Mainstreaming of genomic medicine in gastroenterology, present and future: a nationwide survey of UK gastroenterology trainees

Objective: Genomics and personalised medicine are increasingly relevant for patients with gastroenterological conditions. We aim to capture the current state of genomics training in gastroenterology to review current understanding, clinical experience and long-term educational needs of UK trainees. // Design and setting: A web-based nationwide survey of all UK gastroenterology specialty trainees was conducted in 2017. // Results: 100 trainees (14% of UK gastroenterology trainees) completed this survey. Only 9% and 16% of respondents believe that their local training programme adequately prepares them for the future clinical practice using genomic medicine and personalised medicine, respectively. Barriers identified include the need for greater trainee education (95%), inadequate clinical guidance to base interventions on the results of genomic testing (53%), concerns over misinterpretation by patients (43%) and overuse/misuse of testing by clinicians (34%). Survey respondents felt prepared to perform HFE genotyping (98%), assess TPMT status (97%) and interpret HLA subtyping for suspected coeliac disease (85%). However, only a minority felt prepared to perform the following investigations: polyposis screening (34%), hereditary pancreatitis screening (30%), testing for Lynch yndrome (33%) and KRAS testing for colorectal cancer (20%). Most respondents would support holding dedicated training days on genomic medicine (83%), formal training provisions for the mainstreaming of genomic testing (64%), an update to the UK gastroenterology specialty training curriculum and examinations (57%) and better-defined referral pathways for local genomic services (91%). // Conclusion: Most gastroenterology trainees in this survey feel ill equipped to practise genomic and personalised medicine as consultants. We propose specific revisions to the UK gastroenterology specialty curriculum that addresses trainees needs

The impact of the COVID-19 pandemic on referrals to musculoskeletal services from primary care and subsequent incidence of inflammatory rheumatic musculoskeletal disease: an observational study

Objectives To describe the impact of the COVID-19 pandemic upon referral patterns and incident diagnosis of inflammatory rheumatic and musculoskeletal diseases (iRMDs). Methods UK primary care data was used to describe referral patterns for patients with musculoskeletal conditions. Trends in referrals to musculoskeletal services and incident diagnoses of iRMDs (specifically rheumatoid arthritis (RA) and juvenile inflammatory arthritis (JIA)) were described using Joinpoint Regression and comparisons made between key pandemic time periods. Results The incidence of RA and JIA reduced by -13.3% and -17.4% per month respectively between January 2020 and April 2020, and then increased by 1.9% and 3.7% per month respectively between April 2020 and October 2021. The incidence of all diagnosed iRMDs was stable until October 2021. Referrals decreased between February 2020 and May 2020 by -16.8% per month from 4.8% to 2.4% in patients presenting with a musculoskeletal condition. After May 2020, referrals increased significantly (16.8% per month) to 4.5% in July 2020. Time from first musculoskeletal consultation to RA diagnosis, and referral to RA diagnosis increased in the early-pandemic period (rate ratio (RR) 1.11, 95%CI 1.07-1.15; RR 1.23, 95%CI 1.17-1.30) and remained consistently higher in the late-pandemic (RR 1.13, 95%CI 1.11-1.16; RR 1.27, 95%CI 1.23-1.32) periods respectively, compared to the pre-COVID-19 period. Conclusion Patients with underlying RA and JIA that developed during the pandemic may be yet to present, or be in the referral and/or diagnostic process. Clinicians should remain alert to this possibility and commissioners aware of these findings, enabling the appropriate planning and commissioning of services

Introduction: Rethinking the Impact of the Inter-American Human Rights System

This chapter introduces the central themes of the book and argues that the Inter-American Human Rights System (IAHRS) is activated by political actors and institutions in ways that transcend traditional compliance perspectives and that have the potential to meaningfully alter politics and provoke positive domestic human rights change. The chapter identifies key gaps in existing human rights scholarship, particularly in relation to the IAHRS, and outlines three core perspectives on the System’s impact on human rights. It offers a synthesis of the key findings of the volume, and provides reflections on the future prospects of the System by locating it in its broader global context

SARS-CoV-2-specific memory B cells can persist in the elderly who have lost detectable neutralising antibodies

Memory B cells (MBC) can provide a recall response able to supplement waning antibodies with an affinity-matured response better able to neutralise variant viruses. We studied a cohort of elderly care home residents and younger staff (median age 87yrs and 56yrs respectively) who had survived COVID-19 outbreaks with only mild/asymptomatic infection. The cohort was selected to enrich for a high proportion who had lost neutralising antibodies (nAb), to specifically investigate the reserve immunity from SARS-CoV-2-specific MBC in this setting. Class-switched spike and RBD-tetramer-binding MBC persisted five months post-mild/asymptomatic SARS-CoV-2 infection, irrespective of age. The majority of spike/RBD-specific MBC had a classical phenotype but activated memory B cells, that may indicate ongoing antigenic stimulation or inflammation, were expanded in the elderly. Spike/RBD-specific MBC remained detectable in the majority who had lost nAb, although at lower frequencies and with a reduced IgG/IgA isotype ratio. Functional spike/S1/RBD-specific recall was also detectable by ELISpot in some who had lost nAb, but was significantly impaired in the elderly. Our findings demonstrate a reserve of SARS-CoV-2-specific MBC persists beyond loss of nAb, but highlight the need for careful monitoring of functional defects in spike/RBD-specific B cell immunity in the elderly

Academic careers in global pulmonary and critical care medicine

The burden of respiratory and critical illness is high worldwide, yet specialist care is underrepresented in low- and middle-income countries (LMICs) [1]. For many areas of medicine, the past decade has witnessed tremendous growth in global health opportunities for trainees; however, these opportunities tend to be restricted to individual institutions and geographic regions and academic global pulmonary and critical care medicine (PCCM) remains a relatively novel concept [2]. Consequently, PCCM fellows and junior faculty at institutions with limited global health mentorship have little guidance in building successful global health careers

Listeners form average-based representations of individual voice identities.

Models of voice perception propose that identities are encoded relative to an abstracted average or prototype. While there is some evidence for norm-based coding when learning to discriminate different voices, little is known about how the representation of an individual's voice identity is formed through variable exposure to that voice. In two experiments, we show evidence that participants form abstracted representations of individual voice identities based on averages, despite having never been exposed to these averages during learning. We created 3 perceptually distinct voice identities, fully controlling their within-person variability. Listeners first learned to recognise these identities based on ring-shaped distributions located around the perimeter of within-person voice spaces - crucially, these distributions were missing their centres. At test, listeners' accuracy for old/new judgements was higher for stimuli located on an untrained distribution nested around the centre of each ring-shaped distribution compared to stimuli on the trained ring-shaped distribution

Pathogenesis of progressive scarring trachoma in Ethiopia and Tanzania and its implications for disease control: two cohort studies.

BACKGROUND: Trachoma causes blindness through a conjunctival scarring process initiated by ocular Chlamydia trachomatis infection; however, the rates, drivers and pathophysiological determinants are poorly understood. We investigated progressive scarring and its relationship to conjunctival infection, inflammation and transcript levels of cytokines and fibrogenic factors. METHODOLOGY/PRINCIPAL FINDINGS: We recruited two cohorts, one each in Ethiopia and Tanzania, of individuals with established trachomatous conjunctival scarring. They were followed six-monthly for two years, with clinical examinations and conjunctival swab sample collection. Progressive scarring cases were identified by comparing baseline and two-year photographs, and compared to individuals without progression. Samples were tested for C. trachomatis by PCR and transcript levels of S100A7, IL1B, IL13, IL17A, CXCL5, CTGF, SPARCL1, CEACAM5, MMP7, MMP9 and CD83 were estimated by quantitative RT-PCR. Progressive scarring was found in 135/585 (23.1%) of Ethiopian participants and 173/577 (30.0%) of Tanzanian participants. There was a strong relationship between progressive scarring and increasing inflammatory episodes (Ethiopia: OR 5.93, 95%CI 3.31-10.6, p<0.0001. Tanzania: OR 5.76, 95%CI 2.60-12.7, p<0.0001). No episodes of C. trachomatis infection were detected in the Ethiopian cohort and only 5 episodes in the Tanzanian cohort. Clinical inflammation, but not scarring progression, was associated with increased expression of S100A7, IL1B, IL17A, CXCL5, CTGF, CEACAM5, MMP7, CD83 and reduced SPARCL1. CONCLUSIONS/SIGNIFICANCE: Scarring progressed in the absence of detectable C. trachomatis, which raises uncertainty about the primary drivers of late-stage trachoma. Chronic conjunctival inflammation appears to be central and is associated with enriched expression of pro-inflammatory factors and altered expression of extracellular matrix regulators. Host determinants of scarring progression appear more complex and subtle than the features of inflammation. Overall this indicates a potential role for anti-inflammatory interventions to interrupt progression and the need for trichiasis disease surveillance and surgery long after chlamydial infection has been controlled at community level