George Eliot Hospital NHS Trust

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

The effects of using a tourniquet during total knee arthroplasty were studied in 80 patients randomly allocated to two groups, either with or without a tourniquet. The groups were similar in mean age, gender, preoperative knee score and radiographic grading and the patients were all operated on by the same surgeon using one type of prosthesis. There was no significant difference between the two groups in operating time or total blood loss but postoperative pain was less in the patients in whom a tourniquet had not been used. They achieved straight-leg raising and knee flexion earlier and had fewer superficial wound infections and deep-vein thromboses. Total knee arthroplasty can be safely performed without the use of the tourniquet with the benefit that several adverse effects associated with its use can be avoided.

A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the child's fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid β-oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the β cell. The patient's hyperinsulinism was easily controlled with diazoxide and chlorothiazide.

A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the child's fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid beta-oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the beta cell. The patient's hyperinsulinism was easily controlled with diazoxide and chlorothiazide.

OBJECTIVE: The UK Juvenile-Onset Systemic Lupus Erythematosus (JSLE) Cohort Study is a multicenter collaborative network established with the aim of improving the understanding of juvenile SLE. The present study was undertaken to describe the clinical manifestations and disease course in patients with juvenile SLE from this large, national inception cohort. METHODS: Detailed data on clinical phenotype were collected at baseline and at regular clinic reviews and annual followup assessments in 232 patients from 14 centers across the UK over 4.5 years. Patients with SLE were identified according to the American College of Rheumatology (ACR) SLE classification criteria. The present cohort comprised children with juvenile SLE (n=198) whose diagnosis fulfilled ≥4 of the ACR criteria for SLE. RESULTS: Among patients with juvenile SLE, the female:male sex distribution was 5.6:1 and the median age at diagnosis was 12.6 years (interquartile range 10.4-14.5 years). Male patients were younger than female patients (P<0.01). Standardized ethnicity data demonstrated a greater risk of juvenile SLE in non-Caucasian UK patients (P<0.05). Scores on the pediatric adaptation of the 2004 British Isles Lupus Assessment Group disease activity index demonstrated significantly increased frequencies of musculoskeletal (82%), renal (80%), hematologic (91%), immunologic (54%), and neurologic (26%) involvement among the patients over time. A large proportion of the patients (93%) were taking steroids and 24% of the patients required treatment with cyclophosphamide. Disease damage was common, with 28% of the patients having a Systemic Lupus International Collaborating Clinics/ACR damage score of ≥1. CONCLUSION: The data on these patients from the UK JSLE Cohort Study, comprising one of the largest national inception cohorts of patients with juvenile SLE to date, indicate that severe organ involvement and significant disease activity are primary characteristics in children with juvenile SLE. In addition, accumulation of disease-associated damage could be seen.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Cardiopulmonary exercise testing (CPET) has become an invaluable tool in healthcare, improving the diagnosis of disease and the quality, efficacy, assessment and safety of treatment across a range of pathologies. CPET's superior ability to measure the global exercise response of the respiratory, cardiovascular and skeletal muscle systems simultaneously in a time and cost-efficient manner has led to the application of CPET in a range of settings from diagnosis of disease to preoperative assessment. The Association for Respiratory Technology and Physiology Statement on Cardiopulmonary Exercise Testing 2021 provides the practitioner and scientist with an outstanding resource to support and enhance practice, from equipment to testing to leadership, helping them deliver a quality assured service for the benefit of all patient groups.

Obesity is a worldwide epidemic responsible for 5% of global mortality. The risks of developing other key metabolic disorders like diabetes, hypertension and cardiovascular diseases (CVDs) are increased by obesity, causing a great public health concern. A series of epidemiological studies and animal models have demonstrated a relationship between the importance of vitamin B12 (B12) and various components of metabolic syndrome. High prevalence of low B12 levels has been shown in European (27%) and South Indian (32%) patients with type 2 diabetes (T2D). A longitudinal prospective study in pregnant women has shown that low B12 status could independently predict the development of T2D five years after delivery. Likewise, children born to mothers with low B12 levels may have excess fat accumulation which in turn can result in higher insulin resistance and risk of T2D and/or CVD in adulthood. However, the independent role of B12 on lipid metabolism, a key risk factor for cardiometabolic disorders, has not been explored to a larger extent. In this review, we provide evidence from pre-clinical and clinical studies on the role of low B12 status on lipid metabolism and insights on the possible epigenetic mechanisms including DNA methylation, micro-RNA and histone modifications. Although, there are only a few association studies of B12 on epigenetic mechanisms, novel approaches to understand the functional changes caused by these epigenetic markers are warranted.

Coastal steepening potentially presents an array of management issues in the form of financial implications of sea defence degradation, increased risk posed to the hinterland as wave attenuation is reduced, ‘coastal squeeze’ and statutory requirements in the light of the Habitats Directive. The extent to which coastal steepening has occurred throughout England and Wales has been investigated through use of a GIS and dataset based on historical Ordnance Survey map information. Data were collected along 1084 selected profile lines, positioned so as to be geomorphologically representative of the coast. Features recorded from each map year included the positions of mean high water (MHW) and mean low water (MLW), the relative movements of which infer changing intertidal gradients. The results presented in this paper are on a subject and scale not previously published. It is revealed that 61% of the coastline studied has experienced a tendency towards steepening. Of the remainder, 33% has flattened, and 6% has experienced no rotational movement. This tendency towards steepening has been the dominant movement on each of the west, south, and east coasts.

Patients with confirmed PE being treated in the OP setting should be offered treatment with either low molecular weight heparin (LMWH) and dabigatran, LMWH and edoxaban or a single-drug regimen (apixaban or rivaroxaban). Grade A Patients with suspected PE being treated in the OP setting may be treated with apixaban or on July 24, 2023 by guest.

BACKGROUND: In our departments, curettage and cautery (C&C) and liquid nitrogen cryotherapy are the preferred methods of treatment for Bowen's disease (BD). OBJECTIVES: We aimed to compare these two treatments with regard to efficacy, time to heal, morbidity and recurrence rate. METHODS: Cryotherapy was performed using a liquid nitrogen spray giving two freeze-thaw cycles, each freeze cycle being maintained for 5-10 s after the formation of an ice ball to the intended margin. Curettage was performed with a conventional disposable curette under local anaesthesia, and electrocautery was then used for haemostasis. RESULTS: Eighty lesions in 67 patients (55 female) were analysed. The mean age of the patients was 74 years (range 46-89). The most frequent site was the lower leg, below the knee (n = 59, 74%). The average time taken for complete healing after the procedure was 60 days. The mean size of the lesions was 336 mm(2) (range 30-1890). The patients were followed up for a mean of 22 months (range 6-24, median 2 years). In the cryotherapy group (n = 36 lesions), the median time to complete healing was 46 days (range 14-210; mean 69). Twelve lesions took more than 90 days to heal. Infection requiring antibiotics developed in four patients. Thirteen of the treated lesions had recurred by 24 months. In the C&C group (n = 44 lesions), the median time to healing was 35 days (range 14-330; mean 53). Six of the lesions took more than 90 days to heal. Infection developed in two patients. Recurrence occurred in four lesions over the follow-up period. Considering BD on the lower legs separately, lesions took on average 90 days to heal in the cryotherapy group (n = 23), whereas in the C&C group (n = 36) they took 39 days to heal (P < 0.001). During the procedure and the subsequent 24 h, patients were 10.4 times more likely to report pain of any degree for lesions treated by cryotherapy than by C&C (P < 0.001). CONCLUSIONS: This study suggests a superiority of C&C over cryotherapy in the treatment of BD, especially for lesions on the lower leg. Curettage of lesions of BD is associated with a significantly shorter healing time, less pain, fewer complications and a lower recurrence rate when compared with cryotherapy.

Journal Article Porokeratosis of Mibelli: successful treatment with 5% imiquimod cream Get access S. Agarwal, S. Agarwal Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, U.K Search for other works by this author on: Oxford Academic Google Scholar J. Berth‐Jones J. Berth‐Jones Department of Dermatology, George Eliot Hospital NHS Trust, Nuneaton, Warwickshire CV10 7DJ, U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 146, Issue 2, 1 February 2002, Pages 338–339, https://doi.org/10.1046/j.1365-2133.2002.4653_8.x Published: 01 February 2002

Childhood obesity is a growing epidemic. Early identification of high-risk groups will allow for the development of prevention strategies. Cord blood adipocytokines have been previously examined as biomarkers predicting future obesity. We conducted a systematic review looking at the association between cord blood leptin and adiponectin with adiposity up to 5 years of age. A literature review was performed between January 1994 and August 2020 using two bibliographic databases (Medline/Pubmed and EMBASE) and was registered on PROSPERO (CRD42017069024). Studies using skinfold thickness and direct methods of assessing body composition in full term neonates were considered. Partial correlation and multiple regression models were used to present the results. Meta-analysis was performed, were possible, using a random effects model. Cochran’s Q test was used to assess heterogeneity and I2 statistics to calculate the percentage of variation across studies. The potential for publication bias was assessed using funnel plots. Data from 22 studies were retrieved and reviewed by two independent reviewers. Cord blood leptin was positively associated with adiposity at birth (r = 0.487; 95% CI: 0.444, 0.531) but was inversely related to adiposity up to 3 years of age. The association was not sustained at 5 years. There was a weak positive association between adiponectin in cord blood and adiposity at birth (r = 0.201; 95% CI: 0.125, 0.277). No correlation was found between cord blood adiponectin in young children, but data were limited. This review supports that cord blood leptin and adiponectin are associated with adiposity at birth. The results of this study provide insight into the role of adipocytokines at birth on future metabolic health and their potential use as risk stratification tools.

PURPOSE: During the coronavirus disease 2019 pandemic, face-to-face teaching has been severely disrupted and limited for medical students internationally. This study explores the views of medical students and academic medical staff regarding the suitability and limitations, of a bespoke chatbot tool to support medical education. METHODS: Five focus groups, with a total of 16 participants, were recruited using a convenience sample. The participants included medical students across all year groups and academic staff. The pre-determined focus group topic guide explored how chatbots can augment existing teaching practices. A thematic analysis was conducted using the transcripts to determine key themes. RESULTS: Thematic analysis identified five main themes: (1) chatbot use as a clinical simulation tool; (2) chatbot use as a revision tool; (3) differential usefulness by medical school year group; (4) standardisation of education and assessment; (5) challenges of use and implementation. CONCLUSIONS: Both staff and students have clear benefits from using chatbots in medical education. However, they documented possible limitations to their use. The creation of chatbots to support the medical curriculum should be further explored and urgently evaluated to assess their impact on medical students training both during and after the global pandemic.

Liver abscess formation is a rare complication of gall bladder perforation with cholecystohepatic communication. We describe a patient who presented with right upper quadrant pain and progressive confusion, and was found to have an intrahepatic perforation of the gall bladder. We discuss the diagnostic work-up and the management of this rare entity. In particular, we look at the increasing role of interventional radiology and the limits of laparoscopic cholecystectomy in the management of such cases. The discrepancies and the modifications in the classification of gall bladder perforation (Niemeier's classification) are also discussed.

PURPOSE: The objective of this review was to synthesise studies which address the views of healthcare professionals (HCPs) towards patients with functional neurological disorder (FND). METHODS: An interpretive systematised review was conducted. Seven databases were searched using a comprehensive search strategy (MEDLINE, EMBASE, AMED, CINAHL, PsychINFO, ProQuest Nursing and Allied Health, and Scopus). Qualitative studies and those using survey methods were included. An inductive approach to thematic analysis was used to identify concepts from the data and to synthesise the results. RESULTS: The views of 2769 HCPs were represented in 11 included articles. The overarching theme across the articles was uncertainty: about making the diagnosis of FND, about professional roles, and about optimum management. Fear was also a common theme: of saying the wrong thing, of offending patients, or of breaking the therapeutic relationship. CONCLUSIONS: If all HCPs felt uncertain about how to manage patients with FND and avoided them by passing them on to another discipline, then a "vicious cycle" is formed in which patients are passed from one professional to another but without receiving clear, honest information, or effective treatment. HCPs would benefit from increased training on FND and clear clinical pathways to alleviate feelings of uncertainty.Implications for rehabilitationEvidence-based or, at the very least, consensus-based multi-disciplinary care pathways for the assessment and treatment of patients with functional neurological disorder are required to improve equitability of services.Training packages for healthcare professionals need to be developed, evaluated and implemented in order to improve confidence of making and explaining the diagnosis and to reduce stigma of functional neurological disorders.Improved input for patients with functional neurological disorder is likely to occur if healthcare professionals are open, honest and use effective communication skills, both with their patients and fellow healthcare professionals.

Lower limb ulcers present a common clinical problem and are at risk of malignant change. A Marjolin's ulcer has traditionally been regarded as malignant change in a long standing ulcer and/or scar tissue. We report a case of Marjolin's degeneration that developed in an ulcer only 18 months following the initial injury. Such a short latent period has not been reported for over 70 years. This report highlights the possibility of early Marjolin's change and we propose a ranked diagnostic screen to aid in early identification of possible malignant change, based on the current published evidence.