Rebalancing the research equation in Africa: principles and process.

BACKGROUND: Many examples of research excellence in Africa have been driven by partnerships led by the global North and have involved localised infrastructure improvements to support the best of international research practice. OBJECTIVE: In this article, we explore a possible mechanism by which local research networks, appropriately governed, could begin to support national African research programmes by allying research delivery to clinical service. SUMMARY: This article explores the concept that sustainable research effort needs a well-trained and mentored workforce, working to common standards, but which is practically supported by a much developed information technology (IT) infrastructure throughout the continent. CONCLUSIONS: The balance of investment and ownership of such a research programme needs to be shared between local and international funding, with the emphasis on developing global South-South collaborations and research strategies which address the environmental impact of medical research activity and mitigate the impact of climate change on African populations. Healthcare must be embedded in the post-COVID-19 approach to research development.

Five-day outcome of hepatitis E-induced acute liver failure in the ICU.

BACKGROUND: Hepatitis E virus (HEV) is an important cause of acute liver failure (ALF) in Bangladesh with pregnant mothers being more vulnerable. As HEV occurs in epidemics, it limits medical capabilities in this resource-poor country. Cerebral oedema, resulting in raised intracranial pressure (ICP), is an important cause of morbidity and mortality. Practical treatments are currently few. To study the baseline characteristics and clinical outcome of HEV-induced ALF in a recent HEV epidemicTo detect raised ICP clinically and observe response to mannitol infusion.This was a prospective cohort study from June until August 2018 of 20 patients admitted to the intensive care unit (ICU) of a major Bangladeshi Referral Hospital with HEV-induced ALF. We diagnosed HEV infection by detecting serum anti-HEV IgM antibody. All were negative for hepatitis B surface antigen and hepatitis A IgM antibody. Data were collected on 5-day outcome after admission to ICU, monitoring all patients for signs of raised ICP. An intravenous bolus of 20% mannitol was administered at a single time point to patients with raised ICP. RESULTS: Twenty patients were included in the study. Ten (50%) patients, seven (70%) females, received mannitol infusion. HE worsened in eight (40%): seven female and three pregnant. Glasgow Coma scores deteriorated in six (30%): all (100%) females and three pregnant. Consciousness status was not significantly different between pregnant and non-pregnant subjects, nor between those who received mannitol and those who did not. Six patients met King's College Criteria for liver transplantation. CONCLUSIONS: Female patients had a worse outcome, but pregnancy status was not an additional risk factor in our cohort. Mannitol infusion was also not associated with a significant difference in outcome.

The Role of National Specialist Societies in Influencing Transformational Change in Low-Middle Income Countries - Reflections on the Model of Implementation for a National Endoscopy Training Programme in Bangladesh.

The British Society of Gastroenterology (BSG) and the Bangladesh Gastroenterology Society (BGS) have collaborated on an endoscopy training programme, which has grown up over the past decade from a small scheme borne out of the ideas of consultant gastroenterologists in Swansea, South Wales (United Kingdom) to improve gastroenterology services in Bangladesh to become a formalised training programme with broad reach. In this article, we document the socioeconomic and historical problems that beset Bangladesh, the current training needs of doctors and how the BSG-BGS collaboration has made inroads into changing outcomes both for gastroenterologists in Bangladesh, but also for the populations they serve.

Biomedical research in developing countries: Opportunities, methods, and challenges.

Health research is essential for improving global health, health equity, and economic development. There are vast differences in the disease burden, research budget allocation, and scientific publications between the developed and the low-middle-income countries, which are the homes of 85% of the world's population. There are multiple challenges, as well as opportunities for health research in developing countries. One of the primary reasons for reduced research output from the developing countries is the lack of research capacity. Many developing countries are striving to build their research capacity. They are trying to understand their needs and goals to solve their fundamental health problems, but the opportunity for research education and training remains low. The first joint research meeting of the Bangladesh Gastroenterology Society and the British Society of Gastroenterology took place in February 2020 at the Bangabandhu Sheikh Mujib Medical University in Dhaka, Bangladesh, aimed at providing an overview of medical research for young, aspiring medical researchers. This review article provides an outline of the research day and covers a number of useful topics. This review aims to provide a basic guide for early career researchers, both within the field of gastroenterology and, more generally, to all spheres of medical research.

Restarting gastrointestinal endoscopy in the deceleration and early recovery phases of COVID-19 pandemic: Guidance from the British Society of Gastroenterology.

Many non-emergency clinical services were suspended during COVID-19 pandemic peak. It is essential to develop a plan for restarting services following the peak. It is equally important to protect patients and staff and to use resources and personal protective equipment (PPE) efficiently. The British Society of Gastroenterology Endoscopy Committee and Quality Improvement Programme has produced guidance on how a restart can be safely delivered. Key recommendations include the following: all patients should have need for endoscopy assessed by senior clinicians and prioritised according to criteria we have outlined; once the need for endoscopy is confirmed, patients should undergo telephone screening for symptoms using systematic questionnaires; all outpatients should undergo RT-PCR testing for COVID-19 virus 1-3 days prior to endoscopy; and PPE should be determined by patient risk stratification, the nature of the procedure and the results of testing. While this guidance is tailored to endoscopy services, it could be adapted for any interventional medical discipline.

British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic.

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.

Gender differences in leadership, workforce and scholarly presentation within a national society: a gastroenterology perspective.

In the UK, gastroenterology has been a male predominant medical speciality. Data regarding gender within workforce, academia and leadership at a national level are lacking. Data regarding scholarly presentation at the following annual conferences were collected and analysed; British Society of Gastroenterology (BSG) 2013, 2014, and Digestive Diseases Federation (DDF) in 2015. Data from the 2013-2015 BSG annual workforce reports were examined. In 2015, female higher specialty trainees (STs) made up 39% (328/848) of the trainee workforce, versus 37% and 35% in 2014 and 2013. From 2013 to 2015, less than a fifth of all consultant gastroenterologists were women. Female consultant (18%), ST (39%), associate (86%) and student attendance (47%) at DDF 2015 did not change significantly from 2013 to 2014. Female speakers (trainees and consultants) were significantly lower at DDF 2015 compared with BSG 2014; 43/331 (13%) versus 56/212 (26.4%) (p=0.0001) and BSG 2013 63/231 (27%) (p=0.0001). The number of female chairs, delivery of the named lectures and prizes awarded to women did not differ across the 3-year period. Female leadership via representation at Council and Executive at BSG was 4/30 (13%) in 2015 and did not differ in 2013/2014, with no elected council members since 2008 and one female president in 1973. The proportion of female gastroenterology trainees and consultants is increasing, but remains lower than across all medical specialties and is reflected in attendance and scholarly contributions. Action within the BSG is underway to address female under-representation in leadership roles.

Results of the British Society of Gastroenterology supporting women in gastroenterology mentoring scheme pilot.

INTRODUCTION: Mentorship has long been recognised as beneficial in the business world and has more recently been endorsed by medical and academic professional bodies. Recruitment of women into gastroenterology and leadership roles has traditionally been difficult. The Supporting Women in Gastroenterology network developed this pilot scheme for female gastroenterologists 5 years either side of the Completion Certificate of Specialist Training (CCST) to examine the role that mentorship could play in improving this discrepancy. METHOD: Female gastroenterology trainees and consultant gastroenterologists within 5 years either side of CCST were invited to participate as mentees. Consultant gastroenterologists of both genders were invited to become mentors. 35 pairs of mentor:mentees were matched and completed the scheme over 1 year. Training was provided. RESULTS: The majority of the mentees found the sessions useful (82%) and enjoyable (77%), with the benefit of having time and space to discuss professional or personal challenges with a gastroenterologist who is not a colleague. In the longitudinal study of job satisfaction, work engagement, burnout, resilience, self-efficacy, self-compassion and work-life balance, burnout scale showed a small but non significant improvement over the year (probably an effect of small sample size). Personal accomplishment improved significantly. The main challenges were geography, available time to meet and pair matching. The majority of mentors surveyed found the scheme effective, satisfying, mutually beneficial (70%) and enjoyable (78%). CONCLUSION: Mentorship is shown to be beneficial despite the challenges and is likely to improve the recruitment and retention of women into gastroenterology and leadership roles, but is likely to benefit gastroenterologists of both genders.

Establishing the aims, format and function for multidisciplinary team-driven care within an inflammatory bowel disease service: a multicentre qualitative specialist-based consensus study.

OBJECTIVE: To obtain a specialist-based consensus on the aims, format and function for MDT-driven care within an inflammatory bowel disease (IBD) service. DESIGN: This was a prospective, multicentre study using a Delphi formal consensus-building methodology. SETTING: Participants were recruited nationally across 13 centres from July to August 2014. PARTICIPANTS: 24 participants were included into the Delphi Specialist Consensus Panel. They included six consultant colorectal surgeons, six gastroenterologists, five consultant radiologists, three consultant histopathologists and 4 IBD nurse specialists. INTERVENTIONS: Panellists ranked items on a Likert scale (1=not important to 5=very important). Items with a median score >3 were considered eligible for inclusion. MAIN OUTCOME MEASURES: Consensus was defined with an IQR ≤1. Consensus on categorical responses was defined by an agreement of >60%. RESULTS: A consensus on items (median; IQR) that described the aims of the MDT-driven care that were considered very important included: advance patient care (5;5-5), provide multidisciplinary input for the patient's care plan (5;5-5), provide shared experience and expertise (5;5-5), improve patient outcome (5;5-5), deliver the best possible care for the patient (5;5-5) and to obtain consensus on management for a patient with IBD (5;4-5). A consensus for being a core MDT member was demonstrated for colorectal surgeons (24/24), radiologists (24/24), gastroenterologists (24/24), nurse specialists (24/24), dieticians (14/23), histopathologists (21/23) and coordinators (21/24). CONCLUSIONS: This study has provided a consensus for proposed aims, overall design, format and function MDT-driven care within an IBD service. This can provide a focus for core members, and aid a contractual recognition to ensure attendance and proactive contribution.

Establishing Key Performance Indicators [KPIs] and Their Importance for the Surgical Management of Inflammatory Bowel Disease-Results From a Pan-European, Delphi Consensus Study.

BACKGROUND AND AIMS: Key performance indicators [KPIs] exist across a range of areas in medicine. They help to monitor outcomes, reduce variation, and drive up standards across services. KPIs exist for inflammatory bowel disease [IBD] care, but none specifically cover inflammatory bowel disease [IBD] surgical service provision. METHODS: This was a consensus-based study using a panel of expert IBD clinicians from across Europe. Items were developed and fed through a Delphi process to achieve consensus. Items were ranked on a Likert scale from 1 [not important] to 5 [very important]. Consensus was defined when the inter quartile range was ≤ 1, and items with a median score > 3 were considered for inclusion. RESULTS: A panel of 21 experts [14 surgeons and 7 gastroenterologists] was recruited. Consensus was achieved on procedure-specific KPIs for ileocaecal and perianal surgery for Crohn's disease, [N = 10] with themes relating to morbidity [N = 7], multidisciplinary input [N = 2], and quality of life [N = 1]; and for subtotal colectomy, proctocolectomy and ileoanal pouch surgery for ulcerative colitis [N = 11], with themes relating to mortality [N = 2], morbidity [N = 8], and service provision [N = 1]. Consensus was also achieved for measures of the quality of IBD surgical service provision and quality assurance in IBD surgery. CONCLUSIONS: This study has provided measurable KPIs for the provision of surgical services in IBD. These indicators cover IBD surgery in general, the governance and structures of the surgical services, and separate indicators for specific subareas of surgery. Monitoring of IBD services with these KPIs may reduce variation across services and improve quality.

Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.

To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ∼12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.

Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. FUNDING: Medical Research Council.

Defining the optimal design of the inflammatory bowel disease multidisciplinary team: results from a multicentre qualitative expert-based study.

OBJECTIVE: To elicit expert views to define the aims, optimal design, format and function of an inflammatory bowel disease (IBD) multidisciplinary team (MDT) with the overall purpose of enhancing the quality of MDT-driven care within an IBD service provision. DESIGN: This study was a multicentre, prospective, qualitative study using a standard semistructured interview methodology. PARTICIPANTS: A multidisciplinary sample of 28 semistructured interviews of which there are six consultant colorectal surgeons, six IBD nurse specialists, seven consultant gastroenterologists, five consultant radiologists and four consultant histopathologists. SETTING: Participants were recruited from 10 hospitals, which were a mixture of community hospitals and specialist IBD centres between June and October 2013. RESULTS: Experts argued that the main goal of MDT-driven IBD care is to improve patient outcomes via sharing collective expertise in a formalised manner. Themes regarding the necessary requirements for an IBD MDT to occur included good attendance, proactive contribution, a need to define core members and appropriate and functional computer facilities. Emergent themes regarding the logistics of an effective IBD MDT included an eligibility criterion for case selection and discussion and appropriate scheduling. Themes regarding the overall design of the IBD MDT included a 'hub-and-spoke' model versus a 'single-centre' model. CONCLUSIONS: Defining key elements for an optimal design format for the IBD MDT is necessary to ensure quality of care and reduce variation in care standards. This study has produced a set of expert-based standards that can be used to structure the IBD MDT. These standards now require larger scale validation and consensus prior to becoming a practical guideline for the management of IBD care.

Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway.

The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFß1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.