University Hospital of North Durham

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.

BACKGROUND: We examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study. METHODS AND RESULTS: Our definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of >/=7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of >/=7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort. CONCLUSIONS: We concluded that the assignment to pravastatin therapy resulted in a 30% reduction (P:=0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.

Ultraviolet climatology is outlined including atmospheric ozone and factors affecting terrestrial ultraviolet radiation. Solar dosimetry in photobiology and terrestrial UV monitoring are discussed. Molecular and cellular ultraviolet photobiology are described. The effect of solar UV on aquatic life and plants is outlined. The effects of solar UV on human skin such as sunburn, tanning, vitamin D3 production, photo-ageing, melanomas and skin cancer are described. The effect of solar UV on the eye is discussed.

In a prospective study we assessed the causes of mechanical failure in a series of 230 intertrochanteric femoral fractures which had been internally fixed with either a sliding hip screw or a Küntscher Y-nail. The overall rate of mechanical failure was 16.5%; cutting-out of the implant from the femoral head was the cause in three-quarters of the instances. Implants placed posteriorly in the femoral head cut out more often (27%) than those placed centrally (7%). The cut-out rate was also determined by the quality of the fracture reduction, but age, walking ability and bone density (assessed by the Singh grade and metacarpal indices) had no significant influence. We conclude that these fractures should be reduced as accurately as possible and it is imperative that the implant is placed centrally within the femoral head.

BACKGROUND: Antibiotic-associated diarrhoea (AAD) occurs most frequently in older (≥65 years) inpatients exposed to broad-spectrum antibiotics. When caused by Clostridium difficile, AAD can result in life-threatening illness. Although underlying disease mechanisms are not well understood, microbial preparations have been assessed in the prevention of AAD. However, studies have been mostly small single-centre trials with varying quality, providing insufficient data to reliably assess effectiveness. We aimed to do a pragmatic efficacy trial in older inpatients who would be representative of those admitted to National Health Service (NHS) and similar secondary care institutions and to recruit a sufficient number of patients to generate a definitive result. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial of inpatients aged 65 years and older and exposed to one or more oral or parenteral antibiotics. A computer-generated randomisation scheme was used to allocate participants (in a 1:1 ratio) to receive either a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 × 10(10) organisms, one per day for 21 days, or an identical placebo. Patients, study staff, and specimen and data analysts were masked to assignment. The primary outcomes were occurrence of AAD within 8 weeks and C difficile diarrhoea (CDD) within 12 weeks of recruitment. Analysis was by modified intention-to-treat. This trial is registered, number ISRCTN70017204. FINDINGS: Of 17,420 patients screened, 1493 were randomly assigned to the microbial preparation group and 1488 to the placebo group. 1470 and 1471, respectively, were included in the analyses of the primary endpoints. AAD (including CDD) occurred in 159 (10·8%) participants in the microbial preparation group and 153 (10·4%) participants in the placebo group (relative risk [RR] 1·04; 95% CI 0·84-1·28; p=0·71). CDD was an uncommon cause of AAD and occurred in 12 (0·8%) participants in the microbial preparation group and 17 (1·2%) participants in the placebo group (RR 0·71; 95% CI 0·34-1·47; p=0·35). 578 (19·7%) participants had one or more serious adverse event; the frequency of serious adverse events was much the same in the two study groups and none was attributed to participation in the trial. INTERPRETATION: We identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in prevention of AAD or CDD. An improved understanding of the pathophysiology of AAD is needed to guide future studies. FUNDING: Health Technology Assessment programme; National Institute for Health Research, UK.

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 design and performance of an instrument for quantifying ultraviolet-induced cutaneous erythema are discussed. If the instrument is used to record an 'erythema index' at a site on the skin before and after irradiation, the difference between those two readings is essentially related to an increase in vasodilation and is largely independent of the melanin content of the epidermis.

BACKGROUND: The term pustular psoriasis indicates a group of severe skin disorders characterized by eruptions of neutrophil-filled pustules. The disease, which often manifests with concurrent psoriasis vulgaris, can have an acute systemic (generalized pustular psoriasis [GPP]) or chronic localized (palmoplantar pustulosis [PPP] and acrodermatitis continua of Hallopeau [ACH]) presentation. Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations. OBJECTIVE: We sought to characterize the clinical and genetic features of pustular psoriasis through the analysis of an extended patient cohort. METHODS: We ascertained a data set of unprecedented size, including 863 unrelated patients (251 with GPP, 560 with PPP, 28 with ACH, and 24 with multiple diagnoses). We undertook mutation screening in 473 cases. RESULTS: and .002, respectively). Importantly, IL36RN disease alleles had a dose-dependent effect on age of onset in all forms of pustular psoriasis (P = .003). CONCLUSIONS: The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP.

BACKGROUND: The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear. METHODS: We performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Assessors were unaware of the trial-group assignments. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days. RESULTS: Of 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and 41 participants (4.1%) in the later-treatment group (risk difference, -1.18 percentage points; 95% confidence interval [CI], -2.84 to 0.47) by 30 days. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29 to 1.07) by 30 days and in 18 participants (1.9%) and 30 participants (3.1%), respectively, by 90 days (odds ratio, 0.60; 95% CI, 0.33 to 1.06). Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups by 30 days. CONCLUSIONS: In this trial, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher (based on the 95% confidence interval) with early than with later use of DOACs. (Funded by the Swiss National Science Foundation and others; ELAN ClinicalTrials.gov number, NCT03148457.).

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 ).

OBJECTIVES: To review randomised controlled trials of treatment with a proton pump inhibitor in patients with ulcer bleeding and determine the impact on mortality, rebleeding, and surgical intervention. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Cochrane Collaboration's trials register, Medline, and Embase, handsearched abstracts, and pharmaceutical companies. REVIEW METHODS: Included randomised controlled trials compared proton pump inhibitor with placebo or H2 receptor antagonist in endoscopically proved bleeding ulcer and reported at least one of mortality, rebleeding, or surgical intervention. Trials were graded for methodological quality. Two assessors independently reviewed each trial, and disagreements were resolved by consensus. RESULTS: We included 21 randomised controlled trials comprising 2915 patients. Proton pump inhibitor treatment had no significant effect on mortality (odds ratio 1.11, 95% confidence interval 0.79 to 1.57; number needed to treat (NNT) incalculable) but reduced rebleeding (0.46, 0.33 to 0.64; NNT 12) and surgery (0.59, 0.46 to 0.76; NNT 20). Results were similar when the meta-analysis was restricted to the 10 trials with the highest methodological quality: 0.96, 0.46 to 2.01, for mortality; 0.41, 0.25 to 0.68, NNT 10, for rebleeding; 0.62, 0.46 to 0.83, NNT 25, for surgery. CONCLUSIONS: Treatment with a proton pump inhibitor reduces the risk of rebleeding and the requirement for surgery after ulcer bleeding but has no benefit on overall mortality.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status. A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Synopsis A method is described and evaluated for classifying sunscreen products into different broad spectrum categories. The method is based on spectrophotometric analysis of products applied to a suitable substrate and obviates the need for human or animal studies utilizing clinical endpoints which may be of dubious value in relation to protection from sun exposure. The absorbance spectrum obtained by spectrophotometric assay is reduced to a single index by determining that wavelength lambda(c) where the area under the spectrum from 290 nm (the approximate lower wavelength limit of terrestrial sunlight) to lambda(c) is 90% of the integral of the absorbance spectrum from 290 to 400 nm. A five-point scale is used to classify products as follows: The method makes no underlying assumptions about the form of action spectra for either acute or chronic photobiological damage. However, acknowledgement is made of the fact that the efficiency of ultraviolet radiation to induce a given photobiological endpoint tends to decrease with increasing wavelength by adopting wavelength intervals for classifying the Broad Spectrum Rating which increase in an approximately logarithmic manner.

Laparoscopic cholecystectomy is associated with spillage of gall stones in 5%-40% of procedures, but complications occur very rarely. There are, however, isolated case reports describing a range of complications occurring both at a distance from and near to the subhepatic area. This review looks into the various modes of presentation, ways to minimise spillage, treating the complications, and the legal implications.

AIM: To investigate whether immunohistochemical staining for cytokeratin 20 (CK20) and thyroid transcription factor 1 (TTF-1) is useful in distinguishing Merkel cell carcinomas (MCCs) from metastatic small cell carcinomas (SCCs). METHODS: Eleven cases of MCC and 10 of lung SCC were stained for CK20 and TTF-1. RESULTS: Ten of 11 MCCs stained with the antibody to CK20. None was positive for TTF-1. No SCC stained with anti-CK20 and all stained strongly with anti-TTF-1. CONCLUSIONS: The use of both anti-CK20 and anti-TTF-1 can reliably distinguish between MCC and metastatic SCC, thus avoiding the need for a detailed clinical investigation of patients with MCC in whom metastatic SCC must be excluded.

The weekday and weekend outdoor ultraviolet exposure of young people from primary and secondary schools in three geographically distinct regions of England was determined over a 3-month period in summer. Ultraviolet exposure was measured using personal film badges worn by each young person, and time spent outdoors, in hourly intervals, assessed using exposure records. In each area a class of 9-10-year-old children from a primary school and a class of 14-15-year-old adolescents from a secondary school took part, giving a total of 180 subjects. We found that primary school children received higher outdoor ultraviolet exposure than young people in secondary schools, and geographical differences in exposure could not be accounted for solely by differences in ambient ultraviolet. There was little difference between the exposure of males and females. Children and adolescents did not behave as homogeneous groups with regard to exposure.

The case records of patients with extradural haematomas treated in the Lothian region during 1951-60 and 1968-77 were analysed to assess the effect of delay in treatment on morbidity and mortality. Delay was defined as the time from deterioration in level of consciousness to surgical evacuation of clot. There were 83 supratentorial extradural haematomas unassociated with intradural clot or contusion. The mean delay in patients who died was 15.7 hours, while in good-quality survivors the mean delay was 1.9 hours. Mortality decreased from 33.3% during 1951-60 to 8.9% during 1968-77. In addition, good recovery without morbidity occurred in 40.7% of patients in the earlier period and 67.9% in the later period. Mean delays from deterioration in level of consciousness to operation were 9.8 and 2.4 hours in the earlier and later periods respectively. The results emphasise the need for immediate operation in patients deteriorating with extradural haematomas. Direct admission of all head-injured patients to a head and spinal injuries unit staffed by neurosurgeons resulted in minimal delay times as well as a reduction in morbidity and mortality.

Previous studies have shown that people often apply less sunscreen than the recommended amount of 2 mg/cm2. Our purpose in this study was to determine objectively how photoprotection varies with application thickness. The protection provided by differing quantities of sunscreens containing varying amounts of titanium dioxide was measured in vitro using excised human epidermis as the substrate. It was found that application thickness had a significant effect on the sun protection factor (SPF), with most users probably achieving a mean SPF of between 20-50% of that expected from the product label. Underprotection due to inadequate application, coupled with overexposure to the sun, might partially explain why sunscreen use has been reported to be a risk factor in melanoma.

Summary The degree of sun protection provided by various styles of hat at different anatomical sites on the head was measured using model headforms and ultraviolet-sensitive film badges. It was found that hats with a small brim, such as the flat cap favoured by elderly male photosensitive patients, provided negligible protection at all sites apart from the vertex and forehead. Peaked baseball-style caps offer good protection to the nose but are relatively ineffective at other sites on the face. Hats with a wide (>7.5 cm) brim are necessary in order to provide reasonable protection factors (>3) around the nose and cheeks.