is deficient. Our aim was to analyze whether a suppressor combined antiretroviral treatment (cART) containing Maraviroc (MVC-cART) was associated with a better response to HBV vaccine.

Methods: Fifty seven patients on suppressor cART were administered the HBV vaccine. The final response, the early response and the maintenance of the response were assessed. Anti-HBs titers >10 mIU/mL was considered a positive response. A subgroup of subjects was simultaneously vaccinated against Hepatitis-A virus (HAV). Lineal regression analyses were performed to determine demographic, clinical and immunological factors associated with the anti-HBs titer.

Results: Vaccine response was achieved in 90% of the subjects. After one year, 81% maintained protective titers. Only simultaneous HAV vaccination was independently associated with the magnitude of the response [p=0.045; B (95% CI) 236 (5-468)]. In subjects ≤50 years (n=42), MVC-cART was independently associated with the magnitude of the response [p=0.009; B (95% CI), 297 (79-516)] together with previous vaccination and simultaneous HAV vaccination.

Conclusion: High rates of HBV vaccine response can be achieved by revaccination, simultaneous HAV vaccination and administration of cARTs including MVC. MVC may be considered for future vaccination protocols in patients on suppressive cART.

http://ift.tt/2xD6QkI

Antifungal susceptibility of emerging dimorphic pathogens in the family Ajellomycetaceae [PublishAheadOfPrint]

The in vitro susceptibility of 24 molecularly identified dimorphic fungi belonging to Adiaspiromyces, Blastomyces and Emergomyces within the family Ajellomycetaceae was tested against 8 standard antifungals using CLSI M38-A2. Amphotericin B and posaconazole had the lowest geometric mean MICs (< 0.05μg/ml) followed by itraconazole (< 0.07μg/ml), voriconazole (< 0.15μg/ml) and isavuconazole (< 0.42μg/ml) while fluconazole was not active. Micafungin demonstrated good in vitro antifungal activity against Emergomyces (GM-MEC 0.1μg/ml) and Blastomyces (GM-MEC < 0.017μg/ml).

http://ift.tt/2A1GlqJ

Detection of Mycobacterium tuberculosis pncA mutations by the NIPRO Genoscholar™*PZA-TB II as compared to conventional sequencing [PublishAheadOfPrint]

Pyrazinamide (PZA) is a standard component of first-line treatment regimens for Mycobacterium tuberculosis (Mtb) and is included in treatment regimens for drug-resistant Mtb whenever possible. It is therefore imperative that susceptibility to PZA be reliably assessed prior to initiation of therapy. Currently-available growth-based PZA susceptibility tests are time consuming and results can be inconsistent. Molecular tests have been developed for most first-line antituberculosis drugs, however, a commercial molecular test is not yet available for rapid detection of PZA resistance. Recently, a line probe assay, NIPRO Genoscholar^™⋅PZA-TB II, was developed for the detection of mutations within the pncA gene including the promoter region likely to lead to PZA resistance. The sensitivity and specificity of this assay was evaluated by two independent laboratories using a combined total of 249 strains with mutations in pncA and its promoter as well as 21 strains with wild-type pncA. Overall, the assay showed good sensitivity (93.2%, 95%CI 89.3, 95.8) and moderate specificity (91.2%, 95%CI 77.0, 97.0) for the identification of Mtb predicted to be resistant to PZA based upon the presence of mutations (excluding known PZA susceptible mutations) in the pncA coding region or promoter. The assay shows promise for the molecular prediction of PZA resistance.

http://ift.tt/2xACqzn

Mutations at the ribosomal S10 gene in clinical strains of Staphylococcus aureus with reduced susceptibility to tigecycline [PublishAheadOfPrint]

Mutations on the tip of the extended loop of ribosomal S10 protein have been associated with tigecycline (TGC) resistance in passaged mutants of different bacteria species. This study described the first two clinical TGC-resistant Staphylococcus aureus isolates with these mutations. One strain (TGC-MIC=2 mg/L) had a 12-nucleotide deletion affecting residues 56 to 59 (HKYK) of the S10 protein. The second strain (TGC-MIC=1 mg/L) had amino-acid substitutions (K57M, Y58F) previously described in S. aureus passaged mutants.

http://ift.tt/2zZODiV

Use of Calgary and microfluidic BioFlux systems to test the activity of fosfomycin and tobramycin alone and in combination against cystic fibrosis Pseudomonas aeruginosa biofilms [PublishAheadOfPrint]

Pseudomonas aeruginosa is a major cause of morbidity and mortality in chronically infected cystic fibrosis patients. Novel in vitro biofilm models, which reliably predict therapeutic success of antimicrobial therapies, should be implemented. The activity of fosfomycin, tobramycin and fosfomycin-tobramycin combination was tested against 6 susceptible P. aeruginosa strains isolated from respiratory samples of cystic fibrosis patients by using two in vitro biofilm models: a closed system (Calgary device) and an open model based on microfluidics (BioFlux). All but one of the isolates formed biofilm. The fosfomycin and tobramycin minimal biofilm inhibitory concentrations (MBIC) were 1,024->1,024 μg/ml and 8-32 μg/ml, respectively. According to fractional inhibitory concentration analysis, the combination behaved synergistically in all the isolates except in the P. aeruginosa ATCC 27853 strain.

The dynamic formation of the biofilm was also studied with the BioFlux system and the MIC and MBIC of each antibiotic were tested. For the combination, the lowest tobramycin concentration that was synergistic with fosfomycin was used. The captured images were analyzed measuring the intensity of colored pixels, which is proportional to the biofilm biomass. A statistically significant difference was found when comparing the intensity of the inoculum with the intensity in the microchannel where the MBIC of tobramycin or fosfomycin or their combination was used (p<0.01) but not when applying the MIC (p>0.01).

Fosfomycin-tobramycin demonstrated to be synergistic against cystic fibrosis P. aeruginosa strains in biofilm models, both when testing with the Calgary and the microfluidic BioFlux systems. These results support the clinical use of this combination.

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Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children [PublishAheadOfPrint]

Trimethoprim/sulfamethoxazole (TMP/SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii in children. Pharmacokinetic (PK) data in infants and children are limited and optimal dosing is not known. We performed a multicenter, prospective PK study of TMP/SMX in infants and children. Separate population PK models were developed for enteral TMP and SMX using nonlinear mixed effects modeling. Optimal dosing was determined based on matching adult TMP exposure and attaining the surrogate pharmacodynamic (PD) target for efficacy---a free TMP concentration above the minimal inhibitory concentration (MIC) at 50% of the dosing interval. A total of 153 subjects (240 PK samples) with a median (range) postnatal age of 8 years (0.1–20) contributed to the analysis for both drugs. A 1-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/F) and volume (V/F). Both TMP and SMX CL/F increased with age. In addition, TMP and SMX CL/F were inversely related to serum creatinine and albumin, respectively. Oral TMP/SMX 8/40 mg/kg/day divided every 12h matched adult exposure after TMP/SMX 320/1600 mg/day divided every 12h and achieved the PD target for an MIC of 0.5 mg/L in >90% of infants and children. Oral TMP/SMX 12/60 and 15/75 mg/kg/day divided every 12h matched adult exposure after TMP/SMX 640/3200 mg/day divided every 12h in subjects 6–<21 years and 0–<6 years of age, respectively, and was optimal for bacteria with an MIC up to 1 mg/L.

http://ift.tt/2A1Iz9q

In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS3/4A Protease Inhibitor Glecaprevir [PublishAheadOfPrint]

Glecaprevir (formerly ABT-493) is a novel hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) with pan-genotypic activity. It inhibited the enzymatic activity of purified NS3/4A proteases from HCV genotypes 1 - 6 in vitro (IC₅₀ = 3.5 - 11.3 nM) and the replication of stable HCV subgenomic replicons containing proteases from genotypes 1 - 6 (EC₅₀ = 0.21 - 4.6 nM). Glecaprevir had a median EC₅₀ value of 0.30 nM (range 0.05 - 3.8 nM) for HCV replicons containing proteases from 40 HCV genotype 1 - 5 samples. Importantly, glecaprevir is active against the protease from genotype 3, the most difficult-to-treat HCV genotype, in both enzymatic and replicon assays with comparable activity against other HCV genotypes. In drug-resistant colony selection studies, glecaprevir generally selected substitutions at NS3 amino acid position A156 in replicons containing proteases from genotypes 1a, 1b, 2a, 2b, 3a, and 4a, and substitutions at position D/Q168 in replicons containing proteases from genotypes 3a, 5a and 6a. Although substitutions A156T and A156V in NS3 of genotype 1 reduced susceptibility to glecaprevir, they demonstrated low replication efficiency in vitro. Glecaprevir is active against most of the common NS3 amino acid substitutions that are associated with reduced susceptibility to currently approved HCV PIs, including those at positions 155 and 168. Combination of glecaprevir with HCV inhibitors with other mechanisms of action resulted in additive or synergistic antiviral activity. In summary, glecaprevir is a next-generation HCV PI with potent pan-genotypic activity and a high barrier to the development of resistance.

http://ift.tt/2xDCaQl

A new variant of 16S rRNA methylase, RmtD3, in a clinical isolate of Pseudomonas aeruginosa in Myanmar [PublishAheadOfPrint]

A new variant of a 16S rRNA methylase, RmtD3, was detected in a clinical isolate of Pseudomonas aeruginosa in Myanmar. RmtD3 had 9 amino acid substitutions, such as Trp26Cys, Val39Ala, Met66Leu, Ser102Ile, Thr130Ala, Asn165Asp, Leu169Met, Ala181Thr and Gly236Ser, compared with RmtD. The RmtD3-producing P. aeruginosa was highly resistant to the aminoglycosides that were tested. The genomic environment surrounding rmtD3 was tnp (IS91 family)-orfA-orfB-mraW-rmtD3-orfC-orfD-yraL-tnp (IS91 family) on the chromosome.

http://ift.tt/2A2rdt1

Mutations within embCAB are associated with variable level of ethambutol resistance in Mycobacterium tuberculosis isolates from China [PublishAheadOfPrint]

The EmbCAB proteins have been considered a target for ethambutol (EMB). Mutations in the embCAB are known to confer most EMB resistance. However, knowledge about the effects of embCAB mutations on EMB resistance level and about the role of mutation-mutation interaction is limited in China. Here, we sequenced the embCAB among 125 Mycobacterium tuberculosis (M. tuberculosis) isolates from China and quantified their EMB minimum inhibitory concentration (MIC) by testing growth at 10 concentrations. Furthermore, a multivariate regression model was established to assess the effects of both individual mutation and multiple mutations. Our results revealed that in China, 82.6% of EMB-resistant isolates (71/86 isolates) harbored at least one mutation within embCAB. Most the mutations located in the embB and embA upstream region. Several individual mutation and multiple mutations within this region contributed to the different levels of EMB resistance. Their effects were statistically significant. Additionally, there was an association between high-level EMB resistance and multiple mutations.

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Changes in blood pressure, blood flow toward head and heart rate during 90 deg head-up tilting for 30 min in anaesthetized male rats

Abstract

Changes in cardiovascular parameters during long-term 90 deg head-up tilting (HUT) in animals have been not elucidated in detail. We clarified changes in systemic blood pressure (BP), blood flow toward the head (BF), and heart rate (HR) and the role of the baroreceptor reflex after transition from the supine posture to 90 deg HUT for 30 min in anaesthetized rats (n = 13). Mean BP and BF after the onset of 90 deg HUT significantly decreased by –15.4% ± 5.9% and –26.2% ± 11.5% at 2.9 ± 1.1 s (mean ± SD, n = 12), respectively, from 90 deg HUT control values in nerve-intact of baroreceptor reflex afferents, and then immediately increased and steadied at 30.7 ± 13.1 s (plateau; by –2.8% ± 8.5% in BP and by –17.5% ± 17.4% in BF compared with control values; BP was maintained during 90 deg HUT). After acute sinoaortic denervation (SAD) in seven rats, initial decreases in BP and BF after 90 deg HUT were observed at 3.9 ± 1.0 s, similar to decreases in the nerve-intact rat; the percentage changes from control were –19.2% ± 3.7% and –32.3% ± 8.4%, respectively, the each of them at 22.4 ± 5.8 s as plateau were –8.6% ± 7.7% and –29.5% ± 15.0%, respectively, and then BP decreased gradually throughout 90 deg HUT. HR slightly increased after 90 deg HUT in nerve-intact rats, but after SAD this increase disappeared and HR decreased gradually during 90 deg HUT. These results suggest that the baroreceptor reflex contributes to maintaining adequate BP during long-term 90 deg HUT.

This article is protected by copyright. All rights reserved

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First case report of Providencia Rettgeri neonatal sepsis

Providencia are gram negative motile rods and is a member of the Enterobacteriaceae family. It consists of five species, namely Providencia alcalifaciens, Providencia rustigianii, Providencia stuartii, Providenci...

http://ift.tt/2z1YvbJ

The impact of mass distribution of long lasting insecticide-treated bed-nets on the malaria parasite burden in the Buea Health District in South-West Cameroon: a hospital based chart review of patient’s laboratory records

Malaria remains a leading cause of illness and deaths in Cameroon. The use of long lasting insecticide treated bed nets (LLITN) is the most effective method to reduce the burden of malaria. The aim of this stu...

http://ift.tt/2z5dNyG

Cross-sectional study for determining the prevalence of Q fever in small ruminants and humans at El Minya Governorate, Egypt

Q fever is a febrile illness caused by the bacterial pathogen Coxiella burnetii (C. burnetii) and is transmitted to humans from small ruminants via contaminated secreta and excreta of infected animals. This patho...

http://ift.tt/2yZE27t

Critical appraisal of the risk of secondary cancer induction from breast radiotherapy with volumetric modulated arc therapy relative to 3D conformal therapy

Excess absolute risk (EAR) was estimated for breast cancer patients receiving volumetric modulated arc therapy (VMAT) delivery with two planning approaches (VMAT_tang and VMAT_full), or 3D conformal radiotherapy with field-in-field setting. Dose prescription was 40.05 Gy in 15 fractions. Almost no difference was computed for EAR to contralateral organs between VMAT_tang and field-in-field, with the first presenting significant normal tissue complication probability reduction for ipsilateral organs. VMAT can be safely used for breast cancer treatment.

http://ift.tt/2zlvb2M

Intraoperative electron radiation therapy in retroperitoneal sarcoma

We conducted a retrospective evaluation of 156 patients (56% recurrent status) with retroperitoneal sarcomas treated by surgery, IORT +/- EBRT. The combination approach was feasible and resulted in good LC and OS in this unfavourable cohort. Incomplete resection and recurrent status resulted in clearly inferior outcome. Reasonable efforts should be made already during primary treatment to prevent the onset of a local recurrence.

http://ift.tt/2iNnv2z

The anxiolytic-like effect of 6-styryl-2-pyrone in mice involves GABAergic mechanism of action

Abstract

The present work aims to investigate the anxiolytic activity of 6-styryl-2-pyrone (STY), obtained from Aniba panurensis, in behavioral tests and amino acids dosage on male Swiss mice. The animals were treated with STY (1, 10 or 20 mg), diazepam (DZP 1 or 2 mg/kg) or imipramine (IMI 30 mg/kg). Some groups were administered with flumazenil, 30 min before administration of the STYor DZP. The behavioral tests performed were open field, rota rod, elevated plus maze (EPM), hole-board (HB) and tail suspension test (TST). After behavioral tests, these animals were sacrificed and had their prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) dissected for assaying amino acids (aspartate- ASP, glutamate- GLU, glycine- GLY, taurine- TAU and Gamma-aminobutyric acid- GABA). In EPM test, STY or DZP increased the number of entries and the time of permanence in the open arms, but these effects were reverted by flumazenil. In the HB test, STY increased the number of head dips however this effect was blocked by flumazenil. The effects of the STY on amino acid concentration in PFC showed increased GLU, GABA and TAU concentrations. In hippocampus, STY increased the concentrations of all amino acids studied. In striatum, STY administration at lowest dose reduced GLU concentrations, while the highest dosage caused the opposite effect. GLI, TAU and GABA concentrations increased with STY administration at highest doses. In conclusion, this study showed that STY presents an anxiolytic-like effect in behavioral tests that probably is related to GABAergic mechanism of action.

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Releasing the “GENI”: integrating authentic microbial genomics research into the classroom through GENI-ACT

Abstract

The integration of genomics research into the undergraduate biology curriculum provides students with the opportunity to become familiar with bioinformatics tools and answer original research questions. Our purpose with this research project was to upscale the research experience through integration with classroom experience giving students access to authentic research projects. Students annotated 60 predicted ABC genes of Methanothermobacter thermautotrophicus and Methanobacterium sp. SWAN-1, and they were required to present a research poster to demonstrate their understanding of the project. During this research project a number of tests, assessments and surveys were conducted to assess familiarity with technical and conceptual understanding of genome annotation, satisfaction with annotation instruction, gain in bioinformatics research skills, scientific communications skills and increased student interest in research. We found that students gained significant skills in bioinformatics, specifically genome annotation skills and also gained confidence in their abilities to carry out scientific research. As a result of this authentic undergraduate research experience under-represented students were motivated to pursue future careers in STEM fields.

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Plasmids can transfer to Clostridium difficile CD37 and 630Δ erm both by a DNase resistant conjugation-like mechanism and a DNase sensitive mechanism

Abstract

Broad host range conjugative plasmids that replicate in Escherichia coli have been widely used to mobilise smaller replicons, bearing their cognate origin of transfer (oriT) into a variety of organisms that are less tractable genetically, such as Clostridium (Clostridioides) difficile. In this work we demonstrated that the oriT region of pMTL9301 (derived from RK2) is not required for transfer between E. coli and C. difficile strains 630Δerm and CD37 and that this oriT-independent transfer is abolished in the presence of DNase when CD37 is the recipient. Transfer to the 630Δerm strain is DNase resistant even without an obvious oriT, when E. coli CA434 is used as a donor and is sensitive to DNase when E. coli HB101 is the donor.

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Keeping education fresh—not just in microbiology

Abstract

Innovative practice from around the globe, addressing a range of recent educational themes and trends, was published in the FEMS Microbiology Letters virtual Thematic Issue 'Keeping Education Fresh' in October 2017. Its thought-provoking content is reviewed here to more directly facilitate reflections and discussions in the professional community. The focus is on best practice approaches when enhancing student engagement, how to adjust those to the diversity of learners, learning situations and infrastructures, and to a broad range of subjects. The need for authentic learning and to move away from didactic teaching is emphasized. The 'students as researchers' theme is featured e.g. in context of service learning. Creative approaches are presented such as using performing arts, popular culture and gamification. The development of interdisciplinary and intercultural competences, and the exploration of socioscientific themes and philosophical issues are considered. Revisions of curricula and programmes, reflective of educational advancements and sector drivers, are discussed from undergraduate to postgraduate and professional specialist level also in light of problem-based learning, interactive distance and on-campus learning, and even the legacy of Massive Open Online Courses. Such changes always require resources and skills, and carry risks. Yet, innovation is a risk worth taking to keep education fresh.

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Microbial organic acid production as carbon dioxide sink

Abstract

Mixed-substrate conversions are an under-regarded option to fix carbon dioxide in significant amounts. In such a conversion, carbon dioxide together with one other carbon source such as glucose is converted to a single carbon product. With mixed-substrate conversions, it is possible to incorporate carbon dioxide into products with higher oxidation states than the co-substrate. Using abundant co-substrates such as glucose, glycerol or methanol, it is possible to produce organic acids anaerobically, using CO₂ both as an electron acceptor and as an additional carbon source. Here, we outline the thermodynamic feasibility to produce industrially important organic acids with this approach to provide guidance for future metabolic engineering endeavours.

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Degradation of the recalcitrant oil spill components anthracene and pyrene by a microbially driven Fenton reaction

Abstract

Oil spill components include a range of toxic saturated, aromatic and polar hydrocarbons, including pyrene and anthracene. Such contaminants harm natural ecosystems, adversely affect human health and negatively impact tourism and the fishing industries. Current physical, chemical and biological remediation technologies are often unable to completely remove recalcitrant oil spill components, which accumulate at levels greater than regulatory limits set by the Environmental Protection Agency. In the present study, a microbially driven Fenton reaction, previously shown to produce hydroxyl (HO^•) radicals that degrade chlorinated solvents and associated solvent stabilizers, was also found to degrade source zone concentrations of the oil spill components, pyrene (10 μM) and anthracene (1 μM), at initial rates of 0.82 and 0.20 μM h⁻¹, respectively. The pyrene- and anthracene-degrading Fenton reaction was driven by the metal-reducing facultative anaerobe Shewanella oneidensis exposed to alternating aerobic and anaerobic conditions in the presence of Fe(III). Similar to the chlorinated solvent degradation system, the pyrene and anthracene degradation systems required neither the continual supply of exogenous H₂O₂ nor UV-induced Fe(III) reduction to regenerate Fe(II). The microbially driven Fenton reaction provides the foundation for the development of alternate ex situ and in situ oil and gas spill remediation technologies.

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Bioactive and biocontrol potential of endophytic fungi associated with Brugmansia aurea Lagerh

Abstract

This study describes 32 fungal endophytes isolated from different tissues of Brugmansia aurea Lagerh. Each fungal strain was authenticated based on internal transcribed spacer rDNA sequence. Phylogenetic analysis showed that these fungi are distributed in three classes, seven orders and 12 genera. The dichloromethane extracts of endophytic strains were screened for anticancer and antimicrobial activity. Anticancer activity of extracts against human cancer cell lines revealed that 50% strains are active with IC₅₀ < 10 μg/mL. While analysing antimicrobial potential against both Gram-positive and Gram-negative bacteria, 56.25% endophytic strains displayed activity at least against one of the tested human pathogenic bacteria with minimum inhibitory concentration of 12.5–100 μg/mL. In vitro antagonistic activity of endophytes was analysed against Sclerotinia sp., Aspergillus fumigatus, Fusarium solani, A. flavus and F. oxysporum pathogen. The broad-spectrum anti-phytopathogenic activity was shown by R2BA. The presence of ketoacyl synthase domain of polyketide synthase gene and high degree of bioactivity shown by endophytic fungi suggested that they have potential to produce therapeutic compounds and to serve as biocontrol agent.

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A genome-wide comprehensive analysis of alterations in driver genes in non-small-cell lung cancer.

Lung cancer is one of the most common malignancies and the leading cause of cancer-related deaths worldwide. Although many oncogenes and tumor suppressors have been uncovered in the past decades, the pathogenesis and mechanisms of lung tumorigenesis and progression are unclear. The advancement of high-throughput sequencing technique and bioinformatics methods has led to the discovery of some unknown important protein-coding genes or noncoding RNAs in human cancers. In this study, we tried to identify and validate lung cancer driver genes to facilitate the diagnosis and individualized treatment of patients with this disease. To analyze distinct gene profile in lung cancer, the RNA sequencing data from TCGA and microarray data from Gene Expression Omnibus were used. Then, shRNA-pooled screen data and CRISPR-Cas9-based screen data in lung cancer cells were used to validate the functional roles of identified genes. We found that thousands of gene expression patterns are altered in lung cancer, and genomic alterations contribute to the dysregulation of these genes. Furthermore, we identified some potential lung cancer driver genes, such as TBX2, MCM4, SLC2A1, BIRC5, and CDC20, whose expression is significantly upregulated in lung cancer, and the copy number of these genes is amplified in the genome of patients with lung cancer. More importantly, overexpression of these genes is associated with poorer survival of patients with lung cancer, and knockdown or knockout of these genes results in decreased cell proliferation in lung cancer cells. Taken together, the genomewide comprehensive analysis combined with screen data analyses may provide a valuable help for identifying cancer driver genes for diagnosis and prevention of patients with lung cancer. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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The Role of Genetic Counseling in Familial and Sporadic Cancer: Considerations, Challenges, and Collaboration

With the advent of increasingly affordable genetic sequencing technology, commercial laboratories have begun to offer an array of multigene panels for hereditary cancer assessment. Further, precision medicine efforts aimed at identifying mutational drug targets through tumor (somatic) sequencing are also uncovering inherited mutations. Germline alterations themselves are increasingly being considered as therapeutic targets. Genetic counseling for inherited cancer risk must rapidly evolve to keep pace, and internists are often on the front lines for identifying patients who could benefit from genetic consultation.

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Systemic Infection With Dirofilaria repens in Southwestern France

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46-Year Trends in Systemic Lupus Erythematosus Mortality in the United States, 1968 to 2013 A Nationwide Population-Based Study

Background:

No large population-based studies have been done on systemic lupus erythematosus (SLE) mortality trends in the United States.

Objective:

To identify secular trends and population characteristics associated with SLE mortality.

Design:

Population-based study using a national mortality database and census data.

Setting:

United States.

Participants:

All U.S. residents, 1968 through 2013.

Measurements:

Joinpoint trend analysis of annual age-standardized mortality rates (ASMRs) for SLE and non-SLE causes by sex, race/ethnicity, and geographic region; multiple logistic regression analysis to determine independent associations of demographic variables and period with SLE mortality.

Results:

There were 50 249 SLE deaths and 100 851 288 non-SLE deaths from 1968 through 2013. Over this period, the SLE ASMR decreased less than the non-SLE ASMR, with a 34.6% cumulative increase in the ratio of the former to the latter. The non-SLE ASMR decreased every year starting in 1968, whereas the SLE ASMR decreased between 1968 and 1975, increased between 1975 and 1999, and decreased thereafter. Similar patterns were seen in both sexes, among black persons, and in the South. However, statistically significant increases in the SLE ASMR did not occur among white persons over the 46-year period. Females, black persons, and residents of the South had higher SLE ASMRs and larger cumulative increases in the ratio of the SLE to the non-SLE ASMR (31.4%, 62.5%, and 58.6%, respectively) than males, other racial/ethnic groups, and residents of other regions, respectively. Multiple logistic regression showed independent associations of sex, race, and region with SLE mortality risk and revealed significant racial/ethnic differences in associations of SLE mortality with sex and region.

Limitations:

Underreporting of SLE on death certificates may have resulted in underestimates of SLE ASMRs. Accuracy of coding on death certificates is difficult to ascertain.

Conclusion:

Rates of SLE mortality have decreased since 1968 but remain high relative to non-SLE mortality, and significant sex, racial, and regional disparities persist.

Primary Funding Source:

None.

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Production of bioactive liver-targeting interferon Mu-IFN-CSP by soluble prokaryotic expression

A novel liver-targeting interferon (IFN-CSP) was successfully over-expressed in our previous work. The in vitro and in vivo investigation revealed that IFN-CSP has significant anti-hepatitis B virus (HBV) effe...

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Electronic Health Record Phenotypes for Precision Medicine: Perspectives and Caveats from Treatment of Breast Cancer at a Single Institution

Abstract

Precision medicine is at the forefront of biomedical research. Cancer registries provide rich perspectives and electronic health record(EHR)s are commonly utilized to gather additional clinical data elements needed for translational research. However, manual annotation is resource-intense and not readily scalable. Informatics-based phenotyping presents an ideal solution, but perspectives obtained can be impacted by both data source and algorithm selection. We derived breast cancer(BC) receptor status phenotypes from structured and unstructured EHR data using rule-based algorithms, including natural language processing(NLP). Overall, use of NLP increased BC receptor status coverage by 39.2% from 69.1% with structured medication information alone. Using all available EHR data, estrogen receptor-positive BC cases were ascertained with high precision(P = 0.976) and recall(R = 0.987) compared to gold standard chart-reviewed patients. However, status negation(R = 0.591), decreased 40.2% when relying on structured medications alone. Using multiple EHR data types (and thorough understanding perspectives offered) are necessary to derive robust EHR-based precision medicine phenotypes.

This article is protected by copyright. All rights reserved

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What your community needs to know about the 'Until Help Arrives' program

The program aims to teach bystanders how to keep victims with life-threatening injuries alive until EMS arrives

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A systematic review on multiparametric MR imaging in prostate cancer detection

Abstract

Background

Literature data suggest that multi-parametric Magnetic Resonance Imaging (MRI), including morphologic T2-weigthed images (T2-MRI) and functional approaches such as Dynamic Contrast Enhanced-MRI (DCE-MRI), Diffusion Weighted Imaging (DWI) and Magnetic Resonance Spectroscopic Imaging (MRSI), give an added value in the prostate cancer localization and local staging.

Methods

We performed a systematic review of literature about the role and the potentiality of morphological and functional MRI in prostate cancer, also in a multimodal / multiparametric approach, and we reported the diagnostic accuracy results for different imaging modalities and for different MR coil settings: endorectal coil (ERC) and phased array coil (PAC). Forest plots and receiver operating characteristic curves were performed. Risk of bias and the applicability at study level were calculated.

Results

Thirty three papers were identified for the systematic review. Sensitivity and specificity values were, respectively, for T2-MRI of 75% and of 60%, for DCE-MRI of 80% and of 72%, for MRSI of 89% and of 69%, for combined T2-MRI and DCE-MRI of 87% and of 46%, for combined T2-MRI and MRSI of 79% and of 57%, for combined T2-MRI, DWI and DCE-MRI of 81% and of 84%, and for combined MRSI and DCE-MRI of 83% and of 83%. For MRI studies performed with ERC we obtained a pooled sensitivity and specificity of 81% and of 66% while the pooled values for MRI studies performed with PAC were of 78% and of 64%, respectively (p>0.05 at McNemar test). No studies were excluded from the analysis based on the quality assessment.

Conclusions

ERC use yielded no additional benefit in terms of prostate cancer detection accuracy compared to multi-channel PAC use (71% versus 68%) while the use of additional functional imaging techniques (DCE-MRI, DWI and MRSI) in a multiparametric MRI protocol improves the accuracy of prostate cancer detection allowing both the early cure and the guidance of biopsy.

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Isolation of Intact, Whole Mouse Mammary Glands for Analysis of Extracellular Matrix Expression and Gland Morphology

Here, we present a protocol for the isolation of whole, intact mouse mammary glands to investigate extracellular matrix (ECM) expression and ductal morphology. Mouse #4 abdominal glands were extracted from 8-10 week old female nulliparous mice, fixed in neutral buffered formalin, sectioned and stained using immunohistochemistry for ECM proteins.

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Synthetic regulatory RNAs selectively suppress the progression of bladder cancer

Abstract

The traditional treatment for cancer is lack of specificity and efficacy. Modular synthetic regulatory RNAs, such as inhibitive RNA (iRNA) and active RNA (aRNA), may overcome these limitations. Here, we synthesize a new iRNA to bind the upstream activating sequence (UAS) of a minimal promoter that drives expression of artificial miRNAs (amiRNAs) targeting MYC, which represses the binding interaction between UAS and GAL4 fusion protein (GAL4-VP64) in GAL4/UAS system. The aRNA driven by a tumor-specific mutant human telomerase reverse transcriptase (hTERT) promoter is created to interact with iRNA to expose UAS again in bladder cancer. Without the aRNA, mRNA and protein levels of MYC, cell growth, cell apoptosis and cell migration were no significance in two bladder cancer cell lines, T24 and 5637, and human foreskin fibroblast (HFF) cells. The aRNA significantly inhibited the expression of MYC in mRNA and protein levels, as well as the proliferation and migration of the cancer cells, but not in HFF cells. These results indicated that regulatory RNAs selectively controlled the expression of amiRNAs and ultimately suppress the progression of bladder cancer cells without affecting normal cells. Synthetic regulatory RNAs might be a selective therapeutic approach for bladder cancer.

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Inscope Medical Solutions launches laryngoscope with integrated suction

The Inscope Direct is a disposable laryngoscope that gives clinicians a clear view of the airway

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Assessing cytopathology milestones with checklists and online learning

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Prostate cancer outcomes for men aged younger than 65 years with Medicaid versus private insurance

BACKGROUND

In the current national debate regarding private insurance versus Medicaid expansion, understanding how insurance is associated with racial disparities in prostate cancer (CaP) outcomes has broad policy implications. In the current study, the authors examined the association between insurance status, race, and CaP outcomes.

METHODS

The Surveillance, Epidemiology, and End Results program identified 155,524 men aged < 65 years who were diagnosed with CaP from 2007 through 2014. The association between insurance and stage of disease at the time of presentation was examined. Among men with localized CaP, the associations between insurance and receipt of therapy and prostate cancer-specific mortality (PCSM) were determined.

RESULTS

Compared with private insurance, men with Medicaid were more likely to present with metastatic disease (adjusted odds ratio [AOR], 4.27; 95% confidence interval [95% CI], 4.01-4.55), were less likely to receive definitive treatment (AOR, 0.67; 95% CI, 0.62-0.71), and had increased PCSM (adjusted hazard ratio, 1.83; 95% CI, 1.50-2.24), regardless of race. Significant interactions between race and insurance status indicated that insurance had more than an additive association with race. Among privately insured patients, disparities in PCSM (AOR, 1.2; 95% CI, 1.03-1.40 [P = .019]) and presentation with metastatic disease (AOR, 1.13; 95% CI, 1.06-1.21 [P<.001]) were observed. No disparities were observed among patients with Medicaid insurance with regard to PCSM (AOR, 0.79; 95% CI, 0.52-1.20 [P = .272]) and metastatic disease (AOR, 0.91; 95% CI, 0.80-1.03 [P = .139]).

CONCLUSIONS

Racial disparities in the outcomes of patients with CaP were observed in privately insured cohorts, whereas these disparities appeared to be reduced among patients with Medicaid insurance. However, outcomes need to be improved overall. Whether the equality in outcomes for Medicaid is due to white and African American patients doing "equally poorly" or "equally well" is unclear. Cancer 2017. © 2017 American Cancer Society.

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Adolescent body mass index and risk of colon and rectal cancer in a cohort of 1.79 million Israeli men and women: A population-based study

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Reply to Adolescent body mass index and risk of colon and rectal cancer in a cohort of 1.79 million Israeli men and women: A population-based study

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Clinical and genetic characterization of hereditary breast cancer in a Chinese population

Abstract

Background

Breast cancer develops as a result of multiple gene mutations in combination with environmental risk factors. Causative variants in genes such as BRCA1 and/or BRCA2 have been shown to account for hereditary nature of certain breast cancers. However,other genes, such as ATM, PALB2, BRIP1, CHEK, BARD1, while lower in frequency, may also increase breast cancer risk. There are few studies examining the role of these causative variants. Our study aimed to examine the clinical and genetic characterization of hereditary breast cancer in a Chinese population.

Methods

We tested a panel of 27 genes implicated in breast cancer risk in 240 participants using Next-Generation Sequencing. The prevalence of genetic causative variants was determined and the association between causative variants and clinico-pathological characteristics was analyzed.

Results

Causative variant rate was 19.2% in the breast cancer (case) group and 12.5% in the high-risk group. In the case group 2.5% of patients carried BRCA1 causative variant, 7.5% BRCA2 variants, 1.7% patients had MUTYH, CHEK or PALB2 variants, and 0.8% patients carried ATM, BARD1, NBN, RAD51C or TP53 variants. In the high-risk group 5.8% women carried MUTYH causative variants, 2.5% had causative variants in ATM, 1.7% patients had variants in BRCA2 and 0.8% in BARD1, BRIP1 or CDH1. There was no significant difference in the presence of causative variants among clinical stages of breast cancer, tumor size and lymph nodes status. However, eight of the 12 BRCA1/2 causative variants were found in the TNBC group.

Conclusions

We found increased genetic causative variants in the familial breast cancer group and in high-risk women with a family history of breast cancer. However, the variant MUTYH c.892-2A > G may not be directly associated with hereditary breast carcinoma.

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Rapid, Directed Differentiation of Retinal Pigment Epithelial Cells from Human Embryonic or Induced Pluripotent Stem Cells

This protocol describes how to produce retinal pigment epithelial cells (RPE) from pluripotent stem cells. The method uses a combination of growth factors and small molecules to direct the differentiation of stem cells into immature RPE in fourteen days and mature, functional RPE after three months.

http://ift.tt/2ifXRzq

Conditional survival in patients with gallbladder cancer

Conditional survival (CS) has been established as a clinically relevant prognostic factor for cancer survivors, and the CS in gallbladder (GB) cancer has not yet been fully evaluated. In this study, we evaluat...

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Transcultural adaptation of the user satisfaction scale to the health service: Brazilian version of the EORTC IN-PATSAT32 questionnaire

Abstract

Objective

To describe the cross-cultural adaptation and psychometric properties of the Brazilian version of the IN-PATSAT32 questionnaire.

Methods

The questionnaire was applied to 328 patients in a public hospital, and the retest was performed with 86 patients, approximately 1 week after the test. Psychometric analyses were performed to evaluate the structure, reliability, and internal consistency of the questionnaire.

Results

The adapted questionnaire presented high sensitivity and the intraclass correlation coefficient (ICC > 8) indicated strong convergent validity and discriminant properties of the instrument, as well as high internal consistency (Cronbach's α > 0.8). Exploratory factor analysis divided the questionnaire into five dimensions: satisfaction with a multidisciplinary team (α = 0.953, kp = 0.61, ICC = 0.953), doctors (α = 0.993, kp = 0.817, ICC = 0.966), therapeutic (α = 0.946, kp = 0.869, ICC = 0.972), hospital structure (α = 0.97, kp = 0.87, ICC = 0.947), and hospital discharge.

Conclusion

The results indicated that the Brazilian version maintained its psychometric properties when used in a heterogeneous population and with different diagnoses and stages of treatment for cancer.

Practice implications

This questionnaire can be used in the Brazilian hospital routine to gauge the satisfaction of patients with hospitalization.

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Radiotherapy for vaginal cancer: a multi-institutional survey study of the Japanese Radiation Oncology Study Group

Abstract

Purpose

Our aim was to assess the patterns of practice and treatment outcomes of definitive radiotherapy (RT) for vaginal cancer in Japan.

Materials and methods

RT methods and outcomes of patients with vaginal cancer treated with definitive RT or chemoradiotherapy at 10 institutes of the Japanese Radiation Oncology Study Group between January 2000 and March 2010 were retrospectively evaluated.

Results

A total of 90 patients were enrolled in the study. The clinical stages were I, II, III, and IVA in 34, 36, 16, and 4 patients, respectively. Seventy patients were treated with three-dimensional conformal RT (3DCRT) and brachytherapy (BT), 12 with BT alone, and 8 with 3DCRT alone. Chemotherapy was administered to 29 patients. The 5-year overall survival and local control rates were 77 and 83% with a median follow-up period of 94 months for surviving or lost patients. The 5-year overall survival rates according to stage were 94, 71, 56, and 75% for stages I, II, III, and IVA, respectively. The 5-year local control rates according to stage were 94, 77, 74, and 75% for stages I, II, III, and IVA, respectively. Twenty-nine percent (6 of 21 patients) of local recurrences occurred between 5 and 10 years after RT. The 10-year local control rate of all patients was 71%. Significant prognostic factors for overall survival by univariate and multi-variate analyses were performance status, tumor size, and pelvic lymph node metastasis. Grade 3 late radiation morbidity of the rectum, pelvic bone, urinary bladder, and skin developed in 9% (8 of 90 patients).

Conclusions

Good outcomes similar to those of cervical cancer can be achieved with definitive RT delivered by 3DCRT and/or BT for vaginal cancer. Long follow-up is necessary for a continuing risk of local recurrence after 5 years.

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Multidetector Computed Tomographic Urography (MDCTU): Its Practical Role in Diagnosis of Upper Tract Urothelial Cancer in Patients 50 years and Older with Different Types of Hematuria

Abstract

MDCTU is a preferred method for the investigation of malignant lesions in the upper urinary tract. However, to decrease unnecessary radiation exposure the indications for the exam in different groups of patients should be assessed. In this study, we evaluated the role of MDCTU in patients older than 50 years who presented with different types of hematuria. In a retrospective manner, we assessed the radiologic reports of 173 patients ≥50 years who underwent MDCTU as a part of the evaluation for hematuria. To estimate the accuracy of MDCTU in the detection of upper urinary tract urothelial carcinoma (UUTUC) we compared MDCTU findings with the results of ureteroscopy. We also evaluated which factors can predict ureteroscopic confirmation of MDCTU-based diagnosis. In this list we also included diabetes mellitus and anticoagulant medications. As a result, 140 (103 males and 37 females) patients met the inclusion criteria. Mean patients' age was 69.7±16.98. Smokers and passive smokers comprised 38.6% and 26.4% of our patients, while 37.8% of our patients suffered from DM and 45% took anticoagulant medications. MDCTU suspected urothelial carcinoma in 17% (n=24) of our patients: UUTUC in eight and bladder urothelial carcinoma (BUC) in 16patients. Ureteroscopy had diagnosed UUTUC (with/without concurrent urothelial carcinoma of the bladder) in 9 patients: 6 with suspicious lesions in MDCTU and 3 additional patients with CIS/small low grade TCC. MDCTU had a sensitivity of 66.7%, specificity - 98.5%, positive predictive value - 75% and negative predictive value - 97.7%. The logistic regression model revealed five strong predictors for UUTUC: positive/atypical cytology, recurrent hematuria, MDCTU signs, age and Warfarin treatment. Finally a source of hematuria was diagnosed in 57% of patients, while MDCTU individual accuracy reached 42%. We found that MDCTU can effectively identify patients in whom further endoscopy is unnecessary. Otherwise, elder patients with positive/atypical cytology and recurrent microscopic hematuria, who have MDCTU signs and take Warfarin, should undergo endoscopic evaluation.

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Beyond Dose: Using Pretherapy Biomarkers to Improve Dose Prediction of Outcomes for Radioimmunotherapy of Non-Hodgkin Lymphoma

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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