Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK).

Purpose: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.

Financial Improvements From Short Course Adjuvant Vaginal Cuff Brachytherapy in Early Endometrial Cancer Compared With Standard of Care, "SAVE" Trial.

Purpose: Early-stage endometrial cancer is often treated with hysterectomy followed by adjuvant vaginal cuff brachytherapy (VCB). Financial toxicity from cancer treatment can impact treatment completion. The Short Course Adjuvant Vaginal Cuff Brachytherapy in Early Endometrial Cancer Compared to Standard of Care trial is a multicenter, prospective randomized trial of standard of care (SoC) VCB doses delivered in 3 to 5 fractions per the physician's discretion compared with a 2-fraction course.

The PS4-likelihood ratio calculator: flexible allocation of evidence weighting for case-control data in variant classification.

Background: The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as 'strong' evidence (PS4) towards pathogenicity.

Methods: We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds.

Does the level of mobility on ICU discharge impact post-ICU outcomes? A retrospective analysis.

Purpose: Mobilisation is a common intervention in Intensive Care (ICU). However, few studies have explored the relationship between mobility levels and outcomes. This study assessed the association of the level of mobility on ICU discharge with discharge destination from the hospital and hospital length of stay.

Exploring the application of machine learning to expert evaluation of research impact.

The objective of this study is to investigate the application of machine learning techniques to the large-scale human expert evaluation of the impact of academic research. Using publicly available impact case study data from the UK's Research Excellence Framework (2014), we trained five machine learning models on a range of qualitative and quantitative features, including institution, discipline, narrative style (explicit and implicit), and bibliometric and policy indicators. Our work makes two key contributions.

Dosimetric Evaluation of Organs at Risk From SAVE Protocol.

Purpose: The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial.

Methods And Materials: SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy × 2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy × 3 fx to 5 mm, 5 to 5.

Understanding the funding characteristics of research impact: A proof-of-concept study linking REF 2014 impact case studies with Researchfish grant agreements.

Background: All parts of the research community have an interest in understanding research impact whether that is around the pathways to impact, processes around impact, methods for measurement, describing impact and so on. This proof of concept study explored the relationship between research funding and research impact using the case studies submitted to the UK Research Excellence Framework (REF) exercise in 2014 as a proxy for impact.

Methods: The paper describes an approach to link the REF impact case studies with the underpinning research grants present in the Researchfish dataset, primarily using the publications captured in both datasets.

Fundamental challenges in assessing the impact of research infrastructure.

Clinical research infrastructure is one of the unsung heroes of the scientific response to the current COVID-19 pandemic. The extensive, long-term funding into research support structures, skilled people, and technology allowed the United Kingdom research response to move off the starting blocks at pace by utilizing pre-existing platforms. The increasing focus from funders on evaluating the outcomes and impact of research infrastructure investment requires both a reframing and progression of the current models in order to address the contribution of the underlying support infrastructure.

The indispensable role of pharmacy services and medication therapy management in cystic fibrosis.

Care for people with cystic fibrosis (PWCF) is highly complex and requires a multidisciplinary approach where the pharmacist plays a vital role. The purpose of this manuscript is to serve as a guideline for pharmacists and pharmacy technicians who provide care for PWCF by providing background and current recommendations for the use of cystic fibrosis (CF)-specific medications in both the acute and ambulatory care settings. The article explores current literature surrounding the role of pharmacists and pharmacy technicians, proven pharmacy models to emulate, and pharmacokinetic idiosyncrasies unique to the CF population while also identifying areas of future research.

EVITA 2.0, an updated framework for understanding evidence-based mental health policy agenda-setting: tested and informed by key informant interviews in a multilevel comparative case study.

Background: Mental health remains a neglected issue on the global health policy agenda, particularly in low- and middle-income countries (LMIC), and the translation of research evidence into policy and practice is slow. The new EVITA framework was developed to improve mental health evidence uptake and policy agenda-setting in LMICs. In addition, behavioural science methods may be able to support knowledge translation to policy.

Biliary disease and cholecystectomy after initiation of elexacaftor/ivacaftor/tezacaftor in adults with cystic fibrosis.

Individuals with cystic fibrosis (CF) have an increased risk for gallbladder abnormalities and biliary tract disease, but the reported incidence of these manifestations of CF varies widely in the literature. With the approval of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), increasing numbers of CF patients have been initiated on highly effective cystic fibrosis transmembrane regulator (CFTR) modulator therapy. While elevations in hepatic panel are known potential side effects of CFTR modulators, there have been no published cases of biliary disease or acute cholecystitis attributed to these medications.

Development and Implementation of Clinical Outcome Measures for Automated Collection Within Specialty Pharmacy Practice.

Background: Johns Hopkins Specialty Pharmacy Services recognized the need to identify and develop standardized collection methods for clinical outcome measures (COMs) to demonstrate program quality and value to third-party payers, manufacturers, and internal stakeholders.

Objective: To define specialty COMs and develop a framework for standardized data collection and reporting.

Methods: COMs for specialty pharmacy disease states (cystic fibrosis; hepatitis C; inflammatory conditions in dermatology, gastroenterology and rheumatology; and multiple sclerosis) were identified through a literature search, collaboration with specialty pharmacists, and committee review.

From COVID-19 research to vaccine application: why might it take 17 months not 17 years and what are the wider lessons?

It is often said that it takes 17 years to move medical research from bench to bedside. In a coronavirus disease (COVID-19) world, such time-lags feel intolerable. In these extraordinary circumstances could years be made into months? If so, could those lessons be used to accelerate medical research when the crisis eases?To measure time-lags in health and biomedical research as well as to identify ways of reducing them, we developed and published (in 2015) a matrix consisting of overlapping tracks (or stages/phases) in the translation from discovery research to developed products, policies and practice.

The EVITA framework for evidence-based mental health policy agenda setting in low- and middle-income countries.

The burden of mental illness is excessive, but many countries lack evidence-based policies to improve practice. Mental health research evidence translation into policymaking is a 'wicked problem', often failing despite a robust evidence base. In a recent systematic review, we identified a gap in frameworks on agenda setting and actionability, and pragmatic, effective tools to guide action to link research and policy are needed.

Recurrent early stage endometrial cancer: Patterns of recurrence and results of salvage therapy.

Objective: To analyze our institutional experience and oncologic outcomes for salvage treatment for the recurrence of early-stage endometrial cancer patients.

Methods: We included women of all ages diagnosed with FIGO stage I-II, any grade endometrial cancer from 2000 to 2016 at our institutions who were treated with at least a hysterectomy. Recurrences in the pelvis and/or vagina were considered locoregional recurrences (LRR).

Do vaginal recurrence rates differ among adjuvant vaginal brachytherapy regimens in early-stage endometrial cancer?

Purpose: We sought to retrospectively examine clinical outcomes for three adjuvant vaginal high-dose-rate (HDR) brachytherapy regimens after hysterectomy for early-stage endometrial cancer.

Methods: Included were women of all ages from two independent hospital systems diagnosed with Stage I-II endometrial cancer of any grade between 2000 and 2016 who underwent hysterectomy followed by adjuvant vaginal cylinder HDR brachytherapy with either 7.0 Gy × 3 fractions prescribed to 0.

Economic returns to medical research funding.

Following the publication of the final paper in a planned series of four studies estimating the economic returns from biomedical and health research, we reflect on what we have learnt from these types of assessment.

A systematic review of frameworks for the interrelationships of mental health evidence and policy in low- and middle-income countries.

Background: The interrelationships between research evidence and policy-making are complex. Different theoretical frameworks exist to explain general evidence-policy interactions. One largely unexplored element of these interrelationships is how evidence interrelates with, and influences, policy/political agenda-setting.

ISRIA statement: ten-point guidelines for an effective process of research impact assessment.

As governments, funding agencies and research organisations worldwide seek to maximise both the financial and non-financial returns on investment in research, the way the research process is organised and funded is becoming increasingly under scrutiny. There are growing demands and aspirations to measure research impact (beyond academic publications), to understand how science works, and to optimise its societal and economic impact. In response, a multidisciplinary practice called research impact assessment is rapidly developing.

Estimating the returns to United Kingdom publicly funded musculoskeletal disease research in terms of net value of improved health outcomes.

Background: Building on an approach applied to cardiovascular and cancer research, we estimated the economic returns from United Kingdom public- and charitable-funded musculoskeletal disease (MSD) research that arise from the net value of the improved health outcomes in the United Kingdom.

Methods: To calculate the economic returns from MSD-related research in the United Kingdom, we estimated (1) the public and charitable expenditure on MSD-related research in the United Kingdom between 1970 and 2013; (2) the net monetary benefit (NMB), derived from the health benefit in quality adjusted life years (QALYs) valued in monetary terms (using a base-case value of a QALY of £25,000) minus the cost of delivering that benefit, for a prioritised list of interventions from 1994 to 2013; (3) the proportion of NMB attributable to United Kingdom research; and (4) the elapsed time between research funding and health gain. The data collected from these four key elements were used to estimate the internal rate of return (IRR) from MSD-related research investments on health benefits.

Preoperative radiation dose escalation for rectal cancer using a concomitant boost strategy improves tumor downstaging without increasing toxicity: A matched-pair analysis.

Purpose: Pathologic complete response to neoadjuvant chemoradiation therapy (CRT) is associated with improved outcomes for patients with locally advanced rectal cancer (LARC). Increased response rates have been reported with higher radiation doses, but these studies often lack long-term outcome and/or toxicity data. We conducted a case-control analysis of patients with LARC who underwent definitive CRT to determine the efficacy and safety of intensified treatment with a concomitant boost (CB) approach.

The National Institute for Health Research at 10 Years: An Impact Synthesis: 100 Impact Case Studies.

The National Institute for Health Research (NIHR) funds and supports world-leading clinical and applied health and social care research, as well as research infrastructure in the NHS. Providing £1 billion of funding each year, NIHR aims to: drive the faster translation of new treatments, technologies and diagnostics to improve outcomes for health and care services; promote the wealth of the nation, including via inward investment from the health research community; pull basic science discoveries through into tangible benefits for patients and the public; and provide research evidence to support more effective and cost-effective NHS delivery. To mark its tenth anniversary, the Department of Health commissioned the Policy Research in Science and Medicine unit to consider the question: "What are the ways in which NIHR has benefited the health research landscape in the past ten years?" This study identifies and celebrates 100 examples of positive change resulting from NIHR's support of research.

Bibliometric Analysis of Mental Health Research: 1980--2008.

This article presents the findings of a bibliometric study of mental health research papers published from 1980 to 2008. The aim of this study was to map mental health research in the G20 and other leading countries in order to analyse i) the research productivity of nations; ii) the relative intensity of research; iii) the level of research (clinical or basic); iv) levels of scientific impact; and v) levels of collaboration. This work is the result of a collaboration between Observatoire des sciences et des technologies in Montreal and RAND Europe.

An Observational Study of Outcomes and Tolerances in Patients with Cystic Fibrosis Initiated on Lumacaftor/Ivacaftor.

Rationale: In July 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor for use in patients with cystic fibrosis (CF).