Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Τετάρτη 9 Ιανουαρίου 2019

Making Promotion Count: The Gender Perspective On Behalf of the Society for Academic Emergency Medicine Equity Research Taskforce

Abstract

Women in academic emergency medicine (EM) experience disparities in both compensation and advancement.1‐3 Some hypothesized causes of gender disparities include lack of mentorship and resources,4‐5 unequal distribution of opportunity,6‐7 sexism8 and implicit bias.9‐10 Gender differences in academic rank in EM may also be driven by differences in scholarly productivity, slower ascent to leadership among women, attrition from academic medicine, and potentially a lack of adequate support for faculty that have family obligations competing with work,4 though these factors are largely speculative.

This article is protected by copyright. All rights reserved.



http://bit.ly/2C9TxM1

HLA-mismatched stem cell microtransplantation compared to matched-sibling donor transplantation for intermediate/high-risk acute myeloid leukemia

Abstract

HLA-mismatched stem cell microtransplantation is a new form of transplantation reported in recent years. We compared 59 patients undergoing microtransplantation to 66 patients undergoing HLA-matched sibling donor (MSD) transplantation at the same period from April 2012 to December 2016, who all suffered from intermediate/high-risk acute myelogenous leukemia (AML) in first complete remission (CR1). The estimated overall survival (OS) at 2 years was 74.1% ± 6.2% and 34.3% ± 7.9% in MSD and microtransplantation group, respectively (P = 0.001). The estimated leukemia-free survival (LFS) at 2 years was 73.3% ± 6.1% in the MSD group and 31.6% ± 7.6% in the microtransplantation group (P = 0.000). The 2-year cumulative incidence of relapse was 17.6% and 62.3% in the MSD and microtransplantation groups, respectively (P < 0.0001). The 2-year cumulative incidence of nonrelapse mortality was 10.9% in MSD group and 4.2% in the microtransplantation group (P = 0.251). Hematopoietic recovery time was shorter in the microtransplantation group than in the MSD group (P < 0.05). The infection rate was higher in the MSD group than in the microtransplantation group (P = 0.012). The preliminary results suggested that OS and LFS of microtransplantation were inferior to MSD transplantation for intermediate/high-risk AML in CR1.



http://bit.ly/2VH6nKA

Molecular Features of the Zn2+ Binding Site in the Prion Protein Probed by 113Cd NMR

The cellular prion protein (PrPC) is a zinc binding protein that contributes to the regulation of Zn2+ and other divalent species of the central nervous system. Zn2+ coordinates to the flexible, N-terminal repeat region of PrPC and drives a tertiary contact between this repeat region and a well-defined cleft of the C-terminal domain. The tertiary structure promoted by Zn2+ is thought to regulate inherent PrPC toxicity. Despite the emerging consensus regarding the interaction between Zn2+ and PrPC, there is little direct spectroscopic confirmation of the metal ion's coordination details.

http://bit.ly/2FkRTKO

Core-shell modelling of light scattering by vesicles: effect of size, contents, and lamellarity

Having a fast, reliable method for characterising vesicles is vital for their use as model cell membranes in biophysics, synthetic biology, and origins of life studies. Instead of the traditionally-used Rayleigh-Gans-Debye approximation, we use an exact extended Lorenz-Mie solution for how core-shell particles scatter light to model vesicle turbidity. This approach enables accurate interpretations of simple turbidimetric measurements, and is able to accurately model highly scattering vesicles such as larger vesicles, those with multiple layers, and those with encapsulated material.

http://bit.ly/2CcNpTn

Inflammatory bowel disease and new-onset psychiatric disorders in pregnancy and post partum: a population-based cohort study

Objective

Patients with inflammatory bowel disease (IBD) have an elevated risk of mental illness. We determined the incidence and correlates of new-onset mental illness associated with IBD during pregnancy and post partum.

Design

This cohort study using population-based health administrative data included all women with a singleton live birth in Ontario, Canada (2002–2014). The incidence of new-onset mental illness from conception to 1-year post partum was compared between 3721 women with and 798 908 without IBD, generating adjusted HRs (aHR). Logistic regression was used to identify correlates of new-onset mental illness in the IBD group.

Results

About 22.7% of women with IBD had new-onset mental illness versus 20.4% without, corresponding to incidence rates of 150.2 and 132.8 per 1000 patient-years (aHR 1.12, 95% CI 1.05 to 1.20), or one extra case of new-onset mental illness per 43 pregnant women with IBD. The risk was elevated in the post partum (aHR 1.20, 95% CI 1.09 to 1.31), but not during pregnancy, and for Crohn's disease (aHR 1.12, 95% CI 1.02 to 1.23), but not ulcerative colitis. The risk was specifically elevated for a new-onset mood or anxiety disorder (aHR 1.14, 95% CI 1.04 to 1.26) and alcohol or substance use disorders (aHR 2.73, 95% CI 1.42 to 5.26). Predictors of a mental illness diagnosis were maternal age, delivery year, medical comorbidity, number of prenatal visits, family physician obstetrical care and infant mortality.

Conclusion

Women with IBD were at an increased risk of new-onset psychiatric diagnosis in the postpartum period, but not during pregnancy. Providers should look to increase opportunities for prevention, early identification and treatment accordingly.



http://bit.ly/2VE0yxA

Immunotherapy: last bullet in platinum refractory germ cell testicular cancer

Future Oncology, Ahead of Print.


http://bit.ly/2Qy9MaU

Bone metastases and skeletal-related events: incidence and prognosis according to histological subtype of lung cancer

Future Oncology, Ahead of Print.


http://bit.ly/2VEt4z3

Increased prevalence of anti‐TNF therapy in paediatric inflammatory bowel disease is associated with a decline in surgical resections during childhood

Summary

Background

Anti‐tumour necrosis factor‐α (anti‐TNF) therapy use has risen in paediatric‐onset inflammatory bowel disease (PIBD). Whether this has translated into preventing/delaying childhood surgery is uncertain. The Wessex PIBD cohort was analysed for trends in anti‐TNF‐therapy and surgery.

Design

All patients diagnosed with PIBD within Wessex from 1997 to 2017 were assessed. The prevalence of anti‐TNF‐therapy and yearly surgery rates (resection and perianal) during childhood (<18 years) were analysed (Pearson's correlation, multivariate regression, Fisher's exact).

Results

Eight‐hundred‐and‐twenty‐five children were included (498 Crohn's disease, 272 ulcerative colitis, 55 IBD‐unclassified), mean age at diagnosis 13.6 years (1.6‐17.6), 39.6% female. The prevalence of anti‐TNF‐treated patients increased from 5.1% to 27.1% (2007‐2017), P = 0.0001. Surgical resection‐rate fell (7.1%‐1.5%, P = 0.001), driven by a decrease in Crohn's disease resections (8.9%‐2.3%, P = 0.001). Perianal surgery and ulcerative colitis resection‐rates were unchanged. Time from diagnosis to resection increased (1.6‐2.8 years, P = 0.028) but mean age at resection was unchanged. Patients undergoing resections during childhood were diagnosed at a younger age in the most recent 5 years (2007‐2011 = 13.1 years, 2013‐2017 = 11.9 years, P = 0.014).

Resection‐rate in anti‐TNF‐therapy treated (16.1%) or untreated (12.2%) was no different (P = 0.25). Patients started on anti‐TNF‐therapy <3 years post‐diagnosis (11.6%) vs later (28.6%) had a reduction in resections, P = 0.047. Anti‐TNF‐therapy prevalence was the only significant predictor of resection‐rate using multivariate regression (P = 0.011).

Conclusion

The prevalence of anti‐TNF‐therapy increased significantly, alongside a decrease in surgical resection‐rate. Patients diagnosed at younger ages still underwent surgery during childhood. Anti‐TNF‐therapy may reduce the need for surgical intervention in childhood, thereby influencing the natural history of PIBD.



http://bit.ly/2sksqt3

PD-L1 expression in breast cancer: expression in subtypes and prognostic significance: a systematic review

Abstract

Purpose

To systematically review the literature on the expression of PD-L1 in primary BC, variation of expression between subtypes and effect on overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS). Additionally, for studies in the neoadjuvant setting, we have reviewed the ability of PD-L1 to predict pathological complete response (pCR).

Methods

Articles included in this review were retrieved by searching PubMed (1966–2018) and EMBASE (1980–2018). The following search terms were used: "PD-L1 expression" and "breast cancer" (PubMed234; EMBASE 161).

Results

Thirty-seven articles were found relevant to this study. We summarize important findings from these works, and show that the observed PD-L1 expression in the studies varies greatly, with expression rates ranging from 0 to 83% across subtypes. PD-L1 expression in relation to prognosis both in the adjuvant and neoadjuvant chemotherapy setting remains controversial, with studies finding better, worse, or no effect on prognosis. We also show that a wide variety of strategies are used when evaluating PD-L1 immunohistochemically, e.g., different cut-off points, different cell types evaluated, and different perceptions of when a cell is positive for PD-L1 (cytoplasmic vs membrane staining).

Conclusion

Further investigation of PD-L1 expression in breast cancer and its effect on prognosis is required. There is little consensus on the methods used to evaluate PD-L1 expression immunohistochemically, and this may contribute to the diverging results found in this study.



http://bit.ly/2CfQkKL

Non-Invasive Positive airway Pressure thErapy to Reduce Postoperative Lung complications following Upper abdominal Surgery (NIPPER PLUS): protocol for a single-centre, pilot, randomised controlled trial

Introduction

Postoperative pulmonary complications (PPCs) are a common serious complication following upper abdominal surgery leading to significant consequences including increased mortality, hospital costs and prolonged hospitalisation. The primary objective of this study is to detect whether there is a possible signal towards PPC reduction with the use of additional intermittent non-invasive ventilation (NIV) compared with continuous high-flow nasal oxygen therapy alone following high-risk elective upper abdominal surgery. Secondary objectives are to measure feasibility of: (1) trial conduct and design and (2) physiotherapy-led NIV and a high-flow nasal oxygen therapy protocol, safety of NIV and to provide preliminary costs of care information of NIV and high-flow nasal oxygen therapy.

Methods and analysis

This is a single-centre, parallel group, assessor blinded, pilot, randomised trial, with 130 high-risk upper abdominal surgery patients randomly assigned via concealed allocation to either (1) usual care of continuous high-flow nasal oxygen therapy for 48 hours following extubation or (2) usual care plus five additional 30 min physiotherapy-led NIV sessions within the first two postoperative days. Both groups receive standardised preoperative physiotherapy and postoperative early ambulation. No additional respiratory physiotherapy is provided to either group. Outcome measures will assess incidence of PPC within the first 14 postoperative days, recruitment ability, physiotherapy-led NIV and high-flow nasal oxygen therapy protocol adherence, adverse events relating to NIV delivery and costs of providing a physiotherapy-led NIV and a high-flow nasal oxygen therapy service following upper abdominal surgery.

Ethics and dissemination

Ethics approval has been obtained from the relevant institution and results will be published to inform future multicentre trials.

Trial registration number

ACTRN12617000269336; Pre-results.



http://bit.ly/2H3JYUt

Examining reliability of WHOBARS: a tool to measure the quality of administration of WHO surgical safety checklist using generalisability theory with surgical teams from three New Zealand hospitals

Objectives

To extend reliability of WHO Behaviourally Anchored Rating Scale (WHOBARS) to measure the quality of WHO Surgical Safety Checklist administration using generalisability theory. In this context, extending reliability refers to establishing generalisability of the tool scores across populations of teams and raters by accounting for the relevant sources of measurement errors.

Design

Cross-sectional random effect measurement design assessing surgical teams by the five items on the three Checklist phases, and at three sites by two trained raters simultaneously.

Setting

The data were collected in three tertiary hospitals in Auckland, New Zealand in 2016 and included 60 teams observed in 60 different cases with an equal number of teams (n=20) per site. All elective and acute cases (adults and children) involving surgery under general anaesthesia during normal working hours were eligible.

Participants

The study included 243 surgical staff members, 138 (50.12%) women.

Main outcome measure

Absolute generalisability coefficient that accounts for variance due to items, phases, sites and raters for the WHOBARS measure of the quality of WHO Surgical Safety Checklist administration.

Results

The WHOBARS in its present form has demonstrated good generalisability of scores across teams and raters (G absolute=0.83). The largest source of measurement error was the interaction between the surgical team and the rater, accounting for 16.7% (95% CI 16.4 to 16.9) of the total variance in the data. Removing any items from the WHOBARS led to a decrease in the overall reliability of the instrument.

Conclusions

Assessing checklist administration quality is important for promoting improvement in its use, and WHOBARS offers a reliable approach for doing this.



http://bit.ly/2REU7Ln

Comprehensive overview of computer-based health information tailoring: a systematic scoping review

Objectives

To explore the scope of the published literature on computer-tailoring, considering both the development and the evaluation aspects, with the aim of identifying and categorising main approaches and detecting research gaps, tendencies and trends.

Setting

Original researches from any country and healthcare setting.

Participants

Patients or health consumers with any health condition regardless of their specific characteristics.

Method

A systematic scoping review was undertaken based on the York's five-stage framework outlined by Arksey and O'Malley. Five leading databases were searched: PubMed, Scopus, Science Direct, EBSCO and IEEE for articles published between 1990 and 2017. Tailoring concept was investigated for three aspects: system design, information delivery and evaluation. Both quantitative (ie, frequencies) and qualitative (ie, theme analysis) methods have been used to synthesis the data.

Results

After reviewing 1320 studies, 360 articles were identified for inclusion. Two main routes were identified in tailoring literature including public health research (64%) and computer science research (17%). The most common facets used for tailoring were sociodemographic (73 %), target behaviour status (59%) and psycho-behavioural determinants (56%), respectively. The analysis showed that only 13% of the studies described the tailoring algorithm they used, from which two approaches revealed: information retrieval (12%) and natural language generation (1%). The systematic mapping of the delivery channel indicated that nearly half of the articles used the web (57%) to deliver the tailored information; printout (19%) and email (10%) came next. Analysis of the evaluation approaches showed that nearly half of the articles (53%) used an outcome-based approach, 44% used process evaluation and 3% assessed cost-effectiveness.

Conclusions

This scoping review can inform researchers to identify the methodological approaches of computer tailoring. Improvements in reporting and conduct are imperative. Further research on tailoring methodology is warranted, and in particular, there is a need for a guideline to standardise reporting.



http://bit.ly/2H2zbdu

Protocol for a prospective observational study to develop a frailty index for use in perioperative and critical care

Introduction

Frailty is of increasing importance to perioperative and critical care medicine, as the proportion of older patients increases globally. Evidence continues to emerge of the considerable impact frailty has on adverse outcomes from both surgery and critical care, which has led to a proliferation of different frailty measurement tools in recent years. Despite this, there remains a lack of easily implemented, comprehensive frailty assessment tools specific to these complex populations. Development of a frailty index using routinely collected hospital data, able to leverage the automated aspects of an electronic medical record, would aid risk stratification and benefit clinicians and patients alike.

Methods and analysis

This is a prospective observational study. 150 intensive care unit (ICU) patients aged ≥50 years and 200 surgical patients aged ≥65 years will be enrolled. The primary objective is to develop a frailty index. Secondary objectives include assessing its ability to predict in-hospital mortality and/or discharge to a new non-home location; the performance of the frailty index in predicting postoperative and ICU complications, as well as health-related quality of life at 6 months; to compare the performance of the frailty index against existing frailty measurement and risk stratification tools; and to assess its modification by patients' health assets.

Ethics and dissemination

This study has been approved by the Melbourne Health Human Research Ethics Committee(20 January 2017, HREC/16/MH/321). Dissemination will be via international and national anaesthetic and critical care conferences, and publication in the peer-reviewed literature.



http://bit.ly/2RIyOIY

A pilot randomised controlled trial of metacognitive therapy for prolonged grief

Objectives

Prolonged grief disorder is associated with significant distress and impairment and thus efforts to improve treatments are essential. The present pilot study tested the efficacy and feasibility of group Metacognitive Grief Therapy (MCGT) designed specifically for prolonged grief symptomatology to reduce the psychological distress and impaired function resulting from bereavement.

Design/participants

Twenty-two bereaved adult participants with prolonged grief symptomatology were randomised to a wait-list control (n=10) or an intervention condition (n=12) with a 3-month and 6-month follow-up. The wait-list control group was offered treatment after the post-test assessment.

Intervention

Participants attended six group MCGT sessions that ran for 2 hours per week.

Outcome measures

A primary outcome measure of prolonged grief symptomatology and secondary outcome measures of depression, anxiety, rumination, metacognitive beliefs and quality of life were taken pretreatment and post-treatment for both groups and at the 3-month and 6-month follow-up for the intervention group. A Generalised Linear Mixed Model was used to assess treatment efficacy.

Results

Post-treatment intent-to-treat analyses showed MCGT reduced prolonged grief symptomatology (Cohen's d=1.7), depression (d=1.3), anxiety (d=0.8), stress (d=1.0), rumination (d=0.9) and increased quality of life (d=0.6), and these effects were maintained at the 3-month and 6-month follow-ups. No prepost between-group differences were found in metacognitive beliefs. However, a large significant effect was identified at the 3-month and 6-month follow-ups (d=1.0).

Conclusion

The results show promise for the utility of group MCGT for reducing psychological distress and promoting quality of life. Additionally, the results underscore the need for a full randomised controlled trial of group MCGT, which may be an important addition to the treatment armamentarium available to support people with prolonged grief.

Trial registration number

ACTRN12613001270707; Results.

Original protocol

BMJ Open 2015;5:e007221. doi:10.1136/bmjopen-2014-007221



http://bit.ly/2H2z8yk

Socioeconomic status and pulmonary function, transition from childhood to adulthood: cross-sectional results from the polish part of the HAPIEE study

Objective

Previous studies have reported inverse associations between socioeconomic status (SES) and lung function, but less is known about whether pulmonary function is affected by SES changes. We aimed to describe the relationship of changes of SES between childhood and adulthood with pulmonary function.

Design

Cross-sectional study.

Participants

The study sample included 4104 men and women, aged 45–69 years, residents of Krakow, participating in the Polish part of the Health, Alcohol and Psychosocial Factors in Eastern Europe Project.

Main outcome

Forced expiratory volume (FEV1) and forced vital capacity (FVC) were assessed by the standardised spirometry procedure. Participants were classified into three categories of SES (low, moderate or high) based on information on parent's education, housing standard during childhood, own education, employment status, household amenities and financial status.

Results

The adjusted difference in mean FVC between persons with low and high adulthood SES was 100 mL (p=0.005) in men and 100 mL (p<0.001) in women; the differences in mean FEV1 were 103 mL (p<0.001) and 80 mL (p<0.001), respectively. Upward social mobility and moderate or high SES at both childhood and adulthood were related to significantly higher FEV1 and FVC compared with low SES at both childhood and adulthood or downward social mobility.

Conclusions

Low SES over a life course was associated with the lowest lung function. Downward social mobility was associated with a poorer pulmonary function, while upward mobility or life course and moderate or high SES were associated with a better pulmonary function.



http://bit.ly/2REh5Cn

Corticosteroids injections versus corticosteroids with hyaluronic acid injections in rhizarthrosis: the randomised multicentre RHIZART trial study protocol

Introduction

Osteoarthritis of the trapeziometacarpal joint affects approximately 10%–25% of women, especially those who are postmenopausal. It may result in thumb dysfunction. Among the treatments, intra-articular injections of corticosteroid (CS) and hyaluronic acid (HA) are both effective and recommended. However, clinical trials have shown that HA improves functional capacity, whereas CS only produces a decrease in pain. The synergy of these two drugs has not been evaluated. The primary goal of this study was to determine whether the association between HA and CS produce an additional decrease of more pain during thumb movement at three months postinjection, compared to the level of pain relief from CS alone.

Methods and analysis

RHIZ'ART is a prospective, multicentre, comparative, randomised, controlled, double-blind trial. Patients referred to the rheumatology department for thumb rhizarthrosis will receive an injection of betamethasone with HA or placebo (serum saline) based on central randomisation and stratification by centre. Injections will be given under ultrasound guidance. The primary outcome will compare the pain Visual Analogue Scale with motion at three months for both groups using a mixed model. The expected decrease in pain intensity in the CS group is 25% and 35% in the CS with HA group. In order to achieve a 80% power for detecting this difference with α set at 5%, 73 patients are needed in each group (146 total). The main secondary outcomes are the Cochin score (hand function) and grip strength. Follow-up visits are at 1, 3, 6 and 12 months.

Ethics and dissemination

The study project has been approved by the appropriate ethics committee (CPP île de France III, 2017-002298-20). In agreement with current French regulations, a signed informed written consent will be obtained from each patient. Results of the main trial and of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Trial registration number

NCT03431584.



http://bit.ly/2H4DBQY

Supporting children and young people when making decisions about joining clinical trials: qualitative study to inform multimedia website development

Objectives

To understand stakeholders' views regarding the content and design of paediatric clinical trial multimedia websites. To describe how this knowledge informed the development of the multimedia websites.

Design

Qualitative study comprising two rounds of interviews or focus groups, with thematic analysis of interview transcripts.

Participants

Sixty-two people (21 children and young people with long-term health conditions, 24 parents and 17 professionals).

Setting

One UK children's hospital and one UK Young Persons' Advisory Group.

Results

When asked what was important in deciding whether to join a trial, children, young people and parents prioritised information about what participation would involve, what the trial was testing, potential benefits and risks of participation and knowing they could leave the trial if they later changed their minds. Young people and parents trusted trial teams to follow regulatory and quality requirements and therefore did not think such information was a priority for the websites, although logos of trusted organisations could lend credibility. Professionals largely concurred with these views. Children and young people advised on the importance of designing the multimedia website to ensure its appearance, tone and wording suited the intended audience and on using animated characters to facilitate children's engagement.

Conclusions

Our study provides insights into the information that families value when deciding about healthcare trial participation. It provides guidance on the design of information resources to appeal to children and young people, while also being acceptable to parents and professionals who are often gatekeepers of children's access to information. Our findings will be of use to others developing similar multimedia websites. We report specific information needs and new visual preferences that are not usually addressed in printed trial information. Our work illustrates what qualitative research and participatory design practices can contribute to the development of information resources more generally.

Trial registration number

ISRCTN73136092; Pre-results.



http://bit.ly/2RETYHP

Values-based and acceptance-based intervention to promote adoption and maintenance of habitual physical activity among inactive adults with overweight/obesity: a study protocol for an open trial

Introduction

Despite the importance of regular moderate-intensity to vigorous-intensity physical activity (MVPA) for health benefits and long-term weight management, current comprehensive lifestyle interventions have focused on providing MVPA prescriptions and goals but with only minimal and intermittent focus on psychosocial theoretical constructs and novel strategies, perhaps explaining the often modest impact on adoption and maintenance of higher levels of MVPA. An intervention based on acceptance and commitment therapy (ACT) targeting the increase of values-based autonomous motivation could improve the adoption and maintenance of habitual MVPA among insufficiently active overweight or obese adults in a brief intervention format.

Methods and analysis

The overall aim of this study is to develop and test the feasibility, acceptability and preliminary efficacy of an ACT-based brief workshop intervention for increasing bouted MVPA for inactive adults with overweight/obesity using a single-arm design. A total of 48 inactive adults with overweight/obesity will be recruited and attend a 4-hour, ACT-based workshop followed by weekly emails and monthly phone calls for 3 months. The workshop will teach values clarification and acceptance-based skills to increase values-based autonomous motivation and bouted MVPA. Participants will self-monitor minutes of MVPA and personal values and report on progress via weekly emails and monthly phone calls. Assessments will be conducted at baseline and at 3 and 6 months.

Ethics and dissemination

Study procedures have been approved by the Institutional Review Board. Consent is given in writing and in person. Data collection and storage separates study data from personally identifying information. Two safety officers who are not connected to the study monitor study progress and participant safety.

Trial registration number

NCT03565731; Pre-results.



http://bit.ly/2H4DAwo

Study rationale and protocol of the BARICO study: a longitudinal, prospective, observational study to evaluate the effects of weight loss on brain function and structure after bariatric surgery

Introduction

Weight loss after bariatric surgery (BS) is often associated with improved cognition and structural brain recovery. However, improved cognition after BS is not always exhibited by patients, in fact, in some cases there is even a decline in cognition. Long-term consequences of BS weight loss, in terms of obesity and related diseases, can be hard to determine due to studies having short follow-up periods and small sample sizes.

The aim of the BARICO study (BAriatric surgery Rijnstate and Radboudumc neuroImaging and Cognition in Obesity) is to determine the long-term effect of weight loss after BS on brain function and structure, using sensitive neuropsychological tests and (functional) MRI ((f)MRI). Secondary study endpoints are associated with changes in metabolic and inflammation status of adipose tissue, liver and gut, in relation to brain structure and function. Also, the possible correlation between weight loss, gut microbiota composition change and neuropsychological outcomes will be investigated.

Methods and analysis

Data from 150 Dutch BS patients (ages between 35 and 55, men and women) will be collected at various time points between 2 months before and up to 10 years after surgery. Neuropsychological tests, questionnaires, blood, faeces and tissue samples will be collected before, during and after surgery to measure changes in cognition, microbiota, metabolic activity and inflammation over time. A subgroup of 75 participants will undergo (f)MRI in relation to executive functioning (determined by the Stroop task), grey and white matter volumes and cerebral blood flow. Regression analyses will be used to explore associations between weight loss and outcome measures.

Ethics and dissemination

This study has been approved by the medical review ethics committee CMO Region Arnhem and Nijmegen (NL63493.091.17). Research findings will be published in peer-reviewed journals and at conferences.

Trial registration number

NTR7288.



http://bit.ly/2RHpwgi

Did expansion of health insurance coverage reduce horizontal inequity in healthcare finance? A decomposition analysis for China

Objectives

'Horizontal inequity' in healthcare finance occurs when people with equal income contribute unequally to healthcare payments. Prior research is lacking on horizontal inequity in China. Accordingly, this study set out to examine horizontal inequity in the Chinese healthcare financing system in 2002 and 2007 through two rounds of national household health surveys.

Design

Two rounds of cross-sectional study.

Setting

Heilongjiang Province, China.

Participants

Adopting a multistage stratified random sampling, 3841 households with 11 572 individuals in 2003 and 5530 households with 15 817 individuals in 2008 were selected.

Methods

The decomposition method of Aronson et al was used in the present study to measure the redistributive effects and horizontal inequity in healthcare finance.

Findings

Over the period 2002–2007, the absolute value of horizontal inequity in total healthcare payments decreased from 93.85 percentage points to 35.50 percentage points in urban areas, and from 113.19 percentage points to 37.12 percentage points in rural areas. For public health insurance, it increased from 17.84 percentage points to 28.02 percentage points in urban areas, and decreased from 127.93 percentage points to 0.36 percentage points in rural areas. Horizontal inequity in out-of-pocket payments decreased from 79.92 percentage points to 24.83 percentage points in urban areas, and from 127.71 percentage points to 53.10 percentage points in rural areas.

Conclusions

Our results show that horizontal inequity in total healthcare financing decreased over the period 2002–2007 in China. In addition, out-of-pocket payments contributed most to the extent of horizontal inequity, which were reduced both in urban and rural areas over the period 2002–2007.



http://bit.ly/2H3JXzT

Does endometriosis affect professional life? A matched case-control study in Switzerland, Germany and Austria

Objectives

Endometriosis is a gynaecological disease most commonly causing severe and chronic pelvic pain as well as an impaired quality of life. The aim of this study was to investigate if and how endometriosis affects choices regarding professional life as well as the quality of daily working life.

Design, setting and participants

In the context of a multicentre case–control study, we collected data from 505 women with surgically/histologically confirmed diagnosis of endometriosis and 505 matched controls. Study participants were recruited prospectively in hospitals and doctors' practices in Switzerland, Germany and Austria. Using a detailed questionnaire, the study investigated work–life and career choices of study participants.

Main outcome measures

Associations between endometriosis/disease symptoms and limitations in career development as well as ability to work.

Results

Women with endometriosis were less often able to work in their desired profession than women from the control group (adjusted OR=1.84, 95% CI: 1.15 to 2.94, R2=0.029, p=0.001) and they had to take health-related limitations into consideration in their career decisions to a significantly higher degree than women in the control group (OR=4.79, 95% CI: 2.30 to 9.96, R2=0.063, p<0.001). Among women with endometriosis, chronic pain was significantly associated with increased sick leave (OR=3.52, 95% CI: 2.02 to 6.13, R2=0.072, p<0.001) as well as with loss of productivity at work (OR=3.08, 95% CI: 2.11 to 4.50, R2=0.087, p<0.001).

Conclusions

Endometriosis is associated with impairment of professional life, in particular with regard to career choices. Further research to develop strategies to support endometriosis-affected women in realising professional opportunities is recommended.

Trial registration number

NCT02511626; Pre-results.



http://bit.ly/2RETTUx

Genetic, Inflammatory, and Epithelial Cell Differentiation Factors Control Expression of Human Calpain-14

Eosinophilic esophagitis (EoE) is a chronic, food-driven allergic disease resulting in eosinophilic esophageal inflammation. We recently found that EoE susceptibility is associated with genetic variants in the promoter of CAPN14, a gene with reported esophagus-specific expression. CAPN14 is dynamically up-regulated as a function of EoE disease activity and after exposure of epithelial cells to interleukin-13 (IL-13). Herein, we aimed to explore molecular modulation of CAPN14 expression. We identified three putative binding sites for the IL-13-activated transcription factor STAT6 in the promoter and first intron of CAPN14. Luciferase reporter assays revealed that the two most distal STAT6 elements were required for the ~10-fold increase in promoter activity subsequent to stimulation with IL-13 or IL-4, and also for the genotype-dependent reduction in IL-13-induced promoter activity. One of the STAT6 elements in the promoter was necessary for IL-13-mediated induction of CAPN14 promoter activity while the other STAT6 promoter element was necessary for full induction. Chromatin immunoprecipitation in IL-13 stimulated esophageal epithelial cells was used to further support STAT6 binding to the promoter of CAPN14 at these STAT6 binding sites. The highest CAPN14 and calpain-14 expression occurred with IL-13 or IL-4 stimulation of esophageal epithelial cells under culture conditions that allow the cells to differentiate into a stratified epithelium. This work corroborates a candidate molecular mechanism for EoE disease etiology in which the risk variant at 2p23 dampens mediated CAPN14 expression in differentiated esophageal epithelial cells following IL-13/STAT6 induction of CAPN14 promoter activity.



http://bit.ly/2TGVUNz

Acetyl-CoA metabolism supports multi-step pancreatic tumorigenesis [Research Articles]

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Since acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT-ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA-dependent processes exerts anti-cancer effects.



http://bit.ly/2RHP39k

Obesity Linked to Lower Gray Matter Brain Volume

WEDNESDAY, Jan. 9, 2019 -- Obesity is associated with lower gray matter brain volumes, according to a study published online Jan. 9 in Neurology. Mark Hammer, Ph.D., from Loughborough University, and G. David Batty, D.Sc., from University College...

http://bit.ly/2D1D8et

Smartphone App Can Detect Early Signs of Opioid Overdose

WEDNESDAY, Jan. 9, 2019 -- Specialized smartphone software can be used to detect early signs of opioid overdose, according to research published in the Jan. 9 issue of Science Translational Medicine. Rajalakshmi Nandakumar, from the University of...

http://bit.ly/2TEi2b8

Fewer Than 5 Percent of Thyroid Surgery Patients Readmitted

WEDNESDAY, Jan. 9, 2019 -- Readmissions after thyroid surgery are relatively low, and more than half occur within a week after discharge, according to a study recently published in Surgery. Arturo J. Rios-Diaz, M.D., from Thomas Jefferson University...

http://bit.ly/2D0less

Measles Outbreak in New York State Largest in Recent History

WEDNESDAY, Jan. 9, 2019 -- There have been at least 112 confirmed cases of measles in Rockland and Orange counties and at least 55 in New York City in what officials say is the largest measles outbreak in New York state in recent history. "If you go...

http://bit.ly/2TINvt7

Fewer Complications Found With Hybrid Surgery for Esophageal Cancer

WEDNESDAY, Jan. 9, 2019 -- Hybrid minimally invasive esophagectomy results in lower incidence of intraoperative and postoperative major complications compared with open esophagectomy for esophageal cancer, according to a study published in the Jan....

http://bit.ly/2CZuRr3

Constant Degradation of the Androgen Receptor by MDM2 Conserves Prostate Cancer Stem Cell Integrity

Prostate cancer stem cells (CSCs) are implicated in tumor initiation, cancer progression, metastasis, and the development of therapeutic-resistant disease. It is well known that the bulk of prostate cancer (PCa) cells express androgen receptor (AR) and that androgens are required for PCa growth, progression and emergence of castration-resistant disease. In contrast, the small subpopulation of self-renewing CSCs exhibit an AR-negative (-) signature. The mechanisms underlying the absence of AR are unknown. Using CSC-like cell models isolated from clinical biopsy tissues, we identify the E3 ligase MDM2 as a key regulator of prostate CSC integrity. First, unlike what has been reported for the bulk of AR(+) tumor cells where MDM2 regulates the temporal expression of AR during transcriptional activity, MDM2 in CSCs promoted the constant ubiquitination and degradation of AR, resulting in sustained loss of total AR protein. Second, MDM2 promoted CSC self-renewal, the expression of stem cell factors, and CSC proliferation. Loss of MDM2 reversed these processes and induced expression of full-length AR (and not AR variants), terminal differentiation into luminal cells, and cell death. Selectively blocking MDM2-mediated activity in combination with androgen/AR-targeted therapy may offer a novel strategy for eliminating AR(-) CSCs in addition to the bulk of AR(+) PCa cells, decreasing metastatic tumor burden and inhibiting the emergence of therapeutic resistance.

http://bit.ly/2FmoQ9F

Skin Microbiota in Contact Sports Athletes and Selection of Antiseptics for Professional Hygiene

Background. The aim of this study was to assess changes in skin microbiota of wrestlers during training sessions and to determine the sensitivity of hemolytic bacterial isolates to antiseptics. Methods. The main skin bacterial isolates obtained from the skin of 15 wrestlers were identified by cultivation method, with the following MALDI Biotyper and 16S rRNA gene sequencing methods. The sensitivity of hemolytic isolates to antiseptics (Veltosept-2, Cutasept F, Chlorhexidine, Miramistin, and Hydrogen Peroxide) was evaluated by measuring the size of bacterial growth inhibition zone on agar plates. Results. Opportunistic bacteria of the species Bacillus cereus, Staphylococcus aureus, S. epidermidis, and S. saprophyticus were the most commonly found species in skin microbiota of wrestlers before and after training sessions. Representatives of all these species mostly had a hemolytic activity. An alcohol-containing antiseptic Veltosept-2 showed the strongest inhibitory effect on the bacterial isolates of athletes' skin microbiota most frequently detected in this study. Conclusions. The general increase in the bacterial colonization of wrestlers' skin, as well as the presence of hemolytic forms of opportunistic bacteria in cutaneous microbiota, indicates dysbiotic changes and a decrease in the protective features of the host organism. Veltosept-2 application can reduce the incidence of skin infections in contact sports athletes with the highest efficiency.

http://bit.ly/2AE9zOl

Innate Immune Stimulation in Cancer Therapy

The innate immune system has evolved as a first line of defense against invading pathogens and acts via classes of germline-encoded receptor systems to respond with proinflammatory cytokines. Innate immune cells, predominantly cells of the myeloid compartment, are capable of providing a potent basis for boosting adaptive immunity in malignant diseases. The authors review their current understanding of the molecular mechanisms whereby innate pattern recognition receptors participate in immunosurveillance of cancer cells. They discuss how innate effector mechanisms are currently being targeted pharmacologically and how improved understanding of the biology of these pathways is leading to novel immunotherapies of cancer.

http://bit.ly/2D0FaLC

PC-FACS: January 2, 2019

Effects of Oxytocin

http://bit.ly/2SMO1Gi

An Individualized, Interactive Intervention Promotes Terminally Ill Cancer Patients’ Prognostic Awareness and Reduces Cardiopulmonary Resuscitation Received in the Last Month of Life: Secondary Analysis of a Randomized Clinical Trial

Half of advanced cancer patients do not have accurate prognostic awareness (PA). However, few randomized clinical trials (RCTs) have focused on facilitating patients' PA to reduce their life-sustaining treatments (LSTs) at end of life (EOL). To address these issues, we conducted a double-blinded RCT on terminally ill cancer patients.

http://bit.ly/2ADpYSZ

Agreement between Breathlessness Severity and Unpleasantness in People with Chronic Breathlessness: A Longitudinal Clinical Study

Chronic breathlessness is a cardinal symptom in cardiopulmonary disease where both overall intensity or severity (S) and unpleasantness (U) are commonly quantified. We aimed to evaluate agreement between breathlessness severity and unpleasantness over eight days in patients with chronic breathlessness.

http://bit.ly/2SNxr95

Cortical atrophic-hypometabolic dissociation in the transition from premanifest to early-stage Huntington’s disease

Abstract

Purpose

Huntington's disease (HD) is a fatal neurodegenerative disorder with no effective treatment currently available. Although the pathological hallmark of HD is massive striatal atrophy, it has been suggested that cortical deterioration may concomitantly occur and play a major role in the patient's functional independence. Our objective was to characterize cortical structural and metabolic neurodegeneration in the transition from premanifest to early-stage Huntington's disease (HD).

Methods

Using a surface-based neuroimaging approach, we compared cortical thickness and intracortical FDG-PET uptake in 19 early-symptomatic HD patients with respect to 21 premanifest HD individuals.

Results

Early-HD patients showed significant cortical atrophy and intracortical hypometabolism when compared to premanifest subjects (p < 0.05, corrected for multiple comparisons). However, whereas the atrophy pattern was restricted to precentral and parieto-occipital regions, a pronounced frontotemporal hypometabolism was observed. Importantly, structural changes correlated with motor and cognitive performance, and metabolic changes were associated with the presence and severity of apathy in this population, a core neuropsychiatric feature of this disorder.

Conclusion

Our findings reveal an asynchronous neuronal loss and metabolic compromise across the cerebral cortex in early HD. Hence, the use of structural and metabolic imaging indicators to characterize disease progression in this population should take into consideration the dissociation which occurs between cortical atrophy and hypometabolism.



http://bit.ly/2SO0KZi

Cholangioscopy complicated by gallbladder perforation



http://bit.ly/2RiVWyy

Perforation of the duodenum 2 weeks after lumen-apposing metal stent placement for malignant pyloric stricture



http://bit.ly/2Cb0vjP

Cold snare endoscopic resection of nonpedunculated colorectal polyps larger than 10 mm: a systematic review and pooled-analysis

Hot snare polypectomy and endoscopic mucosal resection (EMR) are the standard of care in resecting colorectal polyps ≥10 mm. To avoid the risk of electrocautery-induced damage, there is recent evidence about using cold snare polypectomy and cold EMR for such lesions. The aim of this pooled analysis is to report outcomes of cold snare resection (CSR) for polyps ≥10 mm.

http://bit.ly/2RiWCnA

Esophageal subepithelial nodule: bronchial artery aneurysm with fistulization to the pulmonary artery (with video)



http://bit.ly/2CeuVSg

Endoscopic full-thickness muscle biopsy for rectal tissue sampling in patients with severe gut motility disorders: an initial experience (with video)

Diagnosis of gastrointestinal neuromuscular diseases is mostly on basis of symptomatology and is often unreliable. Pathological analysis of affected tissue eg, the myenteric plexus and muscle, is a potentially valuable method for both diagnosis and advancement of our knowledge about the biological basis for these syndromes. However, until now access to the deeper layers of the GI tract has been limited, generally requiring invasive surgical techniques.

http://bit.ly/2RiEqdB

The optimal age for screening colonoscopy: a modeling study

Recent guidelines on colorectal cancer (CRC) screening recommend starting screening earlier than before. We performed a simulation study to examine and compare the optimal ages to have once-only screening colonoscopy and repeated colonoscopies.

http://bit.ly/2C9cZIN

Relationship between the expression of PD-1/PD-L1 and 18 F-FDG uptake in bladder cancer

Abstract

Purpose

Immunotherapy aimed at inhibiting the PD-1/PD-L1 immune checkpoint has been approved and used successfully for the treatment of bladder cancer. The identification of markers predictive of response to immune checkpoint inhibitors is critical to advancing the success of this therapy. 18F-FDG PET/CT is a molecular imaging technique that can provide phenotypic information on malignant tumours. It is currently unknown whether there is a relationship between 18F-FDG uptake and expression of PD-1/PD-L1 in bladder cancer. In this study, we investigated whether PD-1/PD-L1 expression is associated with 18F-FDG uptake in bladder cancer, and whether 18F-FDG PET/CT imaging can be used to predict the PD-1/PD-L1 status of bladder cancer.

Methods

A retrospective analysis was performed in 63 patients with bladder cancer who had undergone 18F-FDG PET/CT before surgical resection. Maximum standardized uptake values (SUVmax) were determined.

Results

SUVmax was significantly higher in PD-1-positive patients than in PD-1-negative patients (33.0 ± 13.9 and 19.6 ± 14.2, respectively; P = 0.032), and in PD-L1-positive patients than in PD-L1-negative patients (29.1 ± 15.6 and 15.8 ± 11.4, respectively; P < 0.0001). In a multivariate analysis SUVmax was significantly associated with both PD-1 expression and PD-L1 expression (P = 0.021 and P = 0.003, respectively). Using a SUVmax cut-off value of 22.7, PD-1 status and PD-L1 status could be predicted with accuracies of 71.4% and 77.8%, respectively.

Conclusion

Higher 18F-FDG uptake by bladder cancer is associated with elevated PD-1/PD-L1 expression. 18F-FDG PET/CT may be useful for predicting the PD-1/PD-L1 status of bladder cancer and for determining the optimal therapeutic strategy.



http://bit.ly/2FokAGv

Evaluation of Biomarkers in Glioma by Immunohistochemistry on Paraffin-Embedded 3D Glioma Neurosphere Cultures

Neurospheres grown as 3D cultures constitute a powerful tool to study glioma biology. Here we present a protocol to perform immunohistochemistry while maintaining the 3D structure of glioma neurospheres through paraffin embedding. This method enables the characterization of glioma neurosphere properties such as stemness and neural differentiation.

http://bit.ly/2LYOe6L

A Fluorogenic Peptide Cleavage Assay to Screen for Proteolytic Activity: Applications for coronavirus spike protein activation

We present a fluorogenic peptide cleavage assay that allows a rapid screening of the proteolytic activity of proteases on peptides representing the cleavage site of viral fusion peptides. This method can also be used on any other amino acid motif within a protein sequence to test for the protease activity.

http://bit.ly/2siBHlm

Context Shapes Choice of Healthy Foods

Given a choice between indulgent and healthy foods, what will most people pick? The answer may depend on what other foods sit nearby on the grocery shelf, suggests research published in Psychological Science, a journal of the Association for Psychological Science.

Paradoxically, the nearby presence of an indulgent treat can cause more people to opt for a healthy food, said study coauthor Scott Huettel, professor of psychology and neuroscience at Duke University. Context, in other words, affects food choices.

"When people choose foods, they don't simply reach into their memory and pick the most-preferred food. Instead, how much we prefer something actually depends on what other options are available," Huettel said.

"If you see one healthy food and one unhealthy food, most people will choose the indulgent food," he said. "But if you add more unhealthy foods, it seems, suddenly the healthy food stands out."

With obesity rates climbing, the authors wanted to examine factors that drive dietary choices. So they designed a study to look at how viewing indulgent sweet treats such as Snickers and Oreos affected the choice of healthier foods such as salmon or grapefruit.

They invited study participants — 79 young adults from the Durham-Chapel Hill area — to fast for 4 hours beforehand, so they arrived hungry.

First, study participants chose between indulgent foods (tasty but not healthy) and disciplined foods (healthy but not tasty). When given a simple one-to-one choice, say between canned salmon and Oreo cookies, nearly all subjects preferred the indulgent snack.

But researchers then took the same options and paired each with an indulgent food. For instance, participants saw salmon paired with Oreos, and Snickers paired with Oreos. Participants were told they had a 50 percent chance of getting either item in a pair.

When presented with that choice, participants were twice as likely to choose the pair that included a healthy option, such as salmon and Oreos.

One possible explanation involves attention. The healthy item — salmon, say — was the different item among the choices, so it stood out visually. Researchers tracked subjects' eye movements and found that subjects spent more time looking at salmon and other healthy foods when they were surrounded by indulgent treats.

The results could have implications for the nation's ongoing battle with obesity.

For instance, in many neighborhoods, healthy food is hard to come by. These "food deserts," where junk food and fast food abound while fresh produce and healthy protein sources are scarce, cover large areas of the country. Yet simply adding healthy choices, such as by adding a small produce section to a corner store, typically hasn't worked, said study coauthor Nicolette Sullivan, a postdoctoral associate in psychology at Duke.

The new research suggests part of the problem in that approach may be how food is displayed, Sullivan said.

"When people see a wall of cabbage and broccoli, that may not encourage people to choose it," Sullivan said.

"Right now, food items are very segregated: here's the produce, here are the candy bars," she said. "Yet maybe if we put something healthy in the middle of the snack food section, perhaps that might encourage people to choose it."

She hopes the research can guide new approaches to encouraging healthier diets.

"Individuals struggle with making healthy choices," Sullivan said. "if we can change the set of foods people are choosing between, people may make healthier choices. And that could have a profound impact."

All data and materials have been made publicly available via the Open Science Framework. This article has received the badges for Open Data and Open Materials.



http://bit.ly/2TDADUK

Effect of Neutropenic Diet on Infection Rates in Cancer Patients With Neutropenia: A Meta-analysis of Randomized Controlled Trials

Introduction: Neutropenic diets are commonly prescribed to cancer patients with neutropenia with the intention of reducing rates of infection. These diets are restrictive and are associated with lower patient satisfaction and possibly malnutrition. Further, it is unclear if these restrictive diets are effective in reducing infection. We performed a meta-analysis on the rates of infection reported in trials comparing the neutropenic diet to unrestricted diets in cancer patients with neutropenia. Methods and Materials: A comprehensive database search for all published randomized controlled trials comparing infection rates in cancer patients receiving a neutropenic diet versus an unrestricted diet was performed for all publications in English language from database's inception until September 12, 2017. The search strategy, study selection, and subsequent analysis adhered to PRISMA guidelines. Random effects modeling was used to obtain pooled relative risks. The primary outcome measure was the rate of infection. Results: Five randomized controlled trials with a total of 388 patients were included in the final analysis. Patients mostly had acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or sarcoma. Infection was noted in 53.7% patients in the neutropenic diet group, as compared with 50% in the unrestricted diet group. No significant difference in infection rate was observed between the neutropenic diet versus unrestricted diet groups, pooled risk ratio (RR) 1.13 (95% CI, 0.98-1.30; P=0.10). Conclusions: This meta-analysis of randomized controlled trials suggests that the use of neutropenic diet was not associated with decreased risk of infection in neutropenic cancer patients. The continued use of neutropenic diets should be questioned. S.B. and T.J.B. contributed equally. The authors declare no conflicts of interest. Reprints: Arjun Gupta, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 401 N Broadway, Baltimore, MD 21231. E-mail: guptaarjun90@gmail.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2VGdm6w

Multiplexed Fluorescent Immunohistochemical Staining, Imaging, and Analysis in Histological Samples of Lymphoma

Here we describe a protocol for multiplex fluorescent immunohistochemical staining and imaging for the simultaneous localization of multiple cancer-associated antigens in lymphoma. This protocol can be extended to the colocalization analysis of biomarkers within all tissue sections.

http://bit.ly/2Cbv9cS

Depression Tied to Worse Asthma Outcomes in Urban Teens

WEDNESDAY, Jan. 9, 2019 -- Depressive symptoms are prevalent among urban teens with asthma and are associated with worse outcomes, according to a study published online Dec. 19 in Academic Pediatrics. Michelle Shankar, from the University of...

http://bit.ly/2FjtPsy

IC Nicardipine Promising for Tx of Spontaneous Coronary Slow-Flow

WEDNESDAY, Jan. 9, 2019 -- Intracoronary (IC) administration of nicardipine seems to be highly effective in reversing spontaneous coronary slow-flow (CSF), according to a study published online Dec. 15 in the Journal of Invasive Cardiology. Hetal H....

http://bit.ly/2FqncUH

Many Female Health Care Workers Live in Poverty

WEDNESDAY, Jan. 9, 2019 -- Many U.S. female health care workers, particularly women of color, live in poverty and lack health insurance, according to a study published online Dec. 20 in the American Journal of Public Health. Kathryn E.W....

http://bit.ly/2FiUYMf

Increase in Brand-Name Drug Cost Mainly Due to Existing Drugs

WEDNESDAY, Jan. 9, 2019 -- The costs of oral and injectable brand-name drugs increased from 2008 to 2016, with most of the increase due to existing drugs, while new drugs accounted for cost increases in specialty and generic drugs, according to a...

http://bit.ly/2Flpu7g

Psychotherapy May Reduce Frequency of Nonepileptic Seizures

WEDNESDAY, Jan. 9, 2019 -- Adherence to psychotherapy is associated with improved outcomes in individuals with psychogenic nonepileptic seizures (PNES), according to a study published online Jan. 4 in Neurology. Benjamin Tolchin, M.D., from the Yale...

http://bit.ly/2FiA53S

Chemo-Radiation Combo Tied to Higher Survival in Peds Hodgkin

WEDNESDAY, Jan. 9, 2019 -- Combined modality treatment (CMT) is associated with improved overall survival in pediatric patients with early-stage Hodgkin lymphoma (HL), according to a study published online Jan. 3 in JAMA Oncology. Sachin R. Jhawar,...

http://bit.ly/2FiAnYw

Nine Cases of Wound Botulism ID'd in Injection Drug Users

WEDNESDAY, Jan. 9, 2019 -- Among persons who inject drugs, nine cases of wound botulism were identified in Southern California from September 2017 to April 2018, according to research published in the Jan. 4 issue of the U.S. Centers for Disease...

http://bit.ly/2FjJAyW

Nursing Intervention Promotes Better Sleep for Inpatients

WEDNESDAY, Jan. 9, 2019 -- A Sleep for Inpatients: Empowering Staff to Act (SIESTA) intervention can improve patient sleep with fewer nighttime room entries, according to a study published in the January issue of the Journal of Hospital...

http://bit.ly/2FgYff4

No Increased Fall Risk With HTN Treatment in Older Women

WEDNESDAY, Jan. 9, 2019 -- Treating high blood pressure (BP) is not associated with an increased fall risk among older women, according to a study published online Jan. 7 in the Journal of the American Geriatrics Society. Karen L. Margolis, M.D.,...

http://bit.ly/2Fmtbts

Immunotherapy Effective in Alveolar Soft Part Sarcoma

People with advanced alveolar soft part sarcoma (ASPS), a rare cancer, appear to benefit from a type of immunotherapy called an immune checkpoint inhibitor, according to results from a small clinical trial.



http://bit.ly/2H1RRdm

Dynamin 1 Restrains Vesicular Release to a Subquantal Mode In Mammalian Adrenal Chromaffin Cells

Dynamin 1 (dyn1) is required for clathrin-mediated endocytosis in most secretory (neuronal and neuroendocrine) cells. There are two modes of Ca2+-dependent catecholamine release from single dense-core vesicles: full-quantal (quantal) and subquantal in adrenal chromaffin cells, but their relative occurrences and impacts on total secretion remain unclear. To address this fundamental question in neurotransmission area using both sexes of animals, here we report the following: (1) dyn1-KO increased quantal size (QS, but not vesicle size/content) by ≥250% in dyn1-KO mice; (2) the KO-increased QS was rescued by dyn1 (but not its deficient mutant or dyn2); (3) the ratio of quantal versus subquantal events was increased by KO; (4) following a release event, more protein contents were retained in WT versus KO vesicles; and (5) the fusion pore size (dp) was increased from ≤9 to ≥9 nm by KO. Therefore, Ca2+-induced exocytosis is generally a subquantal release in sympathetic adrenal chromaffin cells, implying that neurotransmitter release is generally regulated by dynamin in neuronal cells.

SIGNIFICANCE STATEMENT Ca2+-dependent neurotransmitter release from a single vesicle is the primary event in all neurotransmission, including synaptic/neuroendocrine forms. To determine whether Ca2+-dependent vesicular neurotransmitter release is "all-or-none" (quantal), we provide compelling evidence that most Ca2+-induced secretory events occur via the subquantal mode in native adrenal chromaffin cells. This subquantal release mode is promoted by dynamin 1, which is universally required for most secretory cells, including neurons and neuroendocrine cells. The present work with dyn1-KO mice further confirms that Ca2+-dependent transmitter release is mainly via subquantal mode, suggesting that subquantal release could be also important in other types of cells.



http://bit.ly/2TGsVtk

Apo-Opsin Exists in Equilibrium Between a Predominant Inactive and a Rare Highly Active State

Bleaching adaptation in rod photoreceptors is mediated by apo-opsin, which activates phototransduction with effective activity 105- to 106-fold lower than that of photoactivated rhodopsin (meta II). However, the mechanism that produces such low opsin activity is unknown. To address this question, we sought to record single opsin responses in mouse rods. We used mutant mice lacking efficient calcium feedback to boosts rod responses and generated a small fraction of opsin by photobleaching ~1% of rhodopsin. The bleach produced a dramatic increase in the frequency of discrete photoresponse-like events. This activity persisted for hours, was quenched by 11-cis-retinal, and was blocked by uncoupling opsin from phototransduction, all indicating opsin as its source. Opsin-driven discrete activity was also observed in rods containing non-activatable rhodopsin, ruling out transactivation of rhodopsin by opsin. We conclude that bleaching adaptation is mediated by opsin that exists in equilibrium between a predominant inactive and a rare meta II-like state.

SIGNIFICANCE STATEMENT Electrophysiological analysis is used to show that the G-protein-coupled receptor opsin exists in equilibrium between a predominant inactive and a rare highly active state that mediates bleaching adaptation in photoreceptors.



http://bit.ly/2CYJRpt

Auditory Thalamostriatal and Corticostriatal Pathways Convey Complementary Information about Sound Features

Multiple parallel neural pathways link sound-related signals to behavioral responses. For instance, the striatum, a brain structure involved in action selection and reward-related learning, receives neuronal projections from both the auditory thalamus and auditory cortex. It is not clear whether sound information that reaches the striatum through these two pathways is redundant or complementary. We used an optogenetic approach in awake mice of both sexes to identify thalamostriatal and corticostriatal neurons during extracellular recordings, and characterized neural responses evoked by sounds of different frequencies and amplitude modulation rates. We found that neurons in both pathways encode sound frequency with similar fidelity, but display different coding strategies for amplitude modulated noise. Whereas corticostriatal neurons provide a more accurate representation of amplitude modulation rate in their overall firing rate, thalamostriatal neurons convey information about the precise timing of acoustic events. These results demonstrate that auditory thalamus and auditory cortex neurons provide complementary information to the striatum, and suggest that these pathways could be differentially recruited depending on the requirements of a sound-driven behavior.

SIGNIFICANCE STATEMENT Sensory signals from the cerebral cortex and the thalamus converge onto the striatum, a nucleus implicated in reward-related learning. It is not clear whether these two sensory inputs convey redundant or complementary information. By characterizing the sound-evoked responses of thalamostriatal and corticostriatal neurons, our work demonstrates that these neural pathways convey complementary information about the temporal features of sounds. This work opens new avenues for investigating how these pathways could be selectively recruited depending on task demands, and provides a framework for studying convergence of cortical and thalamic information onto the striatum in other sensory systems.



http://bit.ly/2D08cuS

Layer 3 Dynamically Coordinates Columnar Activity According to Spatial Context

To reduce statistical redundancy of natural inputs and increase the sparseness of coding, neurons in primary visual cortex (V1) show tuning for stimulus size and surround suppression. This integration of spatial information is a fundamental, context-dependent neural operation involving extensive neural circuits that span across all cortical layers of a V1 column, and reflects both feedforward and feedback processing. However, how spatial integration is dynamically coordinated across cortical layers remains poorly understood. We recorded single- and multiunit activity and local field potentials across V1 layers of awake mice (both sexes) while they viewed stimuli of varying size and used dynamic Bayesian model comparisons to identify when laminar activity and interlaminar functional interactions showed surround suppression, the hallmark of spatial integration. We found that surround suppression is strongest in layer 3 (L3) and L4 activity, where suppression is established within ~10 ms after response onset, and receptive fields dynamically sharpen while suppression strength increases. Importantly, we also found that specific directed functional connections were strongest for intermediate stimulus sizes and suppressed for larger ones, particularly for connections from L3 targeting L5 and L1. Together, the results shed light on the different functional roles of cortical layers in spatial integration and on how L3 dynamically coordinates activity across a cortical column depending on spatial context.

SIGNIFICANCE STATEMENT Neurons in primary visual cortex (V1) show tuning for stimulus size, where responses to stimuli exceeding the receptive field can be suppressed (surround suppression). We demonstrate that functional connectivity between V1 layers can also have a surround-suppressed profile. A particularly prominent role seems to have layer 3, the functional connections to layers 5 and 1 of which are strongest for stimuli of optimal size and decreased for large stimuli. Our results therefore point toward a key role of layer 3 in coordinating activity across the cortical column according to spatial context.



http://bit.ly/2TDkE9y

Thalamocortical and Intracortical Inputs Differentiate Layer-Specific Mouse Auditory Corticocollicular Neurons

Long-range descending projections from the auditory cortex play key roles in shaping response properties in the inferior colliculus. The auditory corticocollicular projection is massive and heterogeneous, with axons emanating from cortical layers 5 and 6, and plays a key role in directing plastic changes in the inferior colliculus. However, little is known about the cortical and thalamic networks within which corticocollicular neurons are embedded. Here, laser scanning photostimulation glutamate uncaging and photoactivation of channelrhodopsin-2 were used to probe the local and long-range network differences between preidentified layer 5 and layer 6 auditory corticocollicular neurons from male and female mice in vitro. Layer 5 corticocollicular neurons were found to vertically integrate supragranular excitatory and inhibitory input to a substantially greater degree than their layer 6 counterparts. In addition, all layer 5 corticocollicular neurons received direct and large thalamic inputs from channelrhodopsin-2-labeled thalamocortical fibers, whereas such inputs were less common in layer 6 corticocollicular neurons. Finally, a new low-calcium/synaptic blockade approach to separate direct from indirect inputs using laser photostimulation was validated. These data demonstrate that layer 5 and 6 corticocollicular neurons receive distinct sets of cortical and thalamic inputs, supporting the hypothesis that they have divergent roles in modulating the inferior colliculus. Furthermore, the direct connection between the auditory thalamus and layer 5 corticocollicular neurons reveals a novel and rapid link connecting ascending and descending pathways.

SIGNIFICANCE STATEMENT Descending projections from the cortex play a critical role in shaping the response properties of sensory neurons. The projection from the auditory cortex to the inferior colliculus is a massive, yet poorly understood, pathway emanating from two distinct cortical layers. Here we show, using a range of optical techniques, that mouse auditory corticocollicular neurons from different layers are embedded into different cortical and thalamic networks. Specifically, we observed that layer 5 corticocollicular neurons integrate information across cortical lamina and receive direct thalamic input. The latter connection provides a hyperdirect link between acoustic sensation and descending control, thus demonstrating a novel mechanism for rapid "online" modulation of sensory perception.



http://bit.ly/2TByZTJ

Determining the Safety and Efficacy of Enhanced Recovery Protocols in Major Oncologic Surgery: An Institutional NSQIP Analysis

Abstract

Background

Enhanced-recovery (ER) protocols are increasingly being utilized in surgical practice. Outside of colorectal surgery, however, their feasibility, safety, and efficacy in major oncologic surgery have not been proven. This study compared patient outcomes before and after multispecialty implementation of ER protocols at a large, comprehensive cancer center.

Methods

Surgical cases performed from 2011 to 2016 and captured by an institutional NSQIP database were reviewed. Following exclusion of outpatient and emergent surgeries, 2747 cases were included in the analyses. Cases were stratified by presence or absence of ER compliance, defined by preoperative patient education and electronic medical record order set-driven opioid-sparing analgesia, goal-directed fluid therapy, and early postoperative diet advancement and ambulation.

Results

Approximately half of patients were treated on ER protocols (46%) and the remaining on traditional postoperative (TP) protocols (54%). Treatment on an ER protocol was associated with decreased overall complication rates (20% vs. 33%, p < 0.0001), severe complication rates (7.4% vs. 10%, p = 0.010), and median hospital length of stay (4 vs. 5 days, p < 0.0001). There was no change in readmission rates (ER vs. TP, 8.6% vs. 9.0%, p = 0.701). Subanalyses of high magnitude cases and specialty-specific outcomes consistently demonstrated improved outcomes with ER protocol adherence, including decreased opioid use.

Conclusions

This assessment of a large-scale ER implementation in multispecialty major oncologic surgery indicates its feasibility, safety, and efficacy. Future efforts should be directed toward defining the long-term oncologic benefits of these protocols.



http://bit.ly/2Fi0vm3

A Precise and Autonomous System for the Detection of Insect Emergence Patterns

58362fig1.jpg

Measurement of insect emergence patterns requires precision. Existing systems are only semi-automated and sample size is limited. We addressed these issues by designing a system using microcontrollers to precisely measure the time of emergence of large numbers of emerging insects.

http://bit.ly/2SJOLMd

Cochlear Implant Surgery and Electrically-evoked Auditory Brainstem Response Recordings in C57BL/6 Mice

Animal models of cochlear implants can advance knowledge of the technological bases of treating permanent sensorineural hearing loss with electrical stimulation. This study presents a surgical protocol for acute deafening and cochlear implantation of an electrode array in mice as well as the functional assessment with auditory brainstem response.

http://bit.ly/2ABdADa

Artificial intelligence and colonoscopy: current status and future perspectives

Abstract

Objective

Application of artificial intelligence in medicine is now attracting substantial attention. In the field of gastrointestinal endoscopy, computer‐aided diagnosis for colonoscopy is the most investigated area, although it is still in the pre‐clinical phase. Because colonoscopy is performed by humans, it is inherently an imperfect procedure. Computer‐aided diagnosis assistance is expected to improve its quality regarding automated polyp detection and characterization (i.e., predicting the polyp's pathology). It could help prevent endoscopists from missing polyps as well as provide a precise optical diagnosis for those detected. Ultimately, these functions that computer‐aided diagnosis provides could produce a higher adenoma detection rate and reduce the cost of polypectomy for hyperplastic polyps.

Methods and Results

Currently, research on automated polyp detection has been limited to experimental assessments using an algorithm based on ex vivo videos or static images. The performance for clinical use was reported to have >90% sensitivity with acceptable specificity. In contrast, the research on automated polyp characterization seems to surpass that for polyp detection. Prospective studies of in vivo use of artificial intelligence technologies have been reported by several groups, some of which showed a >90% negative predictive value for differentiating diminutive (≤5 mm) rectosigmoid adenomas, which exceeded the threshold for optical biopsy.

Conclusion

We introduce the potential of using computer‐aided diagnosis for colonoscopy and describe the most recent conditions for regulatory approval for artificial intelligence‐assisted medical devices.

This article is protected by copyright. All rights reserved.



http://bit.ly/2AFZSyK

Endoscopic full‐thickness resection of a colonic Schwannoma

Abstract

We report the case of a 61‐year‐old female with a submucosal tumor (SMT) located in the proximal transverse colon, incidentally diagnosed on screening colonoscopy. Contrast‐enhanced abdominopelvic computed tomography showed a well‐circumscribed hyperenhancing mass with 20 mm, compatible with a gastrointestinal stromal tumor.

On repeat colonoscopy (Olympus®), after submucosal injection of indigo carmine and saline, a semi‐circumferential incision was performed using the HookKnife (Olympus®).

This article is protected by copyright. All rights reserved.



http://bit.ly/2SL1v5v

Long‐term follow‐up of gastric squamous metaplasia

Abstract

A man in his eighties underwent surveillance esophagogastroduodenoscopy after curative endoscopic submucosal dissection for early gastric cancer in the lesser curvature of gastric angle. Endoscopy showed atrophic gastritis (the serum antibody of H. pylori was positive) and an 8 mm, whitish slightly depressed lesion at the posterior wall of the gastric antrum (Fig. 1). This lesion, which was identified six years earlier during an endoscopic submucosal dissection, had not changed in size and morphology during this period.

This article is protected by copyright. All rights reserved.



http://bit.ly/2VJ8TAj

Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer

Ann Oncol 2014; 25: 592–598 (doi: 10.1093/annonc/mdt543)

http://bit.ly/2H2Su6j

Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors

Ann Oncol 2012; 23: 463–471 (doi: 10.1093/annonc/mdr137)

http://bit.ly/2RC7k7U

Adverse events risk associated with bevacizumab addition to breast cancer chemotherapy: a meta-analysis

Ann Oncol 2012; 23: 1130–1137 (doi: 10.1093/annonc/mdr432)

http://bit.ly/2H2SseH

De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017

Ann Oncol 2017; 28: 1700–1712 (doi: 10.1093/annonc/mdx308)

http://bit.ly/2RJEUZw

Pathway level alterations rather than mutations in single genes predict response to HER2-targeted therapies in the neo-ALTTO trial

Ann Oncol 2017; 28: 128–135 (doi: 10.1093/annonc/mdw434)

http://bit.ly/2H2SqDB

Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab

Ann Oncol 2012; 23: 791–800 (doi: 10.1093/annonc/mdr294)

http://bit.ly/2RFECD3

Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab

Ann Oncol 2017; 28: 761–768 (doi: 10.1093/annonc/mdw695)

http://bit.ly/2H1bWQH

PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab

Ann Oncol 2016; 27: 1519–1528 (doi: 10.1093/annonc/mdw197)

http://bit.ly/2RDeHfi

Impact of lapatinib plus trastuzumab versus single-agent lapatinib on quality of life of patients with trastuzumab-refractory HER2+ metastatic breast cancer

Ann Oncol 2011; 22: 2582–2590 (doi: 10.1093/annonc/mdr014)

http://bit.ly/2H2SmUn

Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors

Ann Oncol 2012; 23: 897–902 (doi: 10.1093/annonc/mdr348)

http://bit.ly/2RGr7TF

Evaluation of the Feasibility, Safety, and Accuracy of an Intraoperative High-intensity Focused Ultrasound Device for Treating Liver Metastases

Here, we present an ablate-and-resect prospective study to evaluate the feasibility, safety, and accuracy of intraoperative high-intensity focused ultrasound ablation in patients undergoing hepatectomy for liver metastases.

http://bit.ly/2CdkdM5

SPP1 inhibition improves the cisplatin chemo-sensitivity of cervical cancer cell lines

Abstract

Purpose

Cisplatin (DDP)-based chemotherapy is a standard strategy for cervical cancer, while chemoresistance remains a huge challenge. In the present study, we aimed to explore the effects of SPP1 on the proliferation and apoptosis rate of the HeLa cervical cancer cell line with cisplatin (DDP) resistance.

Methods

Microarray analysis was employed to select differentially expressed genes in cervical cancer tissues and adjacent tissues. Then, we established a DDP-resistant HeLa cell line (res-HeLa). Western blotting was used to detect SPP1 expression in both tissue and cells. After the transfection with si-SPP1 and pcDNA3.1-SPP1, colony formation and MTT assays were applied to detect cell proliferation changes. Flow cytometry was employed to detect the cell apoptosis rate. Western blotting was performed to verify the activation of PI3K/Akt signal pathway proteins related to DDP resistance.

Results

SPP1 was overexpressed in cervical cancer tissues and cell lines. Compared to normal HeLa cells, expression of SPP1 was significantly enhanced in res-HeLa cells. SPP1 knockdown resulted in repressed proliferation and enhanced apoptosis of res-HeLa cells, which could be reversed by SPP1 overexpression in HeLa cells. Additionally, downregulation of SPP1 improved the DDP sensitivity of HeLa by inhibiting the PI3K/Akt signaling pathway.

Conclusion

SPP1 inhibition could suppress proliferation, induce apoptosis and increase the DDP chemo-sensitivity of HeLa cells.



http://bit.ly/2TDqLua

Downregulation of genes outside the deleted region in individuals with 22q11.2 deletion syndrome

Abstract

The 22q11.2 deletion syndrome (22q11.2DS) is caused by recurrent hemizygous deletions of chromosome 22q11.2. The phenotype of the syndrome is complex and varies widely among individuals. Little is known about the role of the different genes located in 22q11.2, and we hypothesized that genetic risk factors lying elsewhere in the genome might contribute to the phenotype. Here, we present the whole-genome gene expression data of 11 patients with approximately 3 Mb deletions. Apart from the hemizygous genes mapped to the 22q11.2 region, the TUBA8 and GNAZ genes, neighboring the deleted interval but in normal copy number, showed altered expression. When genes mapped to other chromosomes were considered in the gene expression analysis, a genome-wide dysregulation was observed, with increased or decreased expression levels. The enriched pathways of these genes were related to immune response, a deficiency that is frequently observed in 22q11.2DS patients. We also used the hypothesis-free weighted gene co-expression network analysis (WGCNA), which revealed the co-expression gene network modules with clear connection to mechanisms associated with 22q11.2DS such as immune response and schizophrenia. These findings, combined with the traditional gene expression profile, can be used for the identification of potential pathways and genes not previously considered to be related to the 22q11.2 deletion syndrome.



http://bit.ly/2FhYVAG

The Transcriptional Regulator Hbx1 Affects the Expression of Thousands of Genes in the Aflatoxin-Producing Fungus Aspergillus flavus

In filamentous fungi, homeobox proteins are conserved transcriptional regulators described to control conidiogenesis and fruiting body formation. Eight homeobox (hbx) genes are found in the genome of the aflatoxin-producing ascomycete, Aspergillus flavus. While loss-of-function of seven of the eight genes had little to no effect on fungal growth and development, disruption of hbx1, resulted in aconidial colonies and lack of sclerotial production. Furthermore, the hbx1 mutant was unable to produce aflatoxins B1 and B2, cyclopiazonic acid and aflatrem. In the present study, hbx1 transcriptome analysis revealed that hbx1 has a broad effect on A. flavus gene expression, and the effect of hbx1 increases overtime, impacting more than five thousand protein-coding genes. Among the affected genes, those in the category of secondary metabolism (SM), followed by that of cellular transport, were the most affected. Specifically, regarding the effect of hbx1 on SM, we found that genes in 44 SM gene clusters where upregulated while 49 were downregulated in the absence of hbx1, including genes in the SM clusters responsible for the synthesis of asparasone, piperazine and aflavarin, all known to be associated with sclerotia. In addition, our study revealed that hbx1 affects the expression of other transcription factor genes involved in development, including the conidiation central regulatory pathway and flb genes.



http://bit.ly/2FgXBOx

OCMA: Fast, Memory-Efficient Factorization of Prohibitively Large Relationship Matrices

Matrices representing genetic relatedness among individuals (i.e., Genomic Relationship Matrices, GRMs) play a central role in genetic analysis. The eigen-decomposition of GRMs (or its alternative that generates fewer top singular values using genotype matrices) is a necessary step for many analyses including estimation of SNP-heritability, Principal Component Analysis (PCA), and genomic prediction. However, the GRMs and genotype matrices provided by modern biobanks are too large to be stored in active memory. To accommodate the current and future "bigger-data", we develop a disk-based tool, Out-of-Core Matrices Analyzer (OCMA), using state-of-the-art computational techniques that can nimbly perform eigen and Singular Value Decomposition (SVD) analyses. By integrating memory mapping (mmap) and the latest matrix factorization libraries, our tool is fast and memory-efficient. To demonstrate the impressive performance of OCMA, we test it on a personal computer. For full eigen-decomposition, it solves an ordinary GRM (N = 10,000) in 55 sec. For SVD, a commonly used faster alternative of full eigen-decomposition in genomic analyses, OCMA solves the top 200 singular values (SVs) in half an hour, top 2,000 SVs in 0.95 hr, and all 5,000 SVs in 1.77 hr based on a very large genotype matrix (N = 1,000,000, M = 5,000) on the same personal computer. OCMA also supports multi-threading when running in a desktop or HPC cluster. Our OCMA tool can thus alleviate the computing bottleneck of classical analyses on large genomic matrices, and make it possible to scale up current and emerging analytical methods to big genomics data using lightweight computing resources.



http://bit.ly/2FmNjeX

Suppressor Analysis Uncovers That MAPs and Microtubule Dynamics Balance with the Cut7/Kinesin-5 Motor for Mitotic Spindle Assembly in Schizosaccharomyces pombe

The Kinesin-5 motor Cut7 in Schizosaccharomyces pombe plays essential roles in spindle pole separation, leading to the assembly of bipolar spindle. In many organisms, simultaneous inactivation of Kinesin-14s neutralizes Kinesin-5 deficiency. To uncover the molecular network that counteracts Kinesin-5, we have conducted a genetic screening for suppressors that rescue the cut7-22 temperature sensitive mutation, and identified 10 loci. Next generation sequencing analysis reveals that causative mutations are mapped in genes encoding α-, β-tubulins and the microtubule plus-end tracking protein Mal3/EB1, in addition to the components of the Pkl1/Kinesin-14 complex. Moreover, the deletion of various genes required for microtubule nucleation/polymerization also suppresses the cut7 mutant. Intriguingly, Klp2/Kinesin-14 levels on the spindles are significantly increased in cut7 mutants, whereas these increases are negated by suppressors, which may explain the suppression by these mutations/deletions. Consistent with this notion, mild overproduction of Klp2 in these double mutant cells confers temperature sensitivity. Surprisingly, treatment with a microtubule-destabilizing drug not only suppresses cut7 temperature sensitivity but also rescues the lethality resulting from the deletion of cut7, though a single klp2 deletion per se cannot compensate for the loss of Cut7. We propose that microtubule assembly and/or dynamics antagonize Cut7 functions, and that the orchestration between these two factors is crucial for bipolar spindle assembly.



http://bit.ly/2FgF0Cn

Deciphering Hybrid Larch Reaction Norms Using Random Regression

The link between phenotypic plasticity and heterosis is a broad fundamental question, with stakes in breeding. We report a case-study evaluating temporal series of wood ring traits of hybrid larch (Larix decidua x L. kaempferi and reciprocal) in relation to soil water availability. Growth rings record the tree plastic responses to past environmental conditions, and we used random regressions to estimate the reaction norms of ring width and wood density with respect to water availability. We investigated the role of phenotypic plasticity on the construction of hybrid larch heterosis and on the expression of its quantitative genetic parameters. The data came from an intra-/interspecific diallel mating design between both parental species. Progenies were grown in two environmentally contrasted sites, in France. Ring width plasticity with respect to water availability was confirmed, as all three taxa produced narrower rings under the lowest water availability. Hybrid larch appeared to be the most plastic taxon as its superiority over its parental species increased with increasing water availability. Despite the low heritabilities of the investigated traits, we found that the expression of a reliable negative correlation between them was conditional to the water availability environment. Finally, by means of a complementary simulation, we demonstrated that random regression can be applied to model the reaction norms of non-repeated records of phenotypic plasticity bound by a family structure. Random regression is a powerful tool for the modeling of reaction norms in various contexts, especially perennial species.



http://bit.ly/2FiQ9lj

Medaka Population Genome Structure and Demographic History Described via Genotyping-by-Sequencing

Medaka is a model organism in medicine, genetics, developmental biology and population genetics. Lab stocks composed of more than 100 local wild populations are available for research in these fields. Thus, medaka represents a potentially excellent bioresource for screening disease-risk- and adaptation-related genes in genome-wide association studies. Although the genetic population structure should be known before performing such an analysis, a comprehensive study on the genome-wide diversity of wild medaka populations has not been performed. Here, we performed genotyping-by-sequencing (GBS) for 81 and 12 medakas captured from a bioresource and the wild, respectively. Based on the GBS data, we evaluated the genetic population structure and estimated the demographic parameters using an approximate Bayesian computation (ABC) framework. The genome-wide data confirmed that there were substantial differences between local populations and supported our previously proposed hypothesis on medaka dispersal based on mitochondrial genome (mtDNA) data. A new finding was that a local group that was thought to be a hybrid between the northern and the southern Japanese groups was actually an origin of the northern Japanese group. Thus, this paper presents the first population-genomic study of medaka and reveals its population structure and history based on chromosomal genetic diversity.



http://bit.ly/2FkVYzo

The Regulation of Cbf1 by PAS Kinase Is a Pivotal Control Point for Lipogenesis vs. Respiration in Saccharomyces cerevisiae

PAS kinase 1 (Psk1) is a key regulator of respiration in Saccharomyces cerevisiae. Herein the molecular mechanisms of this regulation are explored through the characterization of its substrate, Centromere binding factor 1 (Cbf1). CBF1-deficient yeast displayed a significant decrease in cellular respiration, while PAS kinase-deficient yeast, or yeast harboring a Cbf1 phosphosite mutant (T211A) displayed a significant increase. Transmission electron micrographs showed an increased number of mitochondria in PAS kinase-deficient yeast consistent with the increase in respiration. Although the CBF1-deficient yeast did not appear to have an altered number of mitochondria, a mitochondrial proteomics study revealed significant differences in the mitochondrial composition of CBF1-deficient yeast including altered Atp3 levels, a subunit of the mitochondrial F1-ATP synthase complex. Both beta-galactosidase reporter assays and western blot analysis confirmed direct transcriptional control of ATP3 by Cbf1. In addition, we confirmed the regulation of yeast lipid genes LAC1 and LAG1 by Cbf1. The human homolog of Cbf1, Upstream transcription factor 1 (USF1), is also known to be involved in lipid biogenesis. Herein, we provide the first evidence for a role of USF1 in respiration since it appeared to complement Cbf1in vivo as determined by respiration phenotypes. In addition, we confirmed USF1 as a substrate of human PAS kinase (hPASK) in vitro. Combined, our data supports a model in which Cbf1/USF1 functions to partition glucose toward respiration and away from lipid biogenesis, while PAS kinase inhibits respiration in part through the inhibition of Cbf1/USF1.



http://bit.ly/2FkAUYZ

Dosage Compensation and Gene Expression of the X Chromosome in Sheep

Ohno's hypothesis predicts that the expression of the single X chromosome in males needs compensatory upregulation to balance its dosage with that of the diploid autosomes. Additionally, X chromosome inactivation ensures that quadruple expression of the two X chromosomes is avoided in females. These mechanisms have been actively studied in mice and humans but lag behind in domestic species. Using RNA sequencing data, we analyzed the X chromosome upregulation in sheep fetal tissues from day 135 of gestation under control, over or restricted maternal diets (100%, 140% and 60% of National Research Council Total Digestible Nutrients), and in conceptuses, juvenile, and adult somatic tissues. By computing the mean expression ratio of all X-linked genes to all autosomal genes (X:A), we found that all samples displayed some levels of X chromosome upregulation. The degrees of X upregulation were not significant (P-value = 0.74) between ovine females and males in the same somatic tissues. Brain, however, displayed complete X upregulation. Interestingly, the male and female reproduction-related tissues exhibited divergent X dosage upregulation. Moreover, expression upregulation of the X chromosome in fetal tissues was not affected by maternal diets. Maternal nutrition, however, did change expression levels of several X-linked genes, such as sex determination genes SOX3 and NR0B1. In summary, our results showed that X chromosome upregulation occurred in nearly all sheep somatic tissues analyzed, thus support Ohno's hypothesis in a new species. However, the levels of upregulation differed by different subgroups of genes such as those that are house-keeping and "dosage-sensitive".



http://bit.ly/2FhYbLU

A Gene Expression Screen in Drosophila melanogaster Identifies Novel JAK/STAT and EGFR Targets During Oogenesis

The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) and epidermal growth factor receptor (EGFR) signaling pathways are conserved regulators of tissue patterning, morphogenesis, and other cell biological processes. During Drosophila oogenesis, these pathways determine the fates of epithelial follicle cells (FCs). JAK/STAT and EGFR together specify a population of cells called the posterior follicle cells (PFCs), which signal to the oocyte to establish the embryonic axes. In this study, whole genome expression analysis was performed to identify genes activated by JAK/STAT and/or EGFR. We observed that 317 genes were transcriptionally upregulated in egg chambers with ectopic JAK/STAT and EGFR activity in the FCs. The list was enriched for genes encoding extracellular matrix (ECM) components and ECM-associated proteins. We tested 69 candidates for a role in axis establishment using RNAi knockdown in the FCs. We report that the signaling protein Semaphorin 1b becomes enriched in the PFCs in response to JAK/STAT and EGFR. We also identified ADAM metallopeptidase with thrombospondin type 1 motif A (AdamTS-A) as a novel target of JAK/STAT in the FCs that regulates egg chamber shape. AdamTS-A mRNA becomes enriched at the anterior and posterior poles of the egg chamber at stages 6 to 7 and is regulated by JAK/STAT. Altering AdamTS-A expression in the poles or middle of the egg chamber produces rounder egg chambers. We propose that AdamTS-A regulates egg shape by remodeling the basement membrane.



http://bit.ly/2FkAIcd

Using Maize Chromosome Segment Substitution Line Populations for the Identification of Loci Associated with Multiple Disease Resistance

Southern Leaf Blight (SLB), Northern Leaf Blight (NLB), and Gray Leaf Spot (GLS) caused by Cochliobolus heterostrophus, Setosphaeria turcica, and Cercospora zeae-maydis respectively, are among the most important diseases of corn worldwide. Previously, moderately high and significantly positive genetic correlations between resistance levels to each of these diseases were identified in a panel of 253 diverse maize inbred lines. The goal of this study was to identify loci underlying disease resistance in some of the most multiple disease resistant (MDR) lines by the creation of chromosome segment substitution line (CSSL) populations in multiple disease susceptible (MDS) backgrounds. Four MDR lines (NC304, NC344, Ki3, NC262) were used as donor parents and two MDS lines (Oh7B, H100) were used as recurrent parents to produce eight BC3F4:5 CSSL populations comprising 1,611 lines in total. Each population was genotyped and assessed for each disease in replicated trials in two environments. Moderate to high heritabilities on an entry mean basis were observed (0.32 to 0.83). Several lines in each population were significantly more resistant than the MDS parental lines for each disease. Multiple quantitative trait loci (QTL) for disease resistance were detected for each disease in most of the populations. Seventeen QTL were associated with variation in resistance to more than one disease (SLB/NLB: 2; SLB/GLS: 7; NLB/GLS: 2 and 6 to all three diseases). For most populations and most disease combinations, significant correlations were observed between disease scores and also between marker effects for each disease. The number of lines that were resistant to more than one disease was significantly higher than would be expected by chance. Using the results from individual QTL analyses, a composite statistic based on Mahalanobis distance (Md) was used to identify joint marker associations with multiple diseases. Across all populations and diseases, 246 markers had significant Md values. However further analysis revealed that most of these associations were due to strong QTL effects on a single disease. Together, these findings reinforce our previous conclusions that loci associated with resistance to different diseases are clustered in the genome more often than would be expected by chance. Nevertheless true MDR loci which have significant effects on more than one disease are still much rarer than loci with single disease effects.



http://bit.ly/2Fj3FpD

Fitness and Genomic Consequences of Chronic Exposure to Low Levels of Copper and Nickel in Daphnia pulex Mutation Accumulation Lines

In at least some unicellular organisms, mutation rates are temporarily raised upon exposure to environmental stress, potentially contributing to the evolutionary response to stress. Whether this is true for multicellular organisms, however, has received little attention. This study investigated the effects of chronic mild stress, in the form of low-level copper and nickel exposure, on mutational processes in Daphnia pulex using a combination of mutation accumulation, whole genome sequencing and life-history assays. After over 100 generations of mutation accumulation, we found no effects of metal exposure on the rates of single nucleotide mutations and of loss of heterozygosity events, the two mutation classes that occurred in sufficient numbers to allow statistical analysis. Similarly, rates of decline in fitness, as measured by intrinsic rate of population increase and of body size at first reproduction, were negligibly affected by metal exposure. We can reject the possibility that Daphnia were insufficiently stressed to invoke genetic responses as we have previously shown rates of large-scale deletions and duplications are elevated under metal exposure in this experiment. Overall, the mutation accumulation lines did not significantly depart from initial values for phenotypic traits measured, indicating the lineage used was broadly mutationally robust. Taken together, these results indicate that the mutagenic effects of chronic low-level exposure to these metals are restricted to certain mutation classes and that fitness consequences are likely minor and therefore unlikely to be relevant in determining the evolutionary responses of populations exposed to these stressors.



http://bit.ly/2FmNgQj

Perturbations of Transcription and Gene Expression-Associated Processes Alter Distribution of Cell Size Values in Saccharomyces cerevisiae

The question of what determines whether cells are big or small has been the focus of many studies because it is thought that such determinants underpin the coupling of cell growth with cell division. In contrast, what determines the overall pattern of how cell size is distributed within a population of wild type or mutant cells has received little attention. Knowing how cell size varies around a characteristic pattern could shed light on the processes that generate such a pattern and provide a criterion to identify its genetic basis. Here, we show that cell size values of wild type Saccharomyces cerevisiae cells fit a gamma distribution, in haploid and diploid cells, and under different growth conditions. To identify genes that influence this pattern, we analyzed the cell size distributions of all single-gene deletion strains in Saccharomyces cerevisiae. We found that yeast strains which deviate the most from the gamma distribution are enriched for those lacking gene products functioning in gene expression, especially those in transcription or transcription-linked processes. We also show that cell size is increased in mutants carrying altered activity substitutions in Rpo21p/Rpb1, the largest subunit of RNA polymerase II (Pol II). Lastly, the size distribution of cells carrying extreme altered activity Pol II substitutions deviated from the expected gamma distribution. Our results are consistent with the idea that genetic defects in widely acting transcription factors or Pol II itself compromise both cell size homeostasis and how the size of individual cells is distributed in a population.



http://bit.ly/2FkKSur

High Efficiency Targeting of Non-coding Sequences Using CRISPR/Cas9 System in Tilapia

The CRISPR/Cas9 has been successfully applied for disruption of protein coding sequences in a variety of organisms. The majority of the animal genome is actually non-coding sequences, which are key regulators associated with various biological processes. In this study, to understand the biological significance of these sequences, we used one or dual gRNA guided Cas9 nuclease to achieve specific deletion of non-coding sequences including microRNA and 3' untranslated region (UTR) in tilapia, which is an important fish for studying sex determination and evolution. Co-injection of fertilized eggs with single gRNA targeting seed region of miRNA and Cas9 mRNA resulted in indel mutations. Further, co-injection of fertilized eggs with dual gRNAs and Cas9 mRNA led to the removal of the fragment between the two target loci, yielding maximum efficiency of 11%. This highest genomic deletion efficiency was further improved up to 19% using short ssDNA as a donor. The deletions can be transmitted through the germline to the next generation at average efficiency of 8.7%. Cas9-vasa 3'-UTR was used to increase the efficiency of germline transmission of non-coding sequence deletion up to 14.9%. In addition, the 3'-UTR of the vasa gene was successfully deleted by dual gRNAs. Deletion of vasa 3'-UTR resulted in low expression level of vasa mRNA in the gonad when compared with the control. To summarize, the improved CRISPR/Cas9 system provided a powerful platform that can assist to easily generate desirable non-coding sequences mutants in non-model fish tilapia to discovery their functions.



http://bit.ly/2Fjepod