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Τετάρτη 22 Νοεμβρίου 2017

Cancer-testis gene PIWIL1 promotes cell proliferation, migration, and invasion in lung adenocarcinoma

Abstract

Piwi-like RNA-mediated gene silencing 1 (PIWIL1) has been identified as a novel extremely highly expressed cancer-testis (CT) gene in lung adenocarcinoma. However, the exact function and mechanism of PIWIL1 in lung adenocarcinoma remains unclear. Herein, we sought to investigate the role of PIWIL1 in the occurrence and development of lung adenocarcinoma. We examined the expression pattern of PIWIL1 in The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples, and validated it by Real-Time PCR (RT-PCR) in additional 21 paired lung adenocarcinoma tissues and 16 normal tissues. Subsequently, we explored the biological function of PIWIL1 in A549 and H1299 cell lines by gain and loss-of-function analyses. Using TCGA lung adenocarcinoma data, we further performed coexpression and Gene Ontology (GO) analyses, and analyzed the association of DNA methylation levels in PIWIL1 promoter region with its expression. Finally, we evaluated its expression in different mutation status of significantly mutated genes (SMGs) in TCGA lung adenocarcinoma data. We observed that PIWIL1 was expressed in testis and lung adenocarcinoma but not in other normal tissues, and its high expression was associated with shortened survival of lung cancer patients. Overexpression of PIWIL1 could facilitate the proliferation, invasion and migration of lung adenocarcinoma cells and vice versa. GO analysis revealed that PIWIL1 upregulated genes were enriched in embryonic development, cell proliferation and regulation of transcription. Moreover, promoter DNA hypomethylation of PIWIL1 could contribute to its aberrant expression in tumors. Interestingly, PIWIL1 expression was significantly higher in patients without hepatocyte growth factor (HGF) or serine/threonine kinase 11 (STK11) mutation (= 0.006 and 0.005, respectively). PIWIL1 is an epidriver gene in lung adenocarcinoma, indicating a potential target for further therapy.

Thumbnail image of graphical abstract

PIWIL1 is a novel extremely highly expressed cancer-testis gene in lung adenocarcinoma. PIWIL1 could promote the ability of proliferation, invasion, and migration in lung adenocarcinoma. The expression status of PIWIL1 is regulated by methylation in promoter region.



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Prognostic value of PD-L1 expression in combination with CD8+ TILs density in patients with surgically resected non-small cell lung cancer

Abstract

To investigate the prognostic value of PD-L1 expression combined with CD8+ TILs density in patients with resected NSCLC and correlations with clinicopathological features. We retrospectively enrolled 178 patients with resected NSCLC from 2011 to 2015. All surgical primary and 58 matched metastatic lymph node specimens were tested for PD-L1, CD8+ TILs, and oncogenic alterations. PD-L1+ was detected in 71 (39.9%) and CD8high TILs in 74 (41.6%) cases. Smoking, SqCC, and EGFR were associated with both PD-L1+ and CD8high TILs. Patients with CD8high TILs had longer OS (= 0.012). PD-L1 was significantly associated with longer OS in patients with oncogenic alterations (= 0.047). By multivariate analysis, CD8high TILs (HR = 0.411; 95% CI, 0.177–0.954; = 0.038), rather than PD-L1, was the independent predictive factor for OS. The longest and shortest OS were achieved in patients with PD-L1+/CD8high and PD-L1+/CD8low, respectively (= 0.025). Inconsistent PD-L1 expression levels were observed in 23 of 58 (39.7%) patients with primary and matched metastatic lymph node specimens. Of them, CD8high TILs was significantly associated with longer OS in patients with metastatic lymph nodes and/or consistent PD-L1 expression (= 0.017 and 0.049, respectively). The combination of PD-L1 and CD8+ TILs density, instead of PD-L1 alone, suggested impressive prognostic values in NSCLC patients. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions. The level of PD-L1 expression in advanced NSCLC needs to be evaluated more comprehensively.

Thumbnail image of graphical abstract

Combination of PD-L1 and CD8+ TILs density may suggest impressive prognostic value in NSCLC patients instead of PD-L1 alone. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions, and significance of PD-L1 expression in a single-biopsy specimen in advanced NSCLC may be overestimated in clinical practice.



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Patient satisfaction with information on oral anticancer agent use

Abstract

Adequate information on oral anticancer agent (OACA) use is an essential element of optimal cancer care. The present study aimed to get insight into the experiences of patients with information on OACA treatment and their characteristics regarding information dissatisfaction. Patients of four Dutch university hospitals using OACA participated in this observational study and completed the Satisfaction with Information about Medicines Scale (SIMS), EORTC Quality of Life Questionnaire-C30, Brief Illness Perception Questionnaire, and Beliefs about Medicines Questionnaire-Specific. Logistic regression analyses were used to determine factors associated with dissatisfaction with information. Patients (n = 208) using capecitabine (35%), lenalidomide (15%), imatinib (14%), temozolomide (12%), sunitinib (11%), thalidomide (5%), dasatinib (4%), erlotinib (2%), and nilotinib (2%) participated. Information on the following SIMS-items was inadequate: how OACA elicit their effect, how long it takes before treatment works, how to conclude that treatment is effective, the risk of side effects and its management, interference with sex life, drowsiness, interference with other medication and alcohol and what to do in case of a missed dose. Younger age, hematological malignancy, dyspnoea, positive perception of consequences of the cancer, low perception of treatment control, and indifferent attitude towards OACA were associated with dissatisfaction with information. In conclusion, a considerable number of patients would have appreciated receiving more information on specific issues relating to the consequences of OACA treatment such as the effects and side effects of OACA and the interference of treatment with various aspects of their daily life. Oncologists, hematologists, lung-oncologists and pharmacists may reconsider the provision of information on OACA treatment.

Thumbnail image of graphical abstract

This observational study showed that a substantial number of cancer patients perceived a lack of information on oral anticancer agent (OACA) treatment. Particularly information on the following subjects should be improved: self-monitoring of treatment effectiveness, side effects and their management, interference of treatment with sex life, interference of treatment with other medicines and alcohol use, and what to do in case of missed doses. Healthcare providers may reconsider the provision of information on OACA treatment.



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Phytochemical and pharmacological evaluation of ethanolic extract of Lepisanthes rubiginosa L. leaves

The current study was conducted to evaluate the antioxidant, analgesic, antihyperglycemic, neuropharmacological and antidiarrheal activities of ethanolic extract of Lepisanthes rubiginosa L. leaves in different e...

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In vitro cytotoxic activity of medicinal plants from Nigeria ethnomedicine on Rhabdomyosarcoma cancer cell line and HPLC analysis of active extracts

Cancer is a leading cause of death world-wide, with approximately 17.5 million new cases and 8.7 million cancer related deaths in 2015. The problems of poor selectivity and severe side effects of the available...

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A putative Chondroprotective role for IL-1β and MPO in herbal treatment of experimental osteoarthritis

Herbal treatment may have a chondroprotective and therapeutic effect on Osteoarthritis (OA). We investigated the mechanism of action of ginger and curcumin rhizomes cultivated in Egypt in treatment of OA in ra...

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Use of driving-impairing medicines by a Spanish population: a population-based registry study

Objective

To assess the use of driving-impairing medicines (DIM) in the general population with special reference to length of use and concomitant use.

Design

Population-based registry study.

Setting

The year 2015 granted medicines consumption data recorded in the Castile and León (Spain) medicine dispensation registry was consulted.

Participants

Medicines and DIM consumers from a Spanish population (Castile and León: 2.4 million inhabitants).

Exposure

Medicines and DIM consumption. Patterns of use by age and gender based on the length of use (acute: 1–7 days, subacute: 8–29 days and chronic use: ≥30 days) were of interest. Estimations regarding the distribution of licensed drivers by age and gender were employed to determine the patterns of use of DIM.

Results

DIM were consumed by 34.4% (95% CI 34.3% to 34.5%) of the general population in 2015, more commonly with regularity (chronic use: 22.5% vs acute use: 5.3%) and more frequently by the elderly. On average, 2.3 DIM per person were dispensed, particularly to chronic users (2.8 DIM per person). Age and gender distribution differences were observed between the Castile and León medicine dispensation registry data and the drivers' license census data. Of all DIM dispensed, 83.8% were in the Anatomical Therapeutic Chemical code group nervous system medicines (N), which were prescribed to 29.2% of the population.

Conclusions

The use of DIM was frequent in the general population. Chronic use was common, but acute and subacute use should also be considered. This finding highlights the need to make patients, health professionals, health providers, medicine regulatory agencies and policy-makers at large aware of the role DIM play in traffic safety.



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Maternal and neonatal outcomes of vaginal breech delivery for singleton term pregnancies in a carefully selected Cameroonian population: a cohort study

Background and objectives

Vaginal breech delivery (VBD) is known to be associated with more perinatal and maternal complications. Very few studies on the subject have been carried out in poor-resource settings. The aim of this study was to determine maternal and neonatal outcomes in carefully selected cases of VBD for singleton term pregnancies in a tertiary centre in Cameroon.

Design

A retrospective cohort study.

Setting

A tertiary hospital in Yaounde, Cameroon.

Participants

Cases of VBD of newborns weighing 2500–3500 g were matched in a ratio of 1:4 to consecutive vaginal cephalic deliveries (VCDs) of newborns weighing 2500–3500 g over a 5-year period. Both groups were matched for maternal age and parity. We excluded cases of multiple gestations, footling breech, clinically inadequate maternal pelvis, preterm delivery, post-term pregnancies, fetal demise prior to the onset of labour, placenta praevia and fetal anomaly incompatible with vaginal delivery.

Outcome measures

Neonatal and maternal adverse outcomes of VBD observed till 6 weeks after delivery analysed using Bonferroni correction.

Results

Fifty-three (53) VBDs were matched against 212 VCD. Unlike women who had VCD, those who underwent VBD were more likely to have prolonged labour (OR 8.05; 95% CI 3.00 to 11.47; P<0.001), and their newborns were more likely to suffer from birth asphyxia (OR 10.24; 95% CI 4.92 to 21.31; P<0.001).

Conclusion

The study infers a strong association between VBD of singleton term pregnancies and maternofetal morbidity when specific protocols are applied. This, however, failed to translate into higher differences in perinatal mortality. This finding does not discount the role of VBD in low-income countries, but we emphasise the need for specific precautions like close monitoring of labour and adequate anticipation for neonatal resuscitation in order to reduce these complications.



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Impact of multimorbidity on healthcare professional task shifting potential in patients with type 2 diabetes in primary care: a French cross-sectional study

Objectives

To estimate the transferability of processes of care from general practitioners (GPs) to allied healthcare professionals and the determinants of such transferability.

Design

French national cross-sectional multicentre study

Setting

128 family practices providing supervised training for residents in general practice.

Participants

All patients consulting with their GP over a total number of 20 days (ie, 1 day a week from December 2011 to April 2012). Encounters where type 2 diabetes was one of the managed health problems were selected for analysis.

Primary and secondary outcome measures

Processes that were associated with specific health problems were collected by 54 residents. Potential process transferability was the main outcome assessed, as well as the professionals involved in the collaboration and the eventual conditions associated with transfer.

Results

From 8572 processes of care that concerned 1088 encounters of patients with diabetes, 21.9% (95% CI 21.1% to 22.8%) were considered eligible for transfer from GPs to allied healthcare professionals (78.1% to nurses, 36.7% to pharmacists). Processes were transferable with condition(s) for 70.6% (ie, a protocol, shared record or supervision). The most transferable processes concerned health maintenance (32.1%) and cardiovascular risk factors (hypertension (28.7%), dyslipidaemia (25.3%) and diabetes (24.3%)). Multivariate analysis showed that educational processes or a long-term condition status were associated with increased transferability (OR 3.26 and 1.47, respectively), whereas patients with higher intellectual occupations or those with two or more associated health problems were associated with lower transferability (OR 0.33 and 0.81, respectively).

Conclusions

A significant part of GP activity relating to patients with multimorbidity including type 2 diabetes could be transferred to allied healthcare professionals, mainly on prevention and global education to cardiovascular risk factors. The organisational and finance conditions of team work as views of patients and healthcare professionals must be explored before implementation in primary care.



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Authorship, plagiarism and conflict of interest: views and practices from low/middle-income country health researchers

Objectives

To document low/middle-income country (LMIC) health researchers' views about authorship, redundant publication, plagiarism and conflicts of interest and how common poor practice was in their institutions.

Design

We developed a questionnaire based on scenarios about authorship, redundant publication, plagiarism and conflicts of interest. We asked participants whether the described practices were acceptable and whether these behaviours were common at their institutions. We conducted in-depth interviews with respondents who agreed to be interviewed.

Participants

We invited 607 corresponding authors of Cochrane reviews working in LMICs. From the 583 emails delivered, we obtained 199 responses (34%). We carried out in-depth interviews with 15 respondents.

Results

Seventy-seven per cent reported that guest authorship occurred at their institution, 60% reported text recycling. For plagiarism, 12% of respondents reported that this occurred 'occasionally', and 24% 'rarely'. Forty per cent indicated that their colleagues had not declared conflicts of interest in the past. Respondents generally recognised poor practice in scenarios but reported that they occurred at their institutions. Themes identified from in-depth interviews were (1) authorship rules are simple in theory, but not consistently applied; (2) academic status and power underpin behaviours; (3) institutions and culture fuel bad practices and (4) researchers are uncertain about what conflict of interests means and how this may influence research.

Conclusions

LMIC researchers report that guest authorship is widely accepted and common. While respondents report that plagiarism and undeclared conflicts of interest are unacceptable in practice, they appear common. Determinants of poor practice relate to academic status and power, fuelled by institutional norms and culture.



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Categorising cancers to enable tailored care planning through a secondary analysis of cancer registration data in the UK

Objectives

The aim of this study is to categorise cancers into broad groups based on clusters of common treatment aims, experiences and outcomes to provide a numerical framework for understanding the services required to meet the needs of people with different cancers. This framework will enable a high-level overview of care and support requirements for the whole cancer population.

Setting and participants

People in the UK with 1 of 20 common cancers; an estimated 309 000 diagnoses in 2014, 1 679 000 people diagnosed in a 20-year period and still living in 2010 and 135 000 cancer deaths in 2014.

Primary and secondary outcome measures

Survival and stage at diagnosis data were reviewed alongside clinically led assumptions to identify commonalities and cluster cancer types into three groups. The three cancer groups were then described using incidence, prevalence and mortality data collected and reported by UK cancer registries. This was then reviewed, validated and refined following consultation.

Results

Group 1 includes cancers with the highest survival; 5-year survival is over 80%. Group 3 cancers have shorter term survival. Five-year survival is not >20% for any cancer in this group and many do not survive over a year. Group 2 includes cancers where people typically live more than a year but are less likely to live >5 years. We estimate that the majority (64%) of people living with cancer (20 year prevalence) have a cancer type in group 1 'longer term survival', but significant minorities of people have cancers in group 2 'intermediate survival' (19%) and group 3 'shorter term survival' (10%).

Conclusions

Every person with cancer has unique needs shaped by a multitude of factors including comorbidities, treatment regimens, patient preferences, needs, attitudes and behaviours. However, to deliver personalised care, there needs to be a high-level view of potential care requirements to support service planning.



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Midwife or doctor local opinion leader to implement a national guideline in babies on postnatal wards (DesIGN): protocol of a cluster-randomised, blinded, controlled trial

Introduction

Neonatal hypoglycaemia is a common condition that can cause developmental delay. Treatment of neonatal hypoglycaemia with oral dextrose gel has been shown to reverse hypoglycaemia and reduce admissions to neonatal intensive care for hypoglycaemia. An evidence-based clinical practice guideline was written to guide the use of dextrose gel to treat neonatal hypoglycaemia in New Zealand. However, it is unclear what clinical discipline might most effectively lead the implementation of the guideline recommendations.

Objective

To determine if midwife or doctor local opinion leaders are more effective in implementing a clinical practice guideline for use of oral dextrose gel to treat hypoglycaemia in babies on postnatal wards.

Methods and analysis

A cluster-randomised, blinded, controlled trial. New Zealand maternity hospitals that care for babies born at risk of neonatal hypoglycaemia will be randomised to having either a local midwife or doctor lead the guideline implementation at that hospital. The primary outcome will be the change in the proportion of hypoglycaemic babies treated with dextrose gel from before implementation of the guideline to 3 months after implementation.

Ethics and dissemination

Approved by Health and Disability Ethics Committee: 15/NTA/31. Findings will be disseminated to peer-reviewed journals, guideline developers and the public.

Trial registration number

ISRCTN61154098.



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The effect of nut consumption on markers of inflammation and endothelial function: a systematic review and meta-analysis of randomised controlled trials

Objectives

To examine the effect of nut consumption on inflammatory biomarkers and endothelial function.

Design

A systematic review and meta-analysis.

Data sources

MEDLINE, PubMed, Cumulative Index to Nursing and Allied Health Literature and Cochrane Central Register of Controlled Trials (all years to 13 January 2017).

Eligibility criteria

Randomised controlled trials (with a duration of 3 weeks or more) or prospective cohort designs conducted in adults; studies assessing the effect of consumption of tree nuts or peanuts on C-reactive protein (CRP), adiponectin, tumour necrosis factor alpha, interleukin-6, intercellular adhesion molecule 1, vascular cell adhesion protein 1 and flow-mediated dilation (FMD).

Data extraction and analysis

Relevant data were extracted for summary tables and analyses by two independent researchers. Random effects meta-analyses were conducted to explore weighted mean differences (WMD) in change or final mean values for each outcome.

Results

A total of 32 studies (all randomised controlled trials) were included in the review. The effect of nut consumption on FMD was explored in nine strata from eight studies (involving 652 participants), with consumption of nuts resulting in significant improvements in FMD (WMD: 0.79%(95% CI 0.35 to 1.23)). Nut consumption resulted in small, non-significant differences in CRP (WMD: –0.01 mg/L (95% CI –0.06 to 0.03)) (26 strata from 25 studies), although sensitivity analyses suggest results for CRP may have been influenced by two individual studies. Small, non-significant differences were also found for other biomarkers of inflammation.

Conclusions

This systematic review and meta-analysis of the effects of nut consumption on inflammation and endothelial function found evidence for favourable effects on FMD, a measure of endothelial function. Non-significant changes in other biomarkers indicate a lack of consistent evidence for effects of nut consumption on inflammation. The findings of this analysis suggest a need for more research in this area, with a particular focus on randomised controlled trials.

PROSPERO registration number

CRD42016045424.



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Cerebrospinal fluid biomarkers for the diagnosis and prognosis of Parkinsons disease: protocol for a systematic review and individual participant data meta-analysis

Introduction

Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder related to α-synuclein misfolding and aggregation. For this reason, it belongs to the family of 'synucleinopathies', which also includes some other neurological diseases. Although imaging and ancillary investigations may be helpful in the diagnostic workup, the diagnosis of PD mostly relies on the clinician's expertise. Furthermore, there is a need today for markers that can track the disease progression in PD that might improve the evaluation of novel disease-modifying therapies. The cerebrospinal fluid (CSF) has been widely investigated with the purpose of finding useful diagnostic and prognostic biomarkers for PD.

Methods and analysis

This systematic review protocol has been developed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol 2015 statement and was registered on the PROSPERO international prospective register of systematic reviews. An international collaboration will be established. We will search the Cochrane Library, Web of Science, Medline and Embase from inception, using appropriate search strategies. Individual participant data from all included studies will be merged into a single database. We will include any study assessing the diagnostic and prognostic role of CSF biomarkers in PD. To evaluate the risk of bias and applicability of primary diagnostic accuracy studies, we will use Quality Assessment of Diagnostic Accuracy Studies-2 and Quality in Prognostic Studies. We will use standard meta-analytic procedures. We will first explore the utility of each CSF biomarker in turn. For each biomarker, we will assess its diagnostic and prognostic utility by means of receiver operating characteristic analysis and regression models. We will then move towards a multivariate approach considering different panels of biomarkers.

Ethics and dissemination

Our study will not include confidential data, and no intervention will be involved, so ethical approval is not required. The results of the study will be reported in international peer-reviewed journals.



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Core outcome research measures in anal cancer (CORMAC): protocol for systematic review, qualitative interviews and Delphi survey to develop a core outcome set in anal cancer

Introduction

The incidence of anal squamous cell carcinoma (ASCC) has increased threefold in the last 30 years. Initial treatment is chemoradiotherapy, associated with short-term and long-term side effects. Future therapy innovations aim to reduce morbidity in treatment of early tumours while maintaining treatment efficacy, and to escalate treatment intensity in locally advanced tumours with acceptable quality of life (QoL). However, all phase III randomised controlled trials to-date have utilised different primary outcomes, which hinders evidence synthesis and presents challenges to the selection of optimal outcomes in future trials. No trial comprehensively assessed long-term side effects and QoL, suggesting outcomes reflecting issues important to patients are under-represented. This project aims to determine the priority outcomes for all stakeholders and reach agreement on a standardised core set of outcomes to be measured and reported on in all future ASCC trials.

Methods and analysis

A systematic review will identify all outcomes reported in trials and observational studies of chemoradiotherapy as primary treatment for ASCC. Outcomes of importance to patients will be identified through patient interviews. The long list of outcomes generated from the systematic review and interviews will be used to create a two-round Delphi process, including key stakeholders (patients and healthcare professionals). The results of the Delphi will be discussed at a face-to-face consensus meeting. Discussion will focus on outcomes that did not achieve consensus through the Delphi process and conclude with anonymous voting to ratify the final core outcome set (COS).

Ethics and dissemination

The final COS will feed directly into the PersonaLising Anal cancer radioTherapy dOse (PLATO) national anal cancer trials and the Association of coloproctologists of Great Britain and Ireland (ACPGBI) supported national anal cancer database. Utilisation of the COS will increase the relevance of research output to all stakeholders and increase the capacity for data synthesis between trials. This study has ethical approval and is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative.

Trial registration number

PROSPERO registration ID: CRD42016036540



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Local anaesthetics combined with vasoconstrictors in patients with cardiovascular disease undergoing dental procedures: systematic review and meta-analysis protocol

Introduction

The use of vasoconstrictors combined with local anaesthetics (LAs) in dentistry for patients with cardiovascular disease (CVD) is still controversial in the scientific literature. It raises concerns regarding the possibility of transient episodes, triggering negative cardiovascular outcomes.

Method/design

Trials eligible for our systematic review will enrol patients with CVD who have undergone dental treatments carried out with the use of LAs by comparing two arms: LAs with vasoconstrictors and LAs without vasoconstrictors. The research will be conducted in the electronic databases, namely Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Healthstar (via Ovid), Cumulative Index to Nursing and Allied Health Literature and Web of Science, from their inception to December 2017, without any restrictions in terms of language and status of publication. A team of reviewers will independently assess titles, abstracts and complete text to determine eligibility. For eligible studies, the same reviewers will perform data extraction and evaluate the risk of bias in the selected articles. The selected outcomes comprise death, mortality by a specific cause, stroke, acute myocardial infarction, hospitalisation, pain, bleeding, arrhythmias, ischaemic episodes, anxiety, adverse effects, changes in blood pressure, changes in heart rate, anxiety and results obtained via oximetry. Whenever possible, we will conduct a meta-analysis to establish the effects of LAs with and without vasoconstrictors in the patients with CVD, and the overall quality of evidence for each outcome will be determined using the Grading of Recommendations Assessment, Development and Evaluation classification system.

Ethics and dissemination

Ethics committee approval was not necessary because this is a protocol of systematic review. This systematic review will be submitted for presentation at conferences and for publication in a peer-reviewed journal. Our review will assess the risks of cardiovascular events when using LAs with and without vasoconstrictors in patients with CVD, focusing on important clinical outcomes.

PROSPERO registration number

CRD42016045421.



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Identifying clinical features in primary care electronic health record studies: methods for codelist development

Objective

Analysis of routinely collected electronic health record (EHR) data from primary care is reliant on the creation of codelists to define clinical features of interest. To improve scientific rigour, transparency and replicability, we describe and demonstrate a standardised reproducible methodology for clinical codelist development.

Design

We describe a three-stage process for developing clinical codelists. First, the clear definition a priori of the clinical feature of interest using reliable clinical resources. Second, development of a list of potential codes using statistical software to comprehensively search all available codes. Third, a modified Delphi process to reach consensus between primary care practitioners on the most relevant codes, including the generation of an 'uncertainty' variable to allow sensitivity analysis.

Setting

These methods are illustrated by developing a codelist for shortness of breath in a primary care EHR sample, including modifiable syntax for commonly used statistical software.

Participants

The codelist was used to estimate the frequency of shortness of breath in a cohort of 28 216 patients aged over 18 years who received an incident diagnosis of lung cancer between 1 January 2000 and 30 November 2016 in the Clinical Practice Research Datalink (CPRD).

Results

Of 78 candidate codes, 29 were excluded as inappropriate. Complete agreement was reached for 44 (90%) of the remaining codes, with partial disagreement over 5 (10%). 13 091 episodes of shortness of breath were identified in the cohort of 28 216 patients. Sensitivity analysis demonstrates that codes with the greatest uncertainty tend to be rarely used in clinical practice.

Conclusions

Although initially time consuming, using a rigorous and reproducible method for codelist generation 'future-proofs' findings and an auditable, modifiable syntax for codelist generation enables sharing and replication of EHR studies. Published codelists should be badged by quality and report the methods of codelist generation including: definitions and justifications associated with each codelist; the syntax or search method; the number of candidate codes identified; and the categorisation of codes after Delphi review.



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Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1

Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.



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Novel STRA6 null mutations in the original family described with Matthew–Wood syndrome



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Single suture craniosynostosis: Identification of rare variants in genes associated with syndromic forms

We report RNA-Sequencing results on a cohort of patients with single suture craniosynostosis and demonstrate significant enrichment of heterozygous, rare, and damaging variants among key craniosynostosis-related genes. Genetic burden analysis identified a significant increase in damaging variants in ATR, EFNA4, ERF, MEGF8, SCARF2, and TGFBR2. Of 391 participants, 15% were found to have damaging and potentially causal variants in 29 genes. We observed transmission in 96% of the affected individuals, and thus penetrance, epigenetics, and oligogenic factors need to be considered when recommending genetic testing in patients with nonsyndromic craniosynostosis.



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Congenital limb deficiencies and major associated anomalies in Alberta for the years 1980–2012

There is a wide range of the proportion of congenital anomalies associated with limb deficiencies reported in the literature. This variation is primarily attributed to methodology and classification differences. The distribution of associated anomalies among cases with congenital limb deficiencies in Alberta born between January 1, 1980 and December 31, 2012 is described. Of the 170 cases identified, most were live born (75.3%), male (61.8%), had longitudinal limb deficiencies (78.8%), and had associated anomalies outside the musculoskeletal system (77.6%). Significant associations between the preaxial longitudinal group and the central nervous, gastrointestinal, and cardiovascular systems are reported as well as between the postaxial longitudinal group and congenital hip and foot anomalies. Probable and possible syndrome diagnoses are described for cases with recognized malformation patterns.



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The development of neuromotor skills and hand preference during infancy

Abstract

Assessing infant handedness has been controversial. Different assessment techniques and theoretical approaches produce different results. Evidence from a dynamic systems perspective showed that the development of postural control during infancy affects the expression of an infant's handedness. However, others found that developmental changes in postural control influenced the amount of symmetrical (bimanual) reaching during infancy, but not hand preference. Since most studies of infant handedness use age to assess development, perhaps measures of an infant's developing neuromotor control, irrespective of age, would better predict changes in an infant's hand preference. To assess neuromotor development, items from [Touwen's (1976) Neurological development in infancy. Lavenham, Suffolk: The Lavenham Press, LTD]. "Group III" indices were used. These items assess developmental changes in neuromotor abilities throughout the 6–14-month age period. Hand preference for acquiring objects was measured during these same months. Group Based Trajectory Models (GBTM) of 380 infants identified four different groups of infants according to the trajectory of the development of their hand preferences (32% Early Right, 12% Early Left, 25% Late Right, 30% No Preference). A multilevel model was used to compare these four developmental trajectories according to age and neuromotor development. Age, not neuromotor development, is a better predictor of differences in developmental trajectories of the four hand preference groups. However, Late Right infants are significantly less developed at 6 months than No Preference, Early Right and Left infants and both Early Right and Left infants are most advanced at 6 months. All groups exhibit similar rates of neuromotor development indicating no "catch-up" by the Late Right infants. Thus, any assessment of infant handedness will incorporate necessarily four groups of infants with differently developing hand preferences and neuromotor abilities.



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Genomic risk prediction of aromatase inhibitor-related arthralgia in patients with breast cancer using a novel machine-learning algorithm

Abstract

Many breast cancer (BC) patients treated with aromatase inhibitors (AIs) develop aromatase inhibitor-related arthralgia (AIA). Candidate gene studies to identify AIA risk are limited in scope. We evaluated the potential of a novel analytic algorithm (NAA) to predict AIA using germline single nucleotide polymorphisms (SNP) data obtained before treatment initiation. Systematic chart review of 700 AI-treated patients with stage I-III BC identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. SNP clusters that most closely defined AIA risk were discovered using an NAA that sequentially combined statistical filtering and a machine-learning algorithm. NCBI PhenGenI and Ensemble databases defined gene attribution of the most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Demographics were similar in cases and controls. A cluster of 70 SNPs, correlating to 57 genes, was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally consistent. Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.

Thumbnail image of graphical abstract

Aromatase inhibitor-related arthralgias (AIA) are common and may lead to therapy noncompliance. Whereas traditional gene studies to identify arthralgia risk have been limited in scope, we employed a novel analytic algorithm to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.



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Direct Testing for Allele-Specific Expression Differences Between Conditions

Allelic imbalance (AI) indicates the presence of functional variation in cis regulatory regions. Detecting cis regulatory differences using AI is widespread, yet there is no formal statistical methodology that tests whether AI differs between conditions. Here we present a novel model and formally test differences in AI across conditions using Bayesian credible intervals. The approach tests AI by environment (GxE) interactions and can be used to test AI between environments, genotypes, sex, and any other condition. We incorporate bias into the modeling process. Bias is allowed to vary between conditions, making the formulation of the model general. As gene expression affects power for detection of AI, and as expression may vary between conditions, the model explicitly takes coverage into account. The proposed model has low type I and II error under several scenarios, and is robust to large differences in coverage between conditions. We reanalyze RNA-seq data from a Drosophila melanogaster population panel, with F1 genotypes, to compare levels of AI between mated and virgin female flies and we show that AI*genotype interactions can also be tested. To demonstrate the use of the model to test genetic differences and interactions, a formal test between two F1's was performed, showing the expected 20% difference in AI. The proposed model allows a formal test of GxE and GxG and reaffirms a previous finding, that cis regulation is robust between environments.



http://ift.tt/2zir7N2

Reference Assembly and Annotation of the Pyrenophora teres f. teres Isolate 0-1

Pyrenophora teres f. teres, the causal agent of net form net blotch (NFNB) of barley, is a destructive pathogen in barley growing regions throughout the world. Typical yield losses due to NFNB range from 10-40%, however, complete loss has been observed on highly susceptible barley lines where environmental conditions favor the pathogen. Currently, genomic resources for this economically important pathogen are limited to a fragmented draft genome assembly and annotation with limited RNA support of the P. teres f. teres isolate 0-1. This research presents an updated 0-1 reference assembly facilitated by long read sequencing and scaffolding with the assistance of genetic linkage maps. Additionally, genome annotation was mediated by RNAseq analysis using three infection time points and a pure culture sample resulting in 11,541 high-confidence gene models. The 0-1 genome assembly and annotation presented here now contains the majority of the repetitive content of the genome. Analysis of the 0-1 genome revealed classic characteristics of a 'two-speed' genome, being compartmentalized into GC-equilibrated and AT-rich compartments. The assembly of repetitive AT-rich regions will be important for future investigation of genes known as effectors which often reside in close proximity to repetitive regions. These effectors are responsible for manipulation of the host defense during infection. This updated P. teres f. teres isolate 0-1 reference genome assembly and annotation provides a robust resource for the examination of the barley-P. teres f. teres host-pathogen co-evolution.



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Restorer-of-Fertility Mutations Recovered in Transposon-Active Lines of S Male-Sterile Maize

Mitochondria execute key pathways of central metabolism and serve as cellular sensing and signaling entities - functions that depend upon interactions between mitochondrial and nuclear genetic systems. This is exemplified in cytoplasmic male sterility type S (CMS-S) of Zea mays, where novel mitochondrial open reading frames are associated with a pollen collapse phenotype, but nuclear restorer-of-fertility (restorer) mutations rescue pollen function. To better understand these genetic interactions, we screened Activator-Dissociation (Ac-Ds), Enhancer/Suppressor-mutator (En/Spm) and Mutator (Mu) transposon-active CMS-S stocks to recover new restorer mutants. The frequency of restorer mutations increased in transposon-active stocks compared to transposon-inactive stocks, but most mutants recovered from Ac-Ds and En/Spm stocks were unstable, reverting upon backcrossing to CMS-S inbred lines. Ten independent restorer mutations recovered from CMS-S Mu transposon stocks were, however, stable upon back crossing. Many restorer mutations condition seed-lethal phenotypes that provide a convenient test for allelism. Eight such mutants recovered in this study included one pair of allelic mutations that were also allelic to the previously described rfl2-1 mutant. Targeted analysis of mitochondrial proteins by immunoblot identified two features that consistently distinguished restored CMS-S pollen from comparably staged, normal-cytoplasm, non-mutant pollen - increased abundance of nuclear-encoded alternative oxidase relative to mitochondria-encoded cytochrome oxidase and decreased abundance of mitochondria-encoded ATP synthase subunit 1 compared to nuclear-encoded ATP synthase subunit 2. CMS-S restorer mutants thus revealed a metabolic plasticity in maize pollen, and further study of these mutants will provide new insights into mitochondrial functions critical to pollen and seed development.



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Residual Convolutional Neural Network for Determination of IDH Status in Low- and High-grade Gliomas from MR Imaging

Purpose: Isocitrate dehydrogenase (<IDH) mutations in glioma patients confer longer survival and may guide treatment decision-making. We aimed to predict the IDH status of gliomas from MR imaging by applying a residual convolutional neural network to pre-operative radiographic data. Experimental Design: Preoperative imaging was acquired for 201 patients from the Hospital of University of Pennsylvania (HUP), 157 patients from Brigham and Women's Hospital (BWH), and 138 patients from The Cancer Imaging Archive (TCIA) and divided into training, validation, and testing sets. We trained a residual convolutional neural network for each MR sequence (FLAIR, T2, T1 pre-contrast, and T1 post-contrast) and built a predictive model from the outputs. To increase the size of training set and prevent overfitting, we augmented the training set images by introducing random rotations, translations, flips, shearing, and zooming. Results: With our neural network model, we achieved IDH prediction accuracies of 82.8% (AUC = 0.90), 83.0% (AUC = 0.93), and 85.7% (AUC = 0.94) within training, validation, and testing sets, respectively. When age at diagnosis was incorporated into the model, the training, validation, and testing accuracies increased to 87.3% (AUC = 0.93), 87.6% (AUC = 0.95), and 89.1% (AUC = 0.95), respectively. Conclusions: We developed a deep learning technique to non-invasively predict IDH genotype in grade II-IV glioma using conventional MR imaging using a multi-institutional dataset.



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PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood.  Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo.  Results: We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions:Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC.



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CXCR2 is critical for bacterial control and development of joint damage and pain in Staphylococcus aureus-induced septic arthritis in mouse

Abstract

Staphylococcus aureus is the main pathogen associated with septic arthritis. Upon infection, neutrophils are quickly recruited to the joint by different chemoattractants, especially CXCR1/2 binding chemokines. Although their excessive accumulation is associated with intense pain and permanent articular damage, neutrophils have an important function in controlling bacterial burden. This work aimed to study the role of CXCR2 in the control of infection, hypernociception and tissue damage in S. aureus-induced septic arthritis in mice. The kinetics of neutrophil recruitment correlated with the bacterial load recovered from inflamed joint after intra-articular injection of S. aureus. Treatment of mice from the start of infection with the non-competitive antagonist of CXCR1/2, DF2156A, reduced neutrophil accumulation, cytokine production in the tissue, joint hypernociception and articular damage. However, early DF2156A treatment increased the bacterial load locally. CXCR2 was important for neutrophil activation and clearance of bacteria in vitro and in vivo. Start of treatment with DF2156A 3 days after infection prevented increase in bacterial load and reduced the hypernociception in the following days, but did not improve tissue damage. In conclusion, treatment with DF2156A seems be effective in controlling tissue inflammation and dysfunction but its effects are highly dependent on the timing of the treatment start.

This article is protected by copyright. All rights reserved



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The humanistic burden of Pompe disease: are there still unmet needs? A systematic review

Humanistic burden considers the impact of an illness on a patient's health-related quality of life (HRQoL), activities of daily living (ADL), caregiver health, and caregiver QoL. Humanistic burden also conside...

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HLA Loss in NSCLC: Facilitating Immune Escape [News in Brief]

Computational tool pinpoints allele-specific HLA loss, detects this event in a sizeable fraction of lung cancers.



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The T-cell Receptor {beta}-Chain Is an Immunotherapy Target for Lymphomas [Research Watch]

Targeting the TRBC gene expressed by T-cell malignancies mitigates severe immunosuppression.



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PD-1 Functions as a Tumor Suppressor in T-cell Lymphoma [Research Watch]

Oncogenic T-cell signaling upregulates PD-1, which increases PTEN expression to suppress oncogenesis.



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ARID1A Has Context-Specific Roles in Hepatocellular Carcinoma [Research Watch]

ARID1A promotes tumor initiation in the liver but suppresses metastasis in established tumors.



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Blocking IDO1 Helps Shrink Bladder, Cervical Tumors [News in Brief]

Combination of BMS-986205 and nivolumab shows early promise in phase I/IIa study.



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Procalcitonin-guided antibiotic therapy in intensive care unit patients: a systematic review and meta-analysis

Serum procalcitonin (PCT) concentration is used to guide antibiotic decisions in choice, timing, and duration of anti-infection therapy to avoid antibiotic overuse. Thus, we performed a systematic review and m...

http://ift.tt/2zeEL42

Nonlinear micro-CT based FE modeling of trabecular bone – Sensitivity of apparent response to tissue constitutive law and bone volume fraction

Abstract

In this study, the sensitivity of the apparent response of trabecular bone to different constitutive models at the tissue-level was investigated using finite element modeling based on micro-computed tomography. Trabecular bone specimens from porcine femurs were loaded under a uniaxial compression experimentally and computationally. The apparent behaviors computed using von Mises, Drucker-Prager, and Cast Iron plasticity models were compared. Secondly, the effect of bone volume fraction was studied by changing the bone volume fraction of a trabecular bone sample and while keeping the same basic architecture. Also, constitutive models' parameters of the tissue were calibrated for porcine bone and the effects of different parameters on resulting apparent response were investigated through a parametric study. The calibrated effective tissue elastic modulus of porcine trabecular bone was 10±1.2 GPa, which is in the lower range of modulus values reported in the literature for human and bovine trabecular bones (4-23.8 GPa). It was also observed that, unlike elastic modulus, yield properties of tissue could not be uniquely calibrated by fitting an apparent response from simulations to experiments under a uniaxial compression. Our results demonstrated that using these three tissue constitutive models had only a slight effect on the apparent response. As expected, there was a significant change in the apparent response with varying bone volume fraction. Also, both apparent modulus and maximum stress had a linear relation with bone volume fraction.



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Use of a primary care online consultation system, by whom, when and why: evaluation of a pilot observational study in 36 general practices in South West England

Objectives

Evaluation of a pilot study of an online consultation system in primary care. We describe who used the system, when and why, and the National Health Service costs associated with its use.

Design

15-month observational study.

Setting

Primary care practices in South West England.

Results

36 General practices covering 396 828 patients took part in the pilot. The online consultation website was viewed 35 981 times over the pilot period (mean 9.11 visits per 1000 patients per month). 7472 patients went on to complete an 'e-consultation' (mean 2.00 online consultations per 1000 patients per month). E-consultations were mainly performed on weekdays and during normal working hours. Patient records (n=485) were abstracted for eight practices and showed that women were more likely to use e-consultations than men (64.7% vs 35.3%) and users had a median age of 39 years (IQR 30–50). The most common reason for an e-consultation was an administrative request (eg, test results, letters and repeat prescriptions (22.5%)) followed by infections/immunological issues (14.4%). The majority of patients (65.2%) received a response within 2 days. The most common outcome was a face-to-face (38%) or telephone consultation (32%). The former were more often needed for patients consulting about new conditions (OR 1.56, 95% CI 1.05 to 2.27, p=0.049). The average cost of a practice's response to an e-consultation was £36.28, primarily triage time and resulting face-to-face/telephone consultations needed.

Conclusions

Use of e-consultations is very low, particularly at weekends. Unless this can be improved, any impact on staff workload and patient waiting times is likely to be negligible. It is possible that use of e-consultations increases primary care workload and costs. Online consultation systems could be developed to improve efficiency both for staff and patients. These findings have implications for software developers as well as primary care services and policy-makers who are considering investing in online consultation systems.



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A Human Microdose Study of the Anti-Malarial GSK3191607 in Healthy Volunteers

Summary

Aims

GSK3191607, a novel inhibitor of the Plasmodium falciparum ATP4 (PfATP4) pathway, is being considered for development in humans. However, a key problem encountered during the preclinical evaluation of the compound was its inconsistent PK profile across preclinical species (mouse, rat and dog) which prevented reliable prediction of PK parameters in humans and precluded a well-founded assessment of the potential for clinical development of the compound. Therefore, an open label microdose (100 μg, 6 subjects) FTIH study was conducted in order to assess the human pharmacokinetics of GSK3191607 following IV administration of [14C]-GSK3191607.

Methods

A human microdose study was conducted in order to investigate the clinical pharmacokinetics of GSK3191607 and enable a Go/No Go decision on further progression of the compound. The PK disposition parameters estimated from the microdose study, combined with preclinical in-vitro and in-vivo pharmacodynamic (PD) parameters, were all used to estimate the potential efficacy of various oral dosing regimens in humans.

Results

The pharmacokinetic profile, based on the microdose data, demonstrated a half-life (~17 hrs) which is similar to other antimalarial compounds currently in clinical development. However, combining the microdose data with the PD data provided results that do not support further clinical development of the compound for a single dose cure.

Conclusions

The information generated by this study provides a basis for predicting the expected oral PK profiles of GSK3191607 in man and supports decisions on the future clinical development of the compound.



http://ift.tt/2mUnRpp

Clinical and virological factors associated with gastrointestinal symptoms in patients with acute respiratory infection: a two-year prospective study in general practice medicine

Gastrointestinal (GI) symptoms, such as diarrhea, vomiting, abdominal pain and nausea are not an uncommon manifestation of an acute respiratory infection (ARI).

http://ift.tt/2zg46L1

Diagnosing Kernohan-Woltman notch phenomenon by Somatosensory Evoked Potentials in Intensive Care Unit

Kernohan-Woltman notch phenomenon can occur after hemispheric brain lesions with severe midline herniation. This is clinically defined by the existence of false-localizing signs (such as an ipsilateral hemiparesis) due to a contralateral mesencephalon compression by the tentorial edge, without contralateral hemiparesis by temporal lobe herniation (Codd et al., 2013). Repetitive somatosensory evoked potential (SEP) recordings have been used to help assessing secondary injury related to severe herniation on the intensive care unit (ICU), even if they were not brought to evidence by intracranial pressure (ICP) monitoring (Stocchetti et al., 2014).

http://ift.tt/2AojDfS

Multisession anodal transcranial direct current stimulation induces motor cortex plasticity enhancement and motor learning generalization in an aging population

Transcranial direct-current stimulation (tDCS) is a non-invasive technique of cortical brain neuromodulation with potential therapeutic effects. Using a constant and low intensity direct current that flows between two electrodes over the scalp (Webster et al., 2006, Fregni et al., 2007), this technique influences trans-membrane neuronal potentials and modifies the level of cortical excitability in the targeted brain region (Priori et al., 1998, Fregni et al., 2007, Nitsche et al., 2008, Bastani et al., 2012).

http://ift.tt/2zYUB6v

Acute cerebellitis in adults: a case report and review of the literature

Acute cerebellitis is a rare disease with the majority of cases described in children. Little is known about the clinical characteristics and outcome in adults.

http://ift.tt/2iHaapu

Comparison of Patient Survival Between Hemodialysis and Peritoneal Dialysis Among Patients Eligible for Both Modalities

Although peritoneal dialysis (PD) costs less to the health care system compared to in-center hemodialysis (HD), it is an underused therapy. Neither modality has been consistently shown to confer a clear benefit to patient survival. A key limitation of prior research is that study patients were not restricted to those eligible for both therapies.

http://ift.tt/2A0T1Aw

Updated Trends in Gallbladder and Other Biliary Tract Cancers Worldwide



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Different Cutpoints for Transient Elastography Lead To Different Associations with Cirrhosis

Our results illustrate the sensitivity of odds ratios to the transient elastography cutpoint used to define cirrhosis. Given problems with cutpoints, we recommend regression analysis with a continuous or ordinal-outcome model to obtain a summary across the variation.

http://ift.tt/2zZptTR

Simplifying Resect and Discard Strategies for Real-Time Assessment of Diminutive Colorectal Polyps

During endoscopy, the resect and discard strategy, if performed with high confidence, can be used to determine histologic features of diminutive colorectal polyps (5 mm or less). These polyps can then be removed and discarded without pathology assessment. However, the complexities of real-time optical assessment and follow-up management have provided challenges to widespread use of this approach. We aimed to determine the outcomes of simple alternative strategies, in which all diminutive polyps can be resected and discarded.

http://ift.tt/2hNPLhK

Occipital Dermal Sinus Tract

A 15-month-old boy was referred for recurrent Escherichia coli meningitis. On examination, he had a small lump (Figure) with a pinhole-sized sinus and tuft of coarse hair (Figure, A, arrow) in the occipital midline area. Computed tomography of the head demonstrated a transosseous tract (Figure, B), and magnetic resonance imaging of the brain showed a lesion between the cerebellar hemispheres (Figure, C). He underwent a suboccipital craniotomy for resection of the dermal sinus tract. The lesion (outlined) was smooth, tan colored, and contained hair when opened (arrow), consistent with a dermoid cyst (Figure, D).

http://ift.tt/2A0cq4Y

How to Make Pediatric Trials Better: Transparency and Accountability of Trial Registration and Reporting

In this volume of The Journal, Gates at al showed the changing landscape of pediatric clinical trials, with important shifts in study designs, outcome reporting, and risk of bias analysis.1 Compared with 2007, pediatric trials in 2012 were more complex and significantly more often specified the primary outcome and reported funding and trial oversight by a data monitoring committee. However, it is very troubling that only 38% of trials in the 2012 sample of trials specified a primary outcome, and that one-half of them had high bias or unclear reporting surrounding the blinding schemes and research staff involved in the allocation.

http://ift.tt/2AojLMh

A Lucky Mistake: The Splenic Glands of Marcello Malpighi

Marcello Malpighi (1628–1694) is one of the most important anatomists and physicians in the History of Medicine. His contributions to the understanding of human anatomy and physiology span from the first description of capillary circulation to a thorough analysis of the structure and function of body glands. Malpighi believed that most organs consisted of glandular structures, whose distribution and microscopic features determine each organ specific function. He also applied this view to the study of spleen anatomy, which he recognized as composed of two distinct anatomic compartments (i.e.

http://ift.tt/2zt40nl

In vivo therapeutic potential of Inula racemosa in hepatic ischemia–reperfusion injury following orthotopic liver transplantation in male albino rats

Hepatic ischemia–reperfusion (I/R) injury mainly occurs following hepatic resection and liver transplantation and cause severe liver damage, organ injuries, and dysfunction. Pro-inflammatory cytokines that pro...

http://ift.tt/2hNEZrT

Measuring Influenza Neutralizing Antibody Responses to A(H3N2) Viruses in Human Sera by Microneutralization Assays Using MDCK-SIAT1 Cells

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Influenza neutralizing antibodies correlate with protection of influenza infections. Microneutralization assays measure neutralizing antibodies in human sera and are often used for influenza human serology. We describe a microneutralization assay using MDCK-SIAT1 cells to measure neutralizing antibody titers to contemporary 3C.2a and 3C.3a A(H3N2) viruses following influenza vaccination or infection.

http://ift.tt/2hTvfjh

Expanding Smoking Cessation Services at NCI-designated Cancer Centers: An Interview with Dr. Glen Morgan

NCI's Dr. Glen Morgan discusses NCI's Cancer Center Cessation Initiative, including how and why this smoking cessation initiative was developed and its long-term goals.



http://ift.tt/2Ao1n6e

Proper Positioning and Restraint of a Rat Hind Limb for Focused High Resolution Imaging of Bone Micro-architecture Using In Vivo Micro-computed Tomography

This paper instructs users of in vivo micro-computed tomography (µCT) scanners how to anesthetize, correctly position and restrain the hind limb of a rat for minimal movement during high-resolution imaging of the tibia. The result is high quality images that can be processed to accurately quantify bone micro-architecture.

http://ift.tt/2zZsNyL

In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice

Mitophagy, the process of clearing damaged mitochondria, is necessary for mitochondrial homeostasis and health maintenance. This article presents some of the latest mitophagy detection methods in human cells, Caenorhabditis elegans, and mice.

http://ift.tt/2iIpNgn

Preparation of Meiotic Chromosome Spreads from Mouse Spermatocytes

Meiosis is the developmental process by which gametes are formed through a single round of DNA replication and two successive rounds of chromosome segregation. Mammalian meiosis can be examined by utilizing a technique to prepare meiotic chromosome spreads. Here, we demonstrate a method of preparing surface-spread nuclei from mouse spermatocytes.

http://ift.tt/2B33NUb

MAIT cells: a novel therapeutic target for alcoholic liver disease?

Bacterial infection is one of the most frequent and severe complications of advanced alcoholic liver disease (ALD), including alcoholic cirrhosis and severe alcoholic hepatitis (SAH). Patients who suffered from SAH are susceptible to bacterial infection with one study reporting 50% of them developed bacterial infection.1 Additionally, standard corticosteroid treatment further increased the risk of bacterial infection in patients with SAH.1 Thus, infection is highly relevant for the outcome of SAH and represents an important therapeutic target. However, except antibiotic treatment, there are currently no other specific therapies that effectively control bacterial infection in SAH due to incomplete understanding of the pathogenesis of bacterial infection in these patients.

The mechanisms underlying the increased risk of bacterial infection in ALD are complex and multifactorial. The high incidence of bacterial infection may be partly explained by gut bacterial overgrowth, dysbiosis and translocation of gut bacteria and their products in patients with...



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Serotonin Decreases the Gain of Visual Responses in Awake Macaque V1

Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. We examined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus ("noise-correlation"). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal's behavioral or motivational context, complementing other known state-dependent gain-control mechanisms.

SIGNIFICANCE STATEMENT Serotonin is an important neuromodulator in the brain and a major target for drugs used to treat psychiatric disorders. Nonetheless, surprisingly little is known about how it shapes information processing in sensory areas. Here we examined the serotonergic modulation of visual processing in the primary visual cortex of awake behaving macaque monkeys. We found that serotonin mainly decreased the gain of the visual responses, without systematically changing their selectivity, variability, or covariability. This identifies a simple computational function of serotonin for state-dependent sensory processing, depending on the animal's affective or motivational state.



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Presynaptic Neuronal Nicotinic Receptors Differentially Shape Select Inputs to Auditory Thalamus and Are Negatively Impacted by Aging

Acetylcholine (ACh) is a potent neuromodulator capable of modifying patterns of acoustic information flow. In auditory cortex, cholinergic systems have been shown to increase salience/gain while suppressing extraneous information. However, the mechanism by which cholinergic circuits shape signal processing in the auditory thalamus (medial geniculate body, MGB) is poorly understood. The present study, in male Fischer Brown Norway rats, seeks to determine the location and function of presynaptic neuronal nicotinic ACh receptors (nAChRs) at the major inputs to MGB and characterize how nAChRs change during aging. In vitro electrophysiological/optogenetic methods were used to examine responses of MGB neurons after activation of nAChRs during a paired-pulse paradigm. Presynaptic nAChR activation increased responses evoked by stimulation of excitatory corticothalamic and inhibitory tectothalamic terminals. Conversely, nAChR activation appeared to have little effect on evoked responses from inhibitory thalamic reticular nucleus and excitatory tectothalamic terminals. In situ hybridization data showed nAChR subunit transcripts in GABAergic inferior colliculus neurons and glutamatergic auditory cortical neurons supporting the present slice findings. Responses to nAChR activation at excitatory corticothalamic and inhibitory tectothalamic inputs were diminished by aging. These findings suggest that cholinergic input to the MGB increases the strength of tectothalamic inhibitory projections, potentially improving the signal-to-noise ratio and signal detection while increasing corticothalamic gain, which may facilitate top-down identification of stimulus identity. These mechanisms appear to be affected negatively by aging, potentially diminishing speech perception in noisy environments. Cholinergic inputs to the MGB appear to maximize sensory processing by adjusting both top-down and bottom-up mechanisms in conditions of attention and arousal.

SIGNIFICANCE STATEMENT The pedunculopontine tegmental nucleus is the source of cholinergic innervation for sensory thalamus and is a critical part of an ascending arousal system that controls the firing mode of thalamic cells based on attentional demand. The present study describes the location and impact of aging on presynaptic neuronal nicotinic acetylcholine receptors (nAChRs) within the circuitry of the auditory thalamus (medial geniculate body, MGB). We show that nAChRs are located on ascending inhibitory and descending excitatory presynaptic inputs onto MGB neurons, likely increasing gain selectively and improving temporal clarity. In addition, we show that aging has a deleterious effect on nAChR efficacy. Cholinergic dysfunction at the level of MGB may affect speech understanding negatively in the elderly population.



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Cortical Regulation of Nociception of the Trigeminal Nucleus Caudalis

Pain perception is strongly influenced by descending pathways from "higher" brain centers that regulate the activity of spinal circuits. In addition to the extensively studied descending system originating from the medulla, the neocortex provides dense anatomical projections that directly target neurons in the spinal cord and the spinal trigeminal nucleus caudalis (SpVc). Evidence exists that these corticotrigeminal pathways may modulate the processing of nociceptive inputs by SpVc, and regulate pain perception. We demonstrate here, with anatomical and optogenetic methods, and using both rats and mice (of both sexes), that corticotrigeminal axons densely innervate SpVc, where they target and directly activate inhibitory and excitatory neurons. Electrophysiological recordings reveal that stimulation of primary somatosensory cortex potently suppresses SpVc responses to noxious stimuli and produces behavioral hypoalgesia. These findings demonstrate that the corticotrigeminal pathway is a potent modulator of nociception and a potential target for interventions to alleviate chronic pain.

SIGNIFICANCE STATEMENT Many chronic pain conditions are resistant to conventional therapy. Promising new approaches to pain management capitalize on the brain's own mechanisms for controlling pain perception. Here we demonstrate that cortical neurons directly innervate the brainstem to drive feedforward inhibition of nociceptive neurons. This corticotrigeminal pathway suppresses the activity of these neurons and produces analgesia. This corticotrigeminal pathway may constitute a therapeutic target for chronic pain.



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Gaze-Stabilizing Central Vestibular Neurons Project Asymmetrically to Extraocular Motoneuron Pools

Within reflex circuits, specific anatomical projections allow central neurons to relay sensations to effectors that generate movements. A major challenge is to relate anatomical features of central neural populations, such as asymmetric connectivity, to the computations the populations perform. To address this problem, we mapped the anatomy, modeled the function, and discovered a new behavioral role for a genetically defined population of central vestibular neurons in rhombomeres 5–7 of larval zebrafish. First, we found that neurons within this central population project preferentially to motoneurons that move the eyes downward. Concordantly, when the entire population of asymmetrically projecting neurons was stimulated collectively, only downward eye rotations were observed, demonstrating a functional correlate of the anatomical bias. When these neurons are ablated, fish failed to rotate their eyes following either nose-up or nose-down body tilts. This asymmetrically projecting central population thus participates in both upward and downward gaze stabilization. In addition to projecting to motoneurons, central vestibular neurons also receive direct sensory input from peripheral afferents. To infer whether asymmetric projections can facilitate sensory encoding or motor output, we modeled differentially projecting sets of central vestibular neurons. Whereas motor command strength was independent of projection allocation, asymmetric projections enabled more accurate representation of nose-up stimuli. The model shows how asymmetric connectivity could enhance the representation of imbalance during nose-up postures while preserving gaze stabilization performance. Finally, we found that central vestibular neurons were necessary for a vital behavior requiring maintenance of a nose-up posture: swim bladder inflation. These observations suggest that asymmetric connectivity in the vestibular system facilitates representation of ethologically relevant stimuli without compromising reflexive behavior.

SIGNIFICANCE STATEMENT Interneuron populations use specific anatomical projections to transform sensations into reflexive actions. Here we examined how the anatomical composition of a genetically defined population of balance interneurons in the larval zebrafish relates to the computations it performs. First, we found that the population of interneurons that stabilize gaze preferentially project to motoneurons that move the eyes downward. Next, we discovered through modeling that such projection patterns can enhance the encoding of nose-up sensations without compromising gaze stabilization. Finally, we found that loss of these interneurons impairs a vital behavior, swim bladder inflation, that relies on maintaining a nose-up posture. These observations suggest that anatomical specialization permits neural circuits to represent relevant features of the environment without compromising behavior.



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Striatal dopamine in Parkinson's disease: A meta-analysis of imaging studies

Abstract

A meta-analysis of 141 PET and SPECT studies that have investigated striatal presynaptic dopamine function in Parkinson's disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) defects, suggesting up-regulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. This article is protected by copyright. All rights reserved.



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Blood blister in mouth: Pictures and treatment

Learn about the causes of blood blisters in the mouth, including injury, oral herpes, stress, and oral cancer. How are blood blisters treated?

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Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency

Lin et al. demonstrate that Ascl1+ and Neurog1+ neuronal progenitors can acquire cell fate plasticity after injury using genetic lineage trace and transplantation assays. Injury-induced multipotency occurs through a developmentally reminiscent endogenous upregulation of Sox2, KLF4, and Pax6, and dedifferentiation efficiency can be enhanced by Ezh2 inhibition.

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Injury Activates Transient Olfactory Stem Cell States with Diverse Lineage Capacities

Gadye et al. use multiple single-cell techniques to identify the cell state transitions underlying the stem cell self-renewal and differentiation during injury-induced regeneration of the olfactory epithelium. Olfactory stem cells shift en masse to a transient cell state unique to regeneration in which diverse fates are specified.

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Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming

Ruetz et al. show that constitutively active SMAD2/3 has a surprising ability to boost the efficiency of cell reprogramming both to iPSCs and across lineages and may therefore be a general factor that can enhance transcription-factor-mediated reprogramming in a variety of contexts.

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{alpha}II Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function

Spectrins form a submembranous cytoskeleton proposed to confer strength and flexibility to neurons and to participate in ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Neuronal spectrin cytoskeletons consist of diverse β subunits and αII spectrin. Although αII spectrin is found in neurons in both axonal and somatodendritic domains, using proteomics, biochemistry, and superresolution microscopy, we show that αII and βIV spectrin interact and form a periodic AIS cytoskeleton. To determine the role of spectrins in the nervous system, we generated Sptan1f/f mice for deletion of CNS αII spectrin. We analyzed αII spectrin-deficient mice of both sexes and found that loss of αII spectrin causes profound reductions in all β spectrins. αII spectrin-deficient mice die before 1 month of age and have disrupted AIS and many other neurological impairments including seizures, disrupted cortical lamination, and widespread neurodegeneration. These results demonstrate the importance of the spectrin cytoskeleton both at the AIS and throughout the nervous system.

SIGNIFICANCE STATEMENT Spectrin cytoskeletons play diverse roles in neurons, including assembly of excitable domains such as the axon initial segment (AIS) and nodes of Ranvier. However, the molecular composition and structure of these cytoskeletons remain poorly understood. Here, we show that αII spectrin partners with βIV spectrin to form a periodic cytoskeleton at the AIS. Using a new αII spectrin conditional knock-out mouse, we show that αII spectrin is required for AIS assembly, neuronal excitability, cortical lamination, and to protect against neurodegeneration. These results demonstrate the broad importance of spectrin cytoskeletons for nervous system function and development and have important implications for nervous system injuries and diseases because disruption of the spectrin cytoskeleton is a common molecular pathology.



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An {alpha}II Spectrin-Based Cytoskeleton Protects Large-Diameter Myelinated Axons from Degeneration

Axons must withstand mechanical forces, including tension, torsion, and compression. Spectrins and actin form a periodic cytoskeleton proposed to protect axons against these forces. However, because spectrins also participate in assembly of axon initial segments (AISs) and nodes of Ranvier, it is difficult to uncouple their roles in maintaining axon integrity from their functions at AIS and nodes. To overcome this problem and to determine the importance of spectrin cytoskeletons for axon integrity, we generated mice with αII spectrin-deficient peripheral sensory neurons. The axons of these neurons are very long and exposed to the mechanical forces associated with limb movement; most lack an AIS, and some are unmyelinated and have no nodes. We analyzed αII spectrin-deficient mice of both sexes and found that, in myelinated axons, αII spectrin forms a periodic cytoskeleton with βIV and βII spectrin at nodes of Ranvier and paranodes, respectively, but that loss of αII spectrin disrupts this organization. Avil-cre;Sptan1f/f mice have reduced numbers of nodes, disrupted paranodal junctions, and mislocalized Kv1 K+ channels. We show that the density of nodal βIV spectrin is constant among axons, but the density of nodal αII spectrin increases with axon diameter. Remarkably, Avil-cre;Sptan1f/f mice have intact nociception and small-diameter axons, but severe ataxia due to preferential degeneration of large-diameter myelinated axons. Our results suggest that nodal αII spectrin helps resist the mechanical forces experienced by large-diameter axons, and that αII spectrin-dependent cytoskeletons are also required for assembly of nodes of Ranvier.

SIGNIFICANCE STATEMENT A periodic axonal cytoskeleton consisting of actin and spectrin has been proposed to help axons resist the mechanical forces to which they are exposed (e.g., compression, torsion, and stretch). However, until now, no vertebrate animal model has tested the requirement of the spectrin cytoskeleton in maintenance of axon integrity. We demonstrate the role of the periodic spectrin-dependent cytoskeleton in axons and show that loss of αII spectrin from PNS axons causes preferential degeneration of large-diameter myelinated axons. We show that nodal αII spectrin is found at greater densities in large-diameter myelinated axons, suggesting that nodes are particularly vulnerable domains requiring a specialized cytoskeleton to protect against axon degeneration.



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Concerted Interneuron Activity in the Cerebellar Molecular Layer During Rhythmic Oromotor Behaviors

Molecular layer interneurons (MLIs, stellate and basket cells) of the cerebellar cortex are linked together by chemical and electrical synapses and exert a potent feedforward inhibition on Purkinje cells. The functional role of MLIs during specific motor tasks is uncertain. Here, we used two-photon imaging to study the patterns of activity of neighboring individual MLIs in the Crus II region of awake female mice during two types of oromotor activity, licking and bruxing, using specific expression of the genetically encoded calcium indicator protein GCaMP6s. We found that both stellate and basket cells engaged in synchronized waves of calcium activity during licking and bruxing, with high degrees of correlation among the signals collected in individual MLIs. In contrast, no calcium activity was observed during whisking. MLI activity tended to lag behind the onset of sustained licking episodes, indicating a regulatory action of MLIs during licking. Furthermore, during licking, stellate cell activity was anisotropic: the coordination was constant along the direction of parallel fibers (PFs), but fell off with distance along the orthogonal direction. These results suggest a PF drive for Ca2+ signals during licking. In contrast, during bruxing, MLI activity was neither clearly organized spatially nor temporally correlated with oromotor activity. In conclusion, MLI activity exhibits a high degree of correlation both in licking and in bruxing, but spatiotemporal patterns of activity display significant differences for the two types of behavior.

SIGNIFICANCE STATEMENT It is known that, during movement, the activity of molecular layer interneurons (MLIs) of the cerebellar cortex is enhanced. However, MLI–MLI interactions are complex because they depend both from excitatory electrical synapses and from potentially inhibitory chemical synapses. Accordingly, the pattern of MLI activity during movement has been unclear. Here, during two oromotor tasks, licking and bruxism, individual neighboring MLIs displayed highly coordinated activity, showing that the positive influences binding MLIs together are predominant. We further find that spatiotemporal patterns differ between licking and bruxing, suggesting that the precise pattern of MLI activity depends on the nature of the motor task.



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Application of the Milan system for reporting risk stratification in salivary gland cytopathology



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Reply to Application of the Milan system for reporting risk stratification in salivary gland cytopathology



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Process mapping: A cornerstone of quality improvement



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A hardware-oriented concurrent TZ search algorithm for High-Efficiency Video Coding

High-Efficiency Video Coding (HEVC) is the latest video coding standard, in which the compression performance is double that of its predecessor, the H.264/AVC standard, while the video quality remains unchange...

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The effects of chemoradiotherapy on recurrence and survival in locally advanced rectal cancers with curative total mesorectal excision: a prospective, nonrandomized study

Abstract

Background

There are only two prospective, randomized studies comparing preoperative long-term chemoradiotherapy and postoperative chemoradiotherapy in locally advanced rectal cancer (LARC); however, conflicting results in terms of locoregional recurrence (LR) and survival rates have been reported. This prospective study aims to compare the effects of preoperative versus postoperative chemoradiotherapy on recurrence and survival rates in LARC patients.

Methods

From January 2003 to January 2016, a total of 336 eligible patients who were clinically diagnosed with LARC (T3–T4 tm or node-positive disease) were prospectively assigned into preoperative chemoradiotherapy (n = 177) and postoperative chemoradiotherapy (n = 159) groups. The preoperative treatment consisted of 50.4 Gy total dose of radiotherapy (delivered in fractions of 1.8 Gy) and concomitant two cycles chemotherapy of 5-fluorouracil and leucovorin. The patients in the preoperative group underwent curative total mesorectal excision (TME) following long-term chemoradiotherapy. Surgery was performed 8 (range 4–12) median weeks after the completion of the chemoradiotherapy. Similar protocol was administered to the postoperative group 4 weeks after the operation. Four cycles of adjuvant chemotherapy were added to the groups. The primary end points were locoregional recurrences and 5-year cancer-specific, overall, and disease-free survivals.

Results

The mean follow-up period was 60.4 (range 12 to 168) months. Five-year cumulative incidence of locoregional recurrence (LR) was 7.4% in the preoperative group and 13.4% in the postoperative group (p = 0.021). Five-year cancer-specific survival (CSS) was 87.5% in the preoperative group and 80% in the postoperative group (p = 0.022). Overall survival (OS) was 79.8 versus 74.7% (p = 0.064), disease-free survival (DFS) was 75.2 versus 64.8% (p = 0.062), and severe late toxicity was 7.4 versus 13.2% (p = 0.002), respectively. The rate of patient compliance was higher in the preoperative group (p < 0.001).

Conclusions

Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, significantly improved local control, patient compliance, CSS, and late toxicity and suggested a trend toward improved overall and disease-free survival.



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Weight management and physical activity throughout the cancer care continuum

Abstract

Mounting evidence suggests that weight management and physical activity (PA) improve overall health and well being, and reduce the risk of morbidity and mortality among cancer survivors. Although many opportunities exist to include weight management and PA in routine cancer care, several barriers remain. This review summarizes key topics addressed in a recent National Academies of Science, Engineering, and Medicine workshop entitled, "Incorporating Weight Management and Physical Activity Throughout the Cancer Care Continuum." Discussions related to body weight and PA among cancer survivors included: 1) current knowledge and gaps related to health outcomes; 2) effective intervention approaches; 3) addressing the needs of diverse populations of cancer survivors; 4) opportunities and challenges of workforce, care coordination, and technologies for program implementation; 5) models of care; and 6) program coverage. While more discoveries are still needed for the provision of optimal weight-management and PA programs for cancer survivors, obesity and inactivity currently jeopardize their overall health and quality of life. Actionable future directions are presented for research; practice and policy changes required to assure the availability of effective, affordable, and feasible weight management; and PA services for all cancer survivors as a part of their routine cancer care. CA Cancer J Clin 2017. © 2017 American Cancer Society.



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Past-year Prescription Drug Monitoring Program Opioid Prescriptions and Self-reported Opioid Use in an Emergency Department Population with Opioid Use Disorder

Abstract

Background

Despite increasing reliance on Prescription Drug Monitoring Programs (PDMPs) as a response to the opioid epidemic, the relationship between aberrant drug-related behaviors captured by the PDMP and opioid use disorder is incompletely understood. How PDMP data should guide Emergency Department (ED) assessment has not been studied.

Study Objective

To evaluate a relationship between PDMP opioid prescription records and self-reported non-medical opioid use of prescription opioids in a cohort of opioid dependent ED patients enrolled in a treatment trial.

Methods

PDMP opioid prescription records during one year prior to study enrollment on 329 adults meeting Diagnostic and Statistical Manual IV criteria for opioid dependence entering a randomized clinical trial (RCT) in a large, urban ED were cross tabulated with data on 30-day non-medical prescription opioid use self-report. The association among these two types of data was assessed by the Goodman and Kruskal's Gamma; a logistic regression was used to explore characteristics of participants who had PDMP record of opioid prescriptions.

Results

During one year prior to study enrollment,118/329 (36%) patients had ≥ 1 opioid prescriptions (range 1-51) in our states' PDMP. Patients who reported ≥15 out of 30 days of non-medical prescription opioid use were more likely to have ≥4 PDMP opioid prescriptions (20/38; 53%) than patients reporting 1-14 days (14/38, 37%) or zero days of non-medical prescription opioid use (4/38,11%); p=0.002. Female gender and having health insurance were significantly more represented in the PDMP (p<0.05 for both).

Conclusion

PDMPs may be helpful in identifying patients with certain aberrant drug-related behavior, but are unable to detect many patients with OUD. The majority of ED patients with OUD were not captured by the PDMP, highlighting the importance of using additional methods such as screening and clinical history to identify OUDs in ED patients and the limitations of PDMPs to detect OUDs.

This article is protected by copyright. All rights reserved.



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The Reply to the letter on the cost-effectiveness of human papillomavirus in Punjab further distorts the scientific record



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Factors affecting compliance with confirmatory colonoscopy after a positive fecal immunochemical test in a national colorectal screening program

BACKGROUND

Screening with the fecal immunochemical test (FIT) is effective in reducing deaths from colorectal cancer (CRC). Since 2004, biennial FIT screening has been available to a target population in Taiwan as a national screening program. The objective of the current study was to identify the factors that influence willingness to undergo a confirmatory colonoscopy after a positive FIT, because related references in the published literature were scarce.

METHODS

A semistructured questionnaire was based on the Health Belief Model (HBM) and a literature review. A stratified, random sampling method was used to recruit participants who had a positive FIT from all cities/counties in Taiwan. Cross-sectional, computer-assisted telephone interviews were conducted in 2012, and the results were analyzed using a logistic regression model that took into account population demographics, core content of the HBM, and HBM-modifying variables.

RESULTS

In total, 2807 respondents were included in the analysis. The completion rate was 50%. Multivariate analyses revealed that higher perceived threat (adjusted odds ratio [aOR], 1.62; 95% confidence interval [CI], 1.31-2.01), higher cues for action (aOR, 2.18; 95% CI, 1.68-1.82), lower perceived barriers (aOR, 0.42; 95% CI, 0.34-0.42) and higher health behavior scores (aOR, 1.30; 95% CI, 1.05-1.60) were associated with a greater willingness to participate in confirmatory colonoscopy. Participants who were older (aOR, 0.74; 95% CI, 0.55-0.98) or unmarried (aOR, 0.72; 95% CI, 0.56-0.92) were less likely to participate in verification.

CONCLUSIONS

The government could improve the screening rate by training case managers to assist in following patients until they complete colonoscopy, subsidizing sedated colonoscopies, and providing health education not only to the general public but also to physicians. Cancer 2017. © 2017 American Cancer Society.



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Physician interpretation of genomic test results and treatment selection

BACKGROUND

Genomic testing is increasingly performed in oncology, but concerns remain regarding the clinician's ability to interpret results. In the current study, the authors sought to determine the agreement between physicians and genomic annotators from the Precision Oncology Decision Support (PODS) team at The University of Texas MD Anderson Cancer Center in Houston regarding actionability and the clinical use of test results.

METHODS

On a prospective protocol, patients underwent clinical genomic testing for hotspot mutations in 46 or 50 genes. Six months after sequencing, physicians received questionnaires for patients who demonstrated a variant in an actionable gene, investigating their perceptions regarding the actionability of alterations and clinical use of these findings. Genomic annotators independently classified these variants as actionable, potentially actionable, unknown, or not actionable.

RESULTS

Physicians completed 250 of 288 questionnaires (87% response rate). Physicians considered 168 of 250 patients (67%) as having an actionable alteration; of these, 165 patients (98%) were considered to have an actionable alteration by the PODS team and 3 were of unknown significance. Physicians were aware of genotype-matched therapy available for 119 patients (71%) and 48 of these 119 patients (40%) received matched therapy. Approximately 46% of patients in whom physicians regarded alterations as not actionable (36 of 79 patients) were classified as having an actionable/potentially actionable mutation by the PODS team. However, many of these were only theoretically actionable due to limited trials and/or therapies (eg, KRAS).

CONCLUSIONS

Physicians are aware of recurrent mutations in actionable genes on "hotspot" panels. As larger genomic panels are used, there may be a growing need for annotation of actionability. Decision support to increase awareness of genomically relevant trials and novel treatment options for recurrent mutations (eg, KRAS) also are needed. Cancer 2017. © 2017 American Cancer Society.



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Reply to Genomic profiles of nasopharyngeal carcinoma: The importance of histological subtyping and Epstein-Barr virus in situ assays



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Genomic profiles of nasopharyngeal carcinoma: The importance of histological subtyping and Epstein-Barr virus in situ assays



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Growth Abnormalities of Fetuses and Infants



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Sex and rank affect how infant rhesus macaques look at faces

Abstract

We investigated how differences in infant sex and mothers' dominance status affect infant rhesus macaques' (Macaca mulatta) interest in visually exploring emotional facial expressions. Thirty-eight infants were presented with animated avatars of macaque facial expressions during the first month of life. Sons of high-ranking mothers looked more at faces, especially the eye region, than sons of low-ranking mothers, but no difference in looking duration was found for daughters. Males looked significantly more at eyes than females, but this effect was reversed in infants who were reared without mothers in a primate nursery facility. In addition, in mother-infant interactions, mothers of sons were more likely to gaze at their infant's face compared to mothers of daughters. Combined with previous research indicating that rhesus macaque mothers interact differently with infants based on their own rank and infant's sex, these results support the view that social experiences shape early face preferences in rhesus macaques.



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New Research From Psychological Science

Read about the latest research published in Psychological Science:

Eye-Tracking Causality

Tobias Gerstenberg, Matthew F. Peterson, Noah D. Goodman, David A. Lagnado, and Joshua B. Tenenbaum
How do people make causal judgments? Counterfactual theories of causal judgments suggest that people determine causation based on whether an action would have occurred without the candidate cause. Process theories, in contrast, suggest that people base their causal decisions only on what actually happened — not what might have been. In this study, the researchers examined how people make causal judgments about physical interactions by tracking the eye movements of participants as they watched video clips in which two balls (A and B) collided on a field with a gate at one end. The clips differed in whether Ball B clearly missed the gate, clearly went through the gate, or barely missed or went through the gate. The clips also differed in what would have happened to Ball B if Ball A had not been present. Eye tracking indicated that participants extrapolated the target ball's counterfactual motion path to determine whether the candidate made a difference to the outcome. The more certain participants were that the counterfactual outcome would have been altered from the actual outcome, the more they agreed with statements indicating that one ball made the other go through — or miss — the gate. This study is one of the first to demonstrate the close relationship between counterfactual reasoning and causal judgments.

The Empirical Case for Acquiescing to Intuition

Daniel K. Walco and Jane L. Risen
People sometimes recognize that their intuitive judgments are wrong while still maintaining those judgments — a phenomenon termed acquiescence. Although researchers have previously argued for the existence of acquiescence, a convincing empirical demonstration has been lacking. The authors remedy this in a series of four studies. In the first study, participants completed a ratio-based paradigm. In the second study, participants guessed which of three envelopes contained money. They were then given the chance to trade their one envelope for the other two envelopes. In a third study, participants played hands of blackjack, and in a fourth study, participants indicated whether a football team should punt or "go for it" on a fourth down. Participants were provided with information indicating the optimal strategy in each decision-making task. The researchers found that one third to one half of participants stuck to their intuitive strategy, even when they knew it was not strategically optimal. The researchers indicate that their findings demonstrate the presence of acquiescence and that acquiescence should be considered in dual-process models of judgment and decision making.

Healthy Out-Group Members Are Represented Psychologically as Infected In-Group Members

Michael Bang Petersen

Past research has indicated that people implicitly treat members of outgroups as if they are carrying pathogens — something that may drive prejudice toward these groups. In two studies, the researcher examined whether this link results from an evolutionary adaptation or whether it is a behavioral by-product. In each study, participants completed a memory-confusion protocol (the "who said what?") in which they saw images of four White Americans and four people with an East Indian background. A neutral statement was paired with each pictured individual. Participants then engaged in a distractor task before completing a surprise recall test in which they had to match each statement to the person it was originally paired with. In one condition (control), all pictured individuals appeared healthy and in the other (treatment), in-group members were presented with significant facial rashes. The pattern of results indicated that healthy out-group members were represented using the same psychological category as infected in-group members — a finding that supports the view that the association between pathogens and out-group members is a by-product and not an adaptation.

Preschool Intervention Can Promote Sustained Growth in the Executive-Function Skills of Children Exhibiting Early Deficits

Tyler R. Sasser, Karen L. Bierman, Brenda Heinrichs, and Robert L. Nix

Delays and impairments in executive-functioning (EF) skills have been found to undermine school readiness, adjustment, and learning. Although preschool interventions have been shown to improve EF skills at end-of-intervention-year assessments, few studies have looked at the sustained effect of these interventions on EF development. In this study, Head Start centers were randomly assigned to provide the Head Start Research-Based, Developmentally Informed (REDI) preschool intervention or a "usual practice" control curriculum. The REDI intervention focused on teaching children how to identify and manage strong emotions and how to employ self-regulation techniques. The researchers followed the children from preschool through the third grade and assessed them for components of EF (inhibitory control, attention shifting, and working memory) and academic outcomes. The intervention had the greatest impact on children who had low levels of EF skills at the baseline assessment. The intervention helped these children maintain their EF skills through the third grade. In contrast, children with low EF skills who received the control curriculum showed marked decreases in EF after entry into kindergarten and had poorer academic outcomes than their counterparts who received the intervention.



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