Arrowe Park 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.

Oral candidiasis is a common opportunistic infection of the oral cavity caused by an overgrowth of Candida species, the commonest being Candida albicans. The incidence varies depending on age and certain predisposing factors. There are three broad groupings consisting of acute candidiasis, chronic candidiasis, and angular cheilitis. Risk factors include impaired salivary gland function, drugs, dentures, high carbohydrate diet, and extremes of life, smoking, diabetes mellitus, Cushing's syndrome, malignancies, and immunosuppressive conditions. Management involves taking a history, an examination, and appropriate antifungal treatment with a few requiring samples to be taken for laboratory analysis. In certain high risk groups antifungal prophylaxis reduces the incidence and severity of infections. The prognosis is good in the great majority of cases.

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.

The study of voiding in men and women has been handicapped by the lack of a normal reference range covering urinary flow rates over a wide range of voided volumes. Normal volunteers (331 males and 249 females) were studied. Each voided once into a calibrated Dantec Urodyn 1000 mictiograph. On a second occasion 282 men and 46 women voided. The maximum and average urine flow rates of the first voids in both sexes were compared with the respective voided volumes. Nomogram charts, in centile form, for both the maximum and average urine flow rates were constructed using statistical transformations of the data. Males showed a significant decline in both urinary flow rates with age, although there was no statistically significant variation in either urine flow rate with respect to first versus repeated voiding. Females showed no statistically significant variation in either urine flow rate with respect to age, parity or first versus repeated voiding. The maximum and average urine flow rates in both sexes showed an equally strong relationship to voided volume. No artificial restriction of voided volume, e.g. minimum 200 ml, appeared appropriate. These nomograms offer reference ranges for both maximum and average urinary flow rates in both sexes covering a wide range of voided volumes (15-600 ml).

Of one hundred and twenty-one patients with neoplastic obstruction of the oesophagus or cardia 118 underwent palliative intubation at fibreoptic endoscopy on a total of 135 occasions. Sixty had adenocarcinoma, 49 had squamous carcinoma, and in nine the oesophagus was involved by a growth arising elsewhere. Satisfactory swallowing ws restored in 112 patients. Thirteen patients died in hospital shortly after the procedure. Five fatal and 10 non-fatal perforations were sustained in 135 intubation procedures. Complications of tube function included food blockage on 26 occasions, tumour overgrowth on seven occasions, displacement on 16 occasions, disappearance of the tube in two patients, and late oesophageal perforation on nine occasions. Fifty-six patients survived for three months, 33 for six months, and 10 for a year after intubation. Comparison with series in the literature of patients who underwent surgical palliative intubation suggests that endoscopic palliation has lower mortality and morbidity, and an increased survival time, and is now the method of choice for palliation of oesophagogastric neoplasms.

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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.

Dyspraxia is an enigma to many people, both professional and lay alike--what is it, how does it relate to developmental coordination disorder and associated conditions, how common is it, how is it recognised and diagnosed and how should it be managed? This article attempts to unravel this enigma by: dealing with the terminology of coordination difficulties from the "clumsy child syndrome" through "dyspraxia" to "developmental coordination disorder (DCD)"; briefly examining the debate as to whether dyspraxia or DCD should be regarded as a medical or social disorder; discussing the differential diagnosis of dyspraxia or DCD; considering the assessment of children with dyspraxia or DCD; reviewing the range of current treatment approaches in the UK.

OBJECTIVES: To determine the incidence of severe hyperbilirubinaemia in the newborn, and to identify associated clinical and demographic variables, and short-term outcomes. DESIGN: Prospective, population-based study. SETTING: UK and Republic of Ireland, between 1 May 2003 and 31 May 2005. PARTICIPANTS: Infants in the first month of life with severe hyperbilirubinaemia (maximum unconjugated serum bilirubin >/=510 micromol/l). RESULTS: 108 infants met the case definition, 106 from the UK and 2 from the Republic of Ireland. The UK incidence of severe hyperbilirubinaemia was 7.1/100 000 live births (95% CI 5.8 to 8.6). Only 20 cases presented in hospital; 88 were admitted with severe jaundice. 64 (60.4%) cases were male, and 56 (51.8%) were of ethnic minority origin. 87 (80.5%) cases were exclusively breast fed. Co-morbidity included haemolysis, dehydration, infection and bruising. 14 infants showed evidence of bilirubin encephalopathy, of whom 3 died. The UK incidence of bilirubin encephalopathy was 0.9/100 000 live births (95% CI 0.46 to 1.5). CONCLUSIONS: This is the first large, prospective, population-based study of the incidence of severe hyperbilirubinaemia in the newborn. The clinical and demographic associations, and short-term outcomes identified, are the same as those reported recently in North America and Europe.

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 ).

BACKGROUND: Although 8 per cent of groin hernia repairs are performed in women, there is little published literature relating specifically to women. This study compared differences in outcome between women and men after groin hernia repair. METHODS: Data collected prospectively in the Swedish Hernia Register between 1992 and 2003 were analysed, including 6895 groin hernia repairs in women and 83 753 in men. RESULTS: A higher proportion of emergency operations was carried out in women (16.9 per cent) than men (5.0 per cent), leading to bowel resection in 16.6 and 5.6 per cent respectively. During reoperation femoral hernias were found in 41.6 per cent of the women who were diagnosed with a direct or indirect inguinal hernia at the primary operation. The corresponding proportion for men was 4.6 per cent. The hernia repair was not classified as a standard operation (e.g. Shouldice, Lichtenstein, Plug/Mesh, TAPP/TEP) in 38.2 per cent of women and 11.2 per cent of men. Women had a significantly higher risk of reoperation for recurrence than men, and techniques associated with the lowest risk for reoperation in men had the highest risk in women. CONCLUSION: A greater proportion of women than men require emergency groin hernia repair, with consequently higher rates of bowel resection, complications and death. Surgical techniques developed for use in men may put women at unnecessary risk.

Associated fractures of the distal ulnar metaphysis were present in 19 of 320 distal radial fractures requiring either closed manipulation or surgical treatment over a 2-year period. Four morphological patterns of ulnar fracture were encountered, the commonest being the type 1 simple extra-articular fracture of the distal end of ulna with minimal comminution (eight out of 19). 15 patients were treated conservatively and two each were treated by internal and external fixation. 15 patients were reviewed after a mean follow-up of 23.8 months and there were four excellent, five good, five fair clinical results and one poor result. Radiographically the distal radio-ulnar joint (DRUJ) was normal in eight wrists, but longitudinal or horizontal disruption of the DRUJ was present in seven wrists. Fracture callus encroached on the DRUJ in three patients, who also had limitation of forearm rotation. Two comminuted ulnar fractures (type 4) developed non-union, but both patients had full forearm rotation, in contrast to restriction of forearm rotation in four out of five patients with type 1 fractures.

Post dural puncture headache can be a debilitating complication of epidural and subarachnoid anaesthesia for a new mother. In a survey of 18,337 epidurals and 5021 subarachnoid blocks performed for obstetric procedures over a 23-year period in a district general hospital maternity unit, there were 167 recognised accidental dural punctures after epidurals (0.91%), with 147 patients (88%) developing post dural puncture headache. In addition there were 52 post dural puncture headaches after subarachnoid blocks (1.04%). Successful management of accidental dural puncture and post dural puncture headache requires adherence to clear policies and protocols, with close follow-up of patients by an experienced obstetric anaesthetist.

Unicompartmental knee arthroplasty (UKA) has numerous advantages over total knee arthroplasty (TKA) and one disadvantage, the higher revision rate. The best way to minimize the revision rate is for surgeons to use UKA for at least 20% of their knee arthroplasties. To achieve this, they need to learn and apply the appropriate indications and techniques. This would decrease the revision rate and increase the number of UKAs which were implanted, which would save money and patients would benefit from improved outcomes over their lifetime. Cite this article: Bone Joint J 2018;100-B:432-5.

This paper describes a simple approach to emergency thoracotomy that can be used by a doctor in the prehospital environment and in the resuscitation room.

Background: Type 2 diabetes is associated with an increase in age-related mortality. A systematic review and meta-analysis were performed to define the relative risks (RR) of all-cause or cause-specific mortality in type 2 diabetes and to determine gaps in current research. Methods: A comprehensive literature search was undertaken for studies (published 1990–2010) on mortality in type 2 diabetes. The study reports on the measure of mortality as defined by RR for all-cause and cause-specific mortality, heterogeneity, sensitivity analyses and biases. Results: In total 35 studies (220,689 patients; mean follow-up of 10.7 years) were eligible for inclusion: 33 studies reported increased mortality risks; 24 had full data on 95% confidence intervals (CIs), one study reported no excess mortality in men diagnosed after 65 years whereas three reported increased mortality in similar age groups in both sexes. Meta-analysis showed RR = 1.85 (95% CI 1.79–1.92) for all-cause mortality [men RR=1.57 (95% CI 1.46–1.68); women RR=2.0 (95% CI 1.89–2.12)], RR=1.76 (95% CI 1.66–1.88) for cardiovascular mortality and RR=2.26 (95% CI: 1.7-3.02) for stroke. There was no statistically significant evidence of publication bias. Conclusion: Type 2 diabetes increases mortality approximately two-fold increase and macrovascular disease is the principal cause of death.

This qualitative study has aimed to explore children's, parents' and health professionals' experience of childhood chronic illness. Seven families and their professional carers participated in semistrucured interviews. The children's interviews were augmented with a 'drawing' technique. A grounded theory approach facilitated data collection and analysis. This paper debates the perceived passivity of the voice of children in health care and research and illustrates data collection methods that seek to give children and other disadvantaged groups a voice. The children who participated in this study are described as competent interpreters of their world.

Non-operative diagnosis has become the norm in breast disease assessment and, until relatively recently, fine needle aspiration cytology has been the sampling method of choice. The introduction of automated core biopsy guns in the mid 1990s led to the additional introduction of core biopsy in assessment units. This paper presents a summary of the guidance on handling and routine reporting of breast needle core biopsy specimens in the context of breast disease multidisciplinary assessment. This guidance has been produced by the UK National Coordinating Committee for Breast Screening Pathology and is endorsed by the European Commission working group on breast screening pathology.

BACKGROUND: Omeprazole has a greater intragastric pH elevating effect in Helicobacter pylori positive than negative subjects. Ammonia production by H pylori has been suggested as a probable mechanism. AIMS: To assess the effect of H pylori status on gastric acid secretion during omeprazole treatment, and to examine the possible role of ammonia neutralisation of intragastric acid in increased omeprazole efficacy in infected subjects. METHODS: Twenty H pylori positive and 12 H pylori negative healthy volunteers were examined before and six to eight weeks after commencing omeprazole 40 mg/day. On both occasions plasma gastrin and acid output were measured basally and in response to increasing doses of gastrin 17 (G-17). Gastric juice ammonium concentrations were also measured. RESULTS: Prior to omeprazole, measurements were similar in the H pylori positive and negative subjects. During omeprazole, median basal intragastric pH was higher in the H pylori positive (7.95) versus negative (3.75) subjects (p<0.002). During omeprazole basal, submaximal (180 pmol/kg/h G-17), and maximal acid outputs (800 pmol/kg/h G-17) were lower in H pylori positive subjects (0.0, 3.6, 6.0 mmol/h respectively) versus negative subjects (0.3, 14.2, 18.6 mmol/h) (p<0.03 for each). This effect was not explained by neutralisation by ammonia. CONCLUSION: The presence of H pylori infection leads to a more profound suppression of acid secretion during omeprazole treatment. The effect cannot be explained by neutralisation of intragastric acid by bacterial ammonia production and its precise mechanism has to be explained.

OBJECTIVE: To determine whether urinary incontinence per se and different types of urinary incontinence individually are associated with an increased risk of falls in those aged 70 years and over. To investigate whether the presence of urinary symptoms, poor quality of life and physical limitations in this population with urinary incontinence is associated with falls. DESIGN: Study using data from the cross-sectional postal questionnaire undertaken in the Leicestershire Medical Research Council Incontinence Study. SETTING: Leicestershire. PARTICIPANTS: A total of 5,474 people aged 70 years or more living in the community randomly selected from general practitioners' lists. RESULTS: Urinary incontinence and both urge and stress incontinence were positively related to falls (P < 0.0001, P < 0.001 and P = 0.007, respectively). The larger the volume of urine lost, the greater the risk of falls (P < 0.0001). Falls were associated with the presence of urinary symptoms (P = 0.01 or less), physical limitations (P = 0.001 or less) and having a poorer quality of life (P = 0.004 or less) in respondents with urinary incontinence. CONCLUSIONS: An association has been shown between falling and urinary leakage including the previously unreported association with stress leakage. Falling and urinary incontinence were found to be associated with physical limitations and had an impact on quality of life.