Albrightsvensson8677

Genome-wide association studies (GWAS) have identified several SNPs associated with pancreatic cancer. No studies yet have attempted to replicate these SNPs in US minority populations. We aimed to replicate the associations of 31 GWAS-identified SNPs with pancreatic cancer and build and test a polygenic risk score (PRS) for pancreatic cancer in an ethnically diverse population.

We evaluated 31 risk variants in the Multiethnic Cohort and the Southern Community Cohort Study. We included 691 pancreatic ductal adenocarcinoma (PDAC) cases and 13,778 controls from African-American, Japanese-American, Latino, Native Hawaiian, and white participants. We tested the association between each SNP and PDAC, established a PRS using the 31 SNPs, and tested the association between the score and PDAC risk.

Eleven of the 31 SNPs were replicated in the multiethnic sample. The PRS was associated with PDAC risk [OR top vs. middle quintile = 2.25 (95% confidence interval, 1.73-2.92)]. Notably, the PRS was associated with PDAC risk in all ethnic groups except Native Hawaiian (OR per risk allele ranged from 1.33 in Native Hawaiians to 1.91 in African Americans;

heterogeneity = 0.12).

This is the first study to replicate 11 of the 31 GWAS-identified risk variants for pancreatic cancer in multiethnic populations, including African Americans, Japanese Americans, and Latinos. Our results also suggest a potential utility of PRS with GWAS-identified risk variants for the identification of individuals at increased risk for PDAC across multiple ethnic groups.

PRS can potentially be used to stratify pancreatic cancer risk across multiple ethnic groups.

PRS can potentially be used to stratify pancreatic cancer risk across multiple ethnic groups.

Benefit-harm tradeoffs of melanoma screening depend on disease risk and treatment efficacy. We developed a model to project outcomes of screening for melanoma in populations with different risks under historic and novel systemic treatments.

Computer simulation model of a screening program with specified impact on overall and advanced-stage incidence. Inputs included meta-analyses of treatment trials, cancer registry data, and a melanoma risk prediction study RESULTS Assuming 50% reduction in advanced stage under screening, the model projected 59 and 38 lives saved per 100,000 men under historic and novel treatments, respectively. With 10% increase in stage I, the model projects 2.9 and 4.7 overdiagnosed cases per life saved and number needed to be screened (NNS) equal to 1695 and 2632 under historical and novel treatments. When screening was performed only for the 20% of individuals with highest predicted risk, 34 and 22 lives per 100,000 were saved under historic and novel treatments. Similar results were obtained for women, but lives saved were lower.

Melanoma early detection programs must shift a substantial fraction of cases from advanced to localized stage to be sustainable. Advances in systemic therapies for melanoma might noticeably reduce benefits of screening, but restricting screening to individuals at highest risk will likely reduce intervention efforts and harms while preserving >50% of the benefit of nontargeted screening.

Our accessible modeling framework will help to guide population melanoma screening programs in an era of novel treatments for advanced disease.

Our accessible modeling framework will help to guide population melanoma screening programs in an era of novel treatments for advanced disease.Publicly available RNA-seq data is routinely used for retrospective analysis to elucidate new biology. Novel transcript discovery enabled by joint analysis of large collections of RNA-seq data sets has emerged as one such analysis. Current methods for transcript discovery rely on a '2-Step' approach where the first step encompasses building transcripts from individual data sets, followed by the second step that merges predicted transcripts across data sets. To increase the power of transcript discovery from large collections of RNA-seq data sets, we developed a novel '1-Step' approach named Pooling RNA-seq and Assembling Models (PRAM) that builds transcript models from pooled RNA-seq data sets. We demonstrate in a computational benchmark that 1-Step outperforms 2-Step approaches in predicting overall transcript structures and individual splice junctions, while performing competitively in detecting exonic nucleotides. Applying PRAM to 30 human ENCODE RNA-seq data sets identified unannotated transcripts with epigenetic and RAMPAGE signatures similar to those of recently annotated transcripts. In a case study, we discovered and experimentally validated new transcripts through the application of PRAM to mouse hematopoietic RNA-seq data sets. We uncovered new transcripts that share a differential expression pattern with a neighboring gene Pik3cg implicated in human hematopoietic phenotypes, and we provided evidence for the conservation of this relationship in human. find more PRAM is implemented as an R/Bioconductor package.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterised by severe, recurrent thunderclap headaches (TCHs) and vasoconstriction of cerebral arteries that resolve within 3 months. Abnormalities on non-contrast CT (NCCT) such as ischaemic strokes, intracerebral haemorrhage and subarachnoid haemorrhages are frequently observed on brain imaging of patients with RCVS though their prevalence varies considerably between studies. The aim of this systematic review and meta-analysis is to estimate the prevalence of NCCT abnormalities seen on neuroimaging of adult patients with RCVS.

We will search the Medline, Embase and the Cochrane Library databases for studies on the prevalence of NCCT abnormalities on neuroimaging of patients with RCVS. Search results will be screened for eligibility by title and abstract. Suitable studies will be fully reviewed and relevant data extracted using a data abstraction form. The studies will be assessed for methodological quality, risk of bias and heterogeneity. Prevalence estimates across studies will be pooled using a random-effects model and subgroup analysis will be performed to assess the impact of age, sex, publication year and study design on prevalence of vascular lesions. Sensitivity analysis will be used to investigate the robustness of the findings. This protocol has been devised using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 checklist.

Formal ethics is not required as primary data will not be collected. The findings of this study will be disseminated through a peer-reviewed publication and conference presentations.

CRD42020190637.

CRD42020190637.

To find effective and safe treatments for COVID-19, the WHO recommended to systemically evaluate experimental therapeutics in collaborative randomised clinical trials. As COVID-19 was spreading in Europe, the French national institute for Health and Medical Research (Inserm) established a transdisciplinary team to develop a multi-arm randomised controlled trial named DisCoVeRy. The objective of the trial is to evaluate the clinical efficacy and safety of different investigational re-purposed therapeutics relative to Standard of Care (SoC) in patients hospitalised with COVID-19.

DisCoVeRy is a phase III, open-label, adaptive, controlled, multicentre clinical trial in which hospitalised patients with COVID-19 in need of oxygen therapy are randomised between five arms (1) a control group managed with SoC and four therapeutic arms with re-purposed antiviral agents (2) remdesivir + SoC, (3) lopinavir/ritonavir + SoC, (4) lopinavir/ritonavir associated with interferon (IFN)-β-1a + SoC and (5) hydroxychloroquine + SoC. The primary endpoint is the clinical status at Day 15 on the 7-point ordinal scale of the WHO Master Protocol (V.3.0, 3 March 2020). This trial involves patients hospitalised in conventional departments or intensive care units both from academic or non-academic hospitals throughout Europe. A sample size of 3100 patients (620 patients per arm) is targeted. This trial has begun on 22 March 2020. Since 5 April 2020, DisCoVeRy has been an add-on trial of the Solidarity consortium of trials conducted by the WHO in Europe and worldwide. On 8 June 2020, 754 patients have been included.

Inserm is the sponsor of DisCoVeRy. Ethical approval has been obtained from the institutional review board on 13 March 2020 (20.03.06.51744) and from the French National Agency for Medicines and Health Products (ANSM) on 9 March 2020. Results will be submitted for publication in peer-reviewed journals.

NCT04315948 Eudra-CT 2020-000936-23.

NCT04315948 Eudra-CT 2020-000936-23.

To explore the views of commissioners, service development leads, service managers and senior staff in selected dementia services on increasing the role of primary care in postdiagnostic support for people with dementia.

Qualitative semi-structured telephone interviews and a focus group.

Participants were drawn from National Health Service (NHS) Clinical Commissioning Groups, social care commissioning and a range of dementia services across primary care, secondary mental healthcare, social care and the third sector. All participants were based in England or Wales.

61 professionals, comprising 25 commissioners or service development leads; 25 service managers; and 11 team leads or senior staff.

Participants had varied views on whether a primary care-based approach for postdiagnostic support for people with dementia and their families was appropriate, achievable and/or desirable. Potential benefits of a task-shifted approach were continuity and a more holistic approach to care; familiarity for both patanding and consensus over what postdiagnostic support means in the context of dementia. We will be undertaking such research in the next phase of our programme.

Nicotine replacement therapy (NRT) has proven effective for smoking cessation in clinical trials, however it was found less effective in population-based studies, potentially due to inconsistent or incorrect use of NRT. The aim of this paper is to describe a systematic review protocol to evaluate level of adherence to NRT; the discrepancy of adherence to NRT in clinical and population-based studies and degree of association between level of adherence and success of smoking cessation.

Literature search will use five databases (Medline, Scopus, Embase, CINAHL and PsycINFO). Studies will be appraised for methodological quality using National Institutes of Health Quality Assessment Tool. To reduce heterogeneity, we will analyse clinical trials and population-based studies separately; pooled analyses will be done among studies that used similar measurements. Heterogeneity of studies will be assessed by Higgins' I

statistical test. When studies are adequately homogeneous, results will be pooled using random-effects model with proportion and ORs with 95% CIs and p values for each outcome. We will explain sources of heterogeneity by subgroup analysis or sensitivity analysis. Funnel plots and Egger's regression asymmetry test with p<0.05 will be used as a cut-off point to affirm presence of statistically significant publication bias. Statistical analyses will be carried out using Stata V.16 software. Only studies reporting a valid strategy to control for reverse causality will be included.

This review will provide evidence to support the importance of adherence on rate of smoking cessation and level of adherence to NRT. The findings will be used to inform smoking cessation interventions, researchers and policymakers.

As a systematic literature review, this protocol does not require ethics approval. Research outcomes will be presented at relevant conferences and findings will be published in a relevant peer-reviewed journal.

CRD42020176749.

CRD42020176749.