Glangwili General Hospital

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.

from the procedure, just as this is the main risk of carotid surgery.Only randomized comparison between carotid surgery and angioplasty can determine how these two procedures compare.The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) is the only ongoing randomized trial.The study now has 20 centres in the UK, Europe and North America.Our Monitoring Committee reported in November 1996, after analysing the data on over 300 patients, that there was no reason to stop the trial.We therefore plan to continue randomizing and will be carrying out an analysis with a minimum of 6 months' follow-up in 400 patients in October 1997.We hope that when we have the data available we will be able to answer some of the unanswered questions posed by

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 ).

The Caerphilly and Speedwell studies are based on representative samples of over 3000 subjects in South Wales and over 2000 in Bristol. They include cross sectional studies of risk factors for prevalent ischaemic heart disease (IHD) and of determinants of those risk factors. Prospective studies based on over 2000 men aged 45-59 in each area have been set up. In addition to the examination of lipid and thrombosis factors of possible relevance to IHD, the studies also focus on possible dietary, hormonal, and psychological risk factors, both as possible "risk factors" for IHD and also as possible "determinants" of risk factors.

A prospective, open, multicentre study was performed to investigate the efficacy and safety of long-term treatment with cyclosporin in adults with severe atopic dermatitis. Subjects were treated for a maximum of 48 weeks. For the first 8 weeks, cyclosporin was administered at 2.5 mg/kg per day. The dose was then adjusted according to response. Disease activity was monitored using the six-area, six-sign score and the proportion of skin involved. Pruritus and sleep disturbance were assessed using four-point scales. Response was further evaluated on a five-point scale. Adverse events, blood pressure and serum biochemistry were monitored. Tolerability was assessed on a five-point scale. One hundred subjects were enrolled and 65 completed 48 weeks of treatment. Withdrawals occurred due to remission (three), inadequate response (seven), protocol violations (11) and adverse events (14, of which seven were probably treatment related). Cyclosporin produced rapid and highly significant improvements in all indices of disease activity. Sixty-five subjects considered that they had shown a considerable improvement or complete clearance of disease. Most patients relapsed after cessation of treatment, but neither signs nor symptoms had returned to baseline severity 8 weeks later. Blood pressure and serum creatinine levels increased slightly, and in one subject renal impairment was a major factor contributing to withdrawal of the drug. Overall, 85 subjects rated the tolerability of cyclosporin as good or very good. The results indicate that cyclosporin has a place in the long-term treatment of severe atopic dermatitis provided that appropriate patients are selected and careful monitoring is performed.

INTRODUCTION: Blunt chest wall trauma accounts for over 15% of all trauma admissions to Emergency Departments worldwide. Reported mortality rates vary between 4 and 60%. Management of this patient group is challenging as a result of the delayed on-set of complications. The aim of this study was to develop and validate a prognostic model that can be used to assist in the management of blunt chest wall trauma. METHODS: There were two distinct phases to the overall study; the development and the validation phases. In the first study phase, the prognostic model was developed through the retrospective analysis of all blunt chest wall trauma patients (n = 274) presenting to the Emergency Department of a regional trauma centre in Wales (2009 to 2011). Multivariable logistic regression was used to develop the model and identify the significant predictors for the development of complications. The model's accuracy and predictive capabilities were assessed. In the second study phase, external validation of the model was completed in a multi-centre prospective study (n = 237) in 2012. The model's accuracy and predictive capabilities were re-assessed for the validation sample. A risk score was developed for use in the clinical setting. RESULTS: Significant predictors of the development of complications were age, number of rib fractures, chronic lung disease, use of pre-injury anticoagulants and oxygen saturation levels. The final model demonstrated an excellent c-index of 0.96 (95% confidence intervals: 0.93 to 0.98). CONCLUSIONS: In our two phase study, we have developed and validated a prognostic model that can be used to assist in the management of blunt chest wall trauma patients. The final risk score provides the clinician with the probability of the development of complications for each individual patient.

BACKGROUND: The Global Registry of Acute Coronary Events (GRACE) 2.0 score was developed and validated in predominantly male patient populations. We aimed to assess its sex-specific performance in non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and to develop an improved score (GRACE 3.0) that accounts for sex differences in disease characteristics. METHODS: We evaluated the GRACE 2.0 score in 420 781 consecutive patients with NSTE-ACS in contemporary nationwide cohorts from the UK and Switzerland. Machine learning models to predict in-hospital mortality were informed by the GRACE variables and developed in sex-disaggregated data from 386 591 patients from England, Wales, and Northern Ireland (split into a training cohort of 309 083 [80·0%] patients and a validation cohort of 77 508 [20·0%] patients). External validation of the GRACE 3.0 score was done in 20 727 patients from Switzerland. FINDINGS: Between Jan 1, 2005, and Aug 27, 2020, 400 054 patients with NSTE-ACS in the UK and 20 727 patients with NSTE-ACS in Switzerland were included in the study. Discrimination of in-hospital death by the GRACE 2.0 score was good in male patients (area under the receiver operating characteristic curve [AUC] 0·86, 95% CI 0·86-0·86) and notably lower in female patients (0·82, 95% CI 0·81-0·82; p<0·0001). The GRACE 2.0 score underestimated in-hospital mortality risk in female patients, favouring their incorrect stratification to the low-to-intermediate risk group, for which the score does not indicate early invasive treatment. Accounting for sex differences, GRACE 3.0 showed superior discrimination and good calibration with an AUC of 0·91 (95% CI 0·89-0·92) in male patients and 0·87 (95% CI 0·84-0·89) in female patients in an external cohort validation. GRACE 3·0 led to a clinically relevant reclassification of female patients to the high-risk group. INTERPRETATION: The GRACE 2.0 score has limited discriminatory performance and underestimates in-hospital mortality in female patients with NSTE-ACS. The GRACE 3.0 score performs better in men and women and reduces sex inequalities in risk stratification. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Lindenhof Foundation, Foundation for Cardiovascular Research, and Theodor-Ida-Herzog-Egli Foundation.

AIMS: This study describes the use of the Masquelet technique to treat segmental tibial bone loss in 12 patients. PATIENTS AND METHODS: This retrospective case series reviewed 12 patients treated between 2010 and 2015 to determine their clinical outcome. Patients were mostly male with a mean age of 36 years (16 to 62). The outcomes recorded included union, infection and amputation. The mean follow-up was 675 days (403 to 952). RESULTS: The mean tibial defect measured 5.8 cm (2 to 15) in length. Of the 12 patients, 11 had an open fracture. Eight underwent fixation with an intramedullary nail, three with plates and one with a Taylor Spatial Frame. The mean interval between stages was 57 days (35 to 89). Bony union was achieved in only five patients. Five patients experienced infective complications during treatment, with two requiring amputation because of severe infection. CONCLUSION: 2017;99-B:680-5.

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

AIMS: COVID-19 might have affected the care and outcomes of hospitalized acute myocardial infarction (AMI). We aimed to determine whether the COVID-19 pandemic changed patient response, hospital treatment, and mortality from AMI. METHODS AND RESULTS: Admission was classified as non-ST-elevation myocardial infarction (NSTEMI) or STEMI at 99 hospitals in England through live feeding from the Myocardial Ischaemia National Audit Project between 1 January 2019 and 22 May 2020. Time series plots were estimated using a 7-day simple moving average, adjusted for seasonality. From 23 March 2020 (UK lockdown), median daily hospitalizations decreased more for NSTEMI [69 to 35; incidence risk ratios (IRR) 0.51, 95% confidence interval (CI) 0.47-0.54] than STEMI (35 to 25; IRR 0.74, 95% CI 0.69-0.80) to a nadir on 19 April 2020. During lockdown, patients were younger (mean age 68.7 vs. 66.9 years), less frequently diabetic (24.6% vs. 28.1%), or had cerebrovascular disease (7.0% vs. 8.6%). ST-elevation myocardial infarction more frequently received primary percutaneous coronary intervention (81.8% vs. 78.8%), thrombolysis was negligible (0.5% vs. 0.3%), median admission-to-coronary angiography duration for NSTEMI decreased (26.2 vs. 64.0 h), median duration of hospitalization decreased (4 to 2 days), secondary prevention pharmacotherapy prescription remained unchanged (each > 94.7%). Mortality at 30 days increased for NSTEMI [from 5.4% to 7.5%; odds ratio (OR) 1.41, 95% CI 1.08-1.80], but decreased for STEMI (from 10.2% to 7.7%; OR 0.73, 95% CI 0.54-0.97). CONCLUSION: During COVID-19, there was a substantial decline in admissions with AMI. Those who presented to hospital were younger, less comorbid and, for NSTEMI, had higher 30-day mortality.

BACKGROUND: There is little up-to-date review evidence on the prevalence of Helicobacter pylori across Europe. AIM: To establish regional and national patterns in H. pylori prevalence across Europe. Secondly, to establish trends over time in H. pylori prevalence and gastric cancer incidence and, thirdly, to report on the relationship between H. pylori prevalence and age group across Europe. METHODS: A review of H. pylori prevalence from unselected surveys of adult or general populations across 35 European countries and four European regions since 1990. Secondly, an analysis of trends over time in H. pylori prevalence and in gastric cancer incidence from cancer registry data. RESULTS: Helicobacter pylori prevalence was lower in northern and western Europe than in eastern and southern Europe (P < 0.001). In 11 of 12 European studies that reported on trends, there were sharp reductions in H. pylori prevalence (mean annual reduction = 3.1%). The mean annual reduction in the incidence of gastric cancer across Europe from 1993 to 2007 was 2.1% with little variation regionally across Europe (north 2.2%, west 2.3%, east 1.9% and south 2.0%). Sharp increases in age-related prevalence of H. pylori often levelled off for middle age groups of about 50 years onwards, especially in areas with high prevalence. CONCLUSIONS: This review shows that H. pylori prevalence is much higher in less affluent regions of Europe and that age-related increases in prevalence are confined to younger age groups in some areas. There were sharp reductions in both H. pylori prevalence and gastric cancer incidence throughout Europe.

BACKGROUND: Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide. The growth of ageing populations in developing countries with progressively urbanized lifestyles are major contributors. The key risk factors for CHD such as hypercholesterolemia, diabetes mellitus, and obesity are likely to increase in the future. These risk factors are modifiable through lifestyle. OBJECTIVES: To review current literature on the potential benefit of cholesterol lowering in CHD risk reduction with a particular focus on the evidence of non-pharmacological/lifestyle management of hypercholesterolemia. METHODS: Medline/PubMed systematic search was conducted using a two-tier approach limited to all recent English language papers. Primary search was conducted using key words and phrases and all abstracts were subsequently screened and relevant papers were selected. The next tier of searching was conducted by (1) reviewing the citation lists of the selected papers and (2) by using PubMed weblink for related papers. Over 3600 reports were reviewed. RESULTS: Target cholesterol levels set out in various guidelines could be achieved by lifestyle changes, including diet, weight reduction, and increased physical activity with the goal of reducing total cholesterol to <200 mg/dL and LDL-C<100 mg/dL. Various dietary constituents such as green tea, plant sterols, soy protein have important influences on total cholesterol. Medical intervention should be reserved for those patients who have not reached this goal after 3 months of non-pharmacological approach. CONCLUSION: CHD remains as a leading cause of death worldwide and hypercholesterolemia is an important cause of CHD. Non-pharmacological methods provide initial as well as long-term measures to address this issue.

Alzheimer's disease is classified as a degenerative dementia while vascular dementia is known to be associated with atherothrombosis and classical vascular risk factors. However, over the last decade, there is increasing evidence of the role of haemostatic factors and inflammatory mechanisms in the pathogenesis of Alzheimer's disease. Serum markers of hypercoagulability and markers of inflammation could lead to thrombosis, accelerated atherogenesis and resulting dementia of both Alzheimer's and vascular dementia. In this case control study, we studied these serum markers of coagulation and inflammation in patients suffering from dementia.

. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

The development and introduction of effective treatment for influenza A in the form of neuraminidase inhibitors have made the rapid diagnosis of infection important especially in high-risk populations. The aim of this study was to develop a real-time nucleic acid sequenced based amplification (NASBA) using a molecular beacon that could detect a wide range of influenza A subtypes and strains in a single reaction by targeting a conserved region of the influenza genome, and to evaluate its sensitivity and specificity against traditional laboratory techniques on a range of clinical samples usefulness during the 2003/2004 influenza season. The results demonstrated the assay to be highly sensitive and specific, detecting <0.1 TCID50 of virus stock. Three hundred eighty-nine clinical samples were tested in total from two patient groups. Overall, the real-time NASBA assay detected 64% (66/103) more influenza positive samples than cell culture and direct immunofluorescence (IF) and, therefore, was shown to be more sensitive in detecting influenza A in a wide range of respiratory samples than traditional methods. In conclusion, the real-time influenza A assay demonstrated clinical usefulness in both hospital and community populations.

BACKGROUND: Much work has been done towards the classification of clinical concepts in nursing. However, there is a comparative lack of analysis of non-technical terms, which nevertheless bear closely on professional practice in nursing. Within nursing classifications, the term 'coping' functions as an element in more complex conceptual structures, the term itself being left relatively undefined. The case is similar for the term 'stress'- the set of circumstances with which the individual is attempting to cope. AIMS: The aim of this paper is to arrive at grounds for consensus over the use and meaning of the widely used terms 'stress' and 'coping'. METHODS: A conceptual analysis of the terms 'stress' and 'coping' was carried out, looking at etymology, ordinary usage and theoretical contingencies, in order to generate paradigmatic cases. A range of nursing and non-nursing literature was examined in order to illustrate further the range of the terms. CONCLUSIONS: 'Stress' and 'coping' are terms which are widely used in nursing; their significance has varied overtime and in the literature, and there continues to be lack of clarity over their precise meaning and use.

BACKGROUND: There is currently conflicting evidence surrounding the effects of obesity on postoperative outcomes. Previous studies have found obesity to be associated with adverse events, but others have found no association. The aim of this study was to determine whether increasing body mass index (BMI) is an independent risk factor for development of major postoperative complications. METHODS: This was a multicentre prospective cohort study across the UK and Republic of Ireland. Consecutive patients undergoing elective or emergency gastrointestinal surgery over a 4-month interval (October-December 2014) were eligible for inclusion. The primary outcome was the 30-day major complication rate (Clavien-Dindo grade III-V). BMI was grouped according to the World Health Organization classification. Multilevel logistic regression models were used to adjust for patient, operative and hospital-level effects, creating odds ratios (ORs) and 95 per cent confidence intervals (c.i.). RESULTS: Of 7965 patients, 2545 (32·0 per cent) were of normal weight, 2673 (33·6 per cent) were overweight and 2747 (34·5 per cent) were obese. Overall, 4925 (61·8 per cent) underwent elective and 3038 (38·1 per cent) emergency operations. The 30-day major complication rate was 11·4 per cent (908 of 7965). In adjusted models, a significant interaction was found between BMI and diagnosis, with an association seen between BMI and major complications for patients with malignancy (overweight: OR 1·59, 95 per cent c.i. 1·12 to 2·29, P = 0·008; obese: OR 1·91, 1·31 to 2·83, P = 0·002; compared with normal weight) but not benign disease (overweight: OR 0·89, 0·71 to 1·12, P = 0·329; obese: OR 0·84, 0·66 to 1·06, P = 0·147). CONCLUSION: Overweight and obese patients undergoing surgery for gastrointestinal malignancy are at increased risk of major postoperative complications compared with those of normal weight.