Princess of Wales 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.

SeCTion 4: WhaT iS The evidenCe for TranSmiSSion of nTm BeTWeen individualS? recommendation Adequate infection control policies need to be implemented in both inpatient and outpatient settings to minimise risks of person-to-person transmission of Mycobacterium abscessus in individuals with cystic fibrosis (CF). (Grade B) SeCTion 5: hoW Should The lung diSeaSe aTTriBuTaBle To nTm infeCTion Be defined? recommendation In the absence of robust evidence to support an alternative definition and due to the clinical and research benefits of having a uniform definition, use of the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) 2007 definition of non-tuberculous mycobacterial (NTM) pulmonary disease is recommended 1 (see Box 1). (Grade D) good practice point 3 The management of coexisting lung conditions/ infections should be optimised before ascribing clinical decline to NTM-pulmonary disease.

Background: Asymptomatic atrial fibrillation (AF) is increasingly common in the aging population and implicated in many ischemic strokes. Earlier identification of AF with appropriate anticoagulation may decrease stroke morbidity and mortality. Methods: We conducted a randomized controlled trial of AF screening using an AliveCor Kardia monitor attached to a WiFi-enabled iPod to obtain ECGs (iECGs) in ambulatory patients. Patients ≥65 years of age with a CHADS-VASc score ≥2 free from AF were randomized to the iECG arm or routine care (RC). iECG participants acquired iECGs twice weekly over 12 months (plus additional iECGs if symptomatic) onto a secure study server with overread by an automated AF detection algorithm and by a cardiac physiologist and/or consultant cardiologist. Time to diagnosis of AF was the primary outcome measure. The overall cost of the devices, ECG interpretation, and patient management were captured and used to generate the cost per AF diagnosis in iECG patients. Clinical events and patient attitudes/experience were also evaluated. Results: We studied 1001 patients (500 iECG, 501 RC) who were 72.6±5.4 years of age; 534 were female. Mean CHADS-VASc score was 3.0 (heart failure, 1.4%; hypertension, 54%; diabetes mellitus, 30%; prior stroke/transient ischemic attack, 6.5%; arterial disease, 15.9%; all CHADS-VASc risk factors were evenly distributed between groups). Nineteen patients in the iECG group were diagnosed with AF over the 12-month study period versus 5 in the RC arm (hazard ratio, 3.9; 95% confidence interval=1.4–10.4; P =0.007) at a cost per AF diagnosis of $10 780 (£8255). There was a similar number of stroke/transient ischemic attack/systemic embolic events (6 versus 10, iECG versus RC; hazard ratio=0.61; 95% confidence interval=0.22–1.69; P =0.34). The majority of iECG patients were satisfied with the device, finding it easy to use without restricting activities or causing anxiety. Conclusions: Screening with twice-weekly single-lead iECG with remote interpretation in ambulatory patients ≥65 years of age at increased risk of stroke is significantly more likely to identify incident AF than RC over a 12-month period. This approach is also highly acceptable to this group of patients, supporting further evaluation in an appropriately powered, event-driven clinical trial. Clinical Trial Registration: URL: https://www.isrctn.com . Unique identifier: ISRCTN10709813.

BACKGROUND: Ulcerative colitis is largely a disease of nonsmokers. Because anecdotal reports suggest that smoking and nicotine may improve the symptoms of the disease, we examined the effect of nicotine as a supplemental treatment for ulcerative colitis. METHODS: We treated 72 patients with active ulcerative colitis with either transdermal nicotine patches or placebo patches for six weeks in a randomized, double-blind study. Incremental doses of nicotine were given; most patients tolerated doses of 15 to 25 mg per 24 hours. All the patients had been taking mesalamine, and 12 were receiving low doses of glucocorticoids; these medications were continued without change during the study. Clinical, sigmoidoscopic, and histologic assessments were made at base line and at the end of the study; symptoms were recorded daily on a diary card, and the clinician made a global assessment. Side effects and plasma nicotine and cotinine concentrations were monitored throughout the study. RESULTS: Seventeen of the 35 patients in the nicotine group had complete remissions, as compared with 9 of the 37 patients in the placebo group (P = 0.03). The patients in the nicotine group had greater improvement in the global clinical grade of colitis (P < 0.001) and the histologic grade (P = 0.03), lower stool frequency (a difference of 1.6 stools daily; P = 0.008), less abdominal pain (P = 0.05), and less fecal urgency (P = 0.009). More patients in the nicotine group had side effects (23, vs. 11 in the placebo group; P = 0.002), the most common of which were nausea, lightheadedness, headache, and sleep disturbance. Withdrawals due to ineffective therapy were more common in the placebo group (3 vs. 8, P = 0.12). CONCLUSIONS: The addition of transdermal nicotine to conventional maintenance therapy improves symptoms in patients with ulcerative colitis.

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no 'gold standard' test to define deficiency. Serum cobalamin currently remains the first-line test, with additional second-line plasma methylmalonic acid to help clarify uncertainties of underlying biochemical/functional deficiencies. Serum holotranscobalamin has the potential as a first-line test, but an indeterminate 'grey area' may still exist. Plasma homocysteine may be helpful as a second-line test, but is less specific than methylmalonic acid. The availability of these second-line tests is currently limited. Definitive cut-off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues, and local reference ranges should be established. In the presence of discordance between the test result and strong clinical features of deficiency, treatment should not be delayed to avoid neurological impairment. Treatment of cobalamin deficiency is recommended in line with the British National Formulary. Oral therapy may be suitable and acceptable provided appropriate doses are taken and compliance is not an issue. Serum folate offers equivalent diagnostic capability to red cell folate and is the first-line test of choice to assess folate status.

Common bile duct stones (CBDS) are estimated to be present in 10-20% of individuals with symptomatic gallstones. They can result in a number of health problems, including pain, jaundice, infection and acute pancreatitis. A variety of imaging modalities can be employed to identify the condition, while management of confirmed cases of CBDS may involve endoscopic retrograde cholangiopancreatography, surgery and radiological methods of stone extraction. Clinicians are therefore confronted with a number of potentially valid options to diagnose and treat individuals with suspected CBDS. The British Society of Gastroenterology first published a guideline on the management of CBDS in 2008. Since then a number of developments in management have occurred along with further systematic reviews of the available evidence. The following recommendations reflect these changes and provide updated guidance to healthcare professionals who are involved in the care of adult patients with suspected or proven CBDS. It is not a protocol and the recommendations contained within should not replace individual clinical judgement.

Certain fly larvae can infest corpses or the wounds of live hosts. Those which are least invasive on live hosts have been used therapeutically, to remove dead tissue from wounds, and promote healing. This medicinal use of maggots is increasing around the world, due to its efficacy, safety and simplicity. Given our low cultural esteem for maggots, the increasing use and popularity of maggot therapy is evidence of its utility. Maggot therapy has successfully treated many types of chronic wounds, but much clinical and basic research is needed still. In this review, the biology of myiasis and the history of maggot therapy are presented, the current status of our understanding and clinical use of medicinal maggots is discussed, and opportunities for future research and applications are proposed.

OBJECTIVES: To evaluate a paging system designed to improve independence in people with memory problems and executive deficits. METHODS: After a successful pilot study, a randomised control trial was conducted involving a crossover design with 143 people aged between 8 and 83 years. All had one or more of the following: memory, planning, attention, or organisation problems. Most had sustained a traumatic head injury or a stroke although a few had developmental learning difficulties or other conditions. The crossover design ensured that some people received a pager after a 2 week baseline whereas others were required to wait for 7 weeks after the baseline before receiving the pager. Participants were assessed at three time periods-namely, at baseline, 7 weeks, and at 14 weeks postbaseline. RESULTS: More than 80% of those who completed the 16 week trial were significantly more successful in carrying out everyday activities (such as self care, self medication, and keeping appointments) when using the pager in comparison with the baseline period. For most of these, significant improvement was maintained when they were monitored 7 weeks after returning the pager. CONCLUSIONS: This particular paging system significantly reduces everyday failures of memory and planning in people with brain injury.

BACKGROUND: The aim of the study was to develop a dedicated colorectal Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (CR-POSSUM) equation for predicting operative mortality, and to compare its performance with the Portsmouth (P)-POSSUM model. METHODS: Data were collected prospectively from 6883 patients undergoing colorectal surgery in 15 UK hospitals between 1993 and 2001. After excluding missing data and 93 patients who did not satisfy the inclusion criteria, 4632 patients (68.2 per cent) underwent elective surgery and 2107 had an emergency operation (31.0 per cent); 2437 operations (35.9 per cent) for malignant and 4267 (62.8 per cent) for non-malignant diseases were scored. Stepwise logistic regression analysis was used to develop an age-adjusted POSSUM model and a dedicated CR-POSSUM model. A 60:40 per cent split-sample validation technique was adopted for model development and testing. Observed and expected mortality rates were compared. RESULTS: The operative mortality rate for the series was 5.7 per cent (387 of 6790 patients) (elective operations 2.8 per cent; emergency surgery 12.0 per cent). The CR-POSSUM, age-adjusted POSSUM and P-POSSUM models had similar areas under the receiver-operator characteristic curves. Model calibration was similar for CR-POSSUM and age-adjusted POSSUM models, and superior to that for the P-POSSUM model. The CR-POSSUM model offered the best overall accuracy, with an observed : expected ratio of 1.000, 0.998 and 0.911 respectively (test population). CONCLUSION: The CR-POSSUM model provided an accurate predictor of operative mortality. External validation is required in hospitals different from those in which the model was developed.

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.

In Brief Background: This study was designed to investigate the early outcomes after surgical treatment of malignant large bowel obstruction (MBO) and to identify risk factors affecting operative mortality. Methods: Data were prospectively collected from 1046 patients with MBO by 294 surgeons in 148 UK hospitals during a 12-month period from April 1998. A predictive model of in-hospital mortality was developed using a 3-level Bayesian logistic regression analysis. Results: The median age of patients was 73 years (interquartile range 64–80). Of the 989 patients having surgery, 91.7% underwent bowel resection with an overall mortality of 15.7%. The multilevel model used the following independent risk factors to predict mortality: age (odds ratio [OR] 1.85 per 10 year increase), American Society of Anesthesiologists grade (OR for American Society of Anesthesiologists grade I versus II,III,IV-V = 3.3,11.7,22.2), Dukes’ staging (OR for Dukes’ A versus B,C,D = 2.0, 2.1, 6.0), and mode of surgery (OR for scheduled versus urgent, emergency = 1.6, 2.3). A significant interhospital variability in operative mortality was evident with increasing age (variance = 0.004, SE = 0.001, P < 0.001). No detectable caseload effect was demonstrated between specialist colorectal and other general surgeons. Conclusions: Using prognostic models, it was possible to develop a risk-stratification index that accurately predicted survival in patients presenting with malignant large bowel obstruction. The methodology and model for risk adjusted survival can set the reference point for more accurate and reliable comparative analysis and be used as an adjunct to the process of informed consent. Malignant large bowel obstruction is a high-risk condition, occurring in 15% of patients presenting with colorectal cancer. We describe a prospective multicenter study, describing a prognostic model for quantifying operative risk for such patients. The model can be applied in everyday practice as an adjunct to the process of informed consent.

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.

Large quantities of alginate dressings are used each year to treat exuding wounds, such as leg ulcers, pressure sores and infected surgical wounds. Originally these dressings were a loose fleece formed primarily from fibres of calcium alginate. More recently they have been developed so that the fibres have been entangled to form a product with more cohesive structure, which increases the fabric's strength when it is soaked with exudate or blood. Some products also contain a significant proportion of sodium alginate to improve the gelling properties of the dressing in use. Other dressings have been produced from freeze-dried alginate. Once in contact with an exuding wound, an ion-exchange reaction takes place between the calcium ions in the dressing and sodium ions in serum or wound fluid. When a significant proportion of the calcium ions on the fibre have been replaced by sodium, the fibre swells and partially dissolves forming a gel-like mass. The degree of swelling is determined principally by the chemical composition of the alginate, which depends on its botanical source. Although it is recognised that the differences between the various brands of dressings may influence their handling characteristics--particularly when wet--it is generally assumed that these differences are of limited relevance to the dressing's performance clinically or at a cellular level. There is some evidence to suggest, however, that these assumptions may be wrong and that alginates may influence wound healing in a number of ways not yet fully understood. This three-part review of the literature encompasses the history, origin, structure, chemistry and clinical applications of alginates and alginate dressings. This review reveals that, despite their widespread use, alginates have been the subject of very few well-controlled clinical studies. There is fairly convincing evidence, however, that they do offer advantages over more traditional dressings for at least some clinical indications. It has also become obvious that there is a general lack of understanding about the importance of secondary dressing systems that must be used in with alginate dressings. Careful examination of the design and outcomes of the published studies suggests that the choice of both the primary alginate dressing and the secondary dressing can play a major role in determining treatment outcomes.

The full guideline for the management of non-tuberculous mycobacterial pulmonary disease is published in Thorax . The following is a summary of the recommendations and good practice points. The sections referred to in the summary refer to the full guideline.

OBJECTIVE: To develop a mathematical model that will predict the probability of death after surgery for colorectal cancer. DESIGN: Descriptive study using routinely collected clinical data. DATA SOURCE: The database of the Association of Coloproctology of Great Britain and Ireland (ACPGBI), encompassing 8077 patients with a new diagnosis of colorectal cancer in 73 hospitals during a 12 month period. STATISTICAL ANALYSIS: A three level hierarchical logistic regression model was used to identify independent predictors of operative mortality. The model was developed on 60% of the patient population and its validity tested on the remaining 40%. RESULTS: Overall postoperative mortality was 7.5% (95% confidence interval 6.9% to 8.1%). Independent predictors of death were age, American Society of Anesthesiology (ASA) grade, Dukes's stage, urgency of the operation, and cancer excision. When tested the predictive model showed good discrimination (area under the receiver operating characteristic curve = (0.775) and calibration (comparison of observed with expected mortality across different procedures; Hosmer-Lemeshow statistic = 6.34, 8 df, P = 0.610). CONCLUSIONS: Clinicians can predict postoperative death by using a simple numerical table derived from the statistical model of the ACPGBI. The model can be used in everyday practice for preoperative counselling of patients and their carers as a part of multidisciplinary care. It may also be used to compare the outcomes between multidisciplinary teams for colorectal cancer.

This case study describes the use of a wearable camera, SenseCam, which automatically captures several hundred images per day, to aid autobiographical memory in a patient, Mrs B, with severe memory impairment following limbic encephalitis. By using SenseCam to record personally experienced events we intended that SenseCam pictures would form a pictorial diary to cue and consolidate autobiographical memories. After wearing SenseCam, Mrs B plugged the camera into a PC which uploaded the recorded images and allowed them to be viewed at speed, like watching a movie. In the control condition, a written diary was used to record and remind her of autobiographical events. After viewing SenseCam images, Mrs B was able to recall approximately 80% of recent, personally experienced events. Retention of events was maintained in the long-term, 11 months afterwards, and without viewing SenseCam images for three months. After using the written diary, Mrs B was able to remember around 49% of an event; after one month with no diary readings she had no recall of the same events. We suggest that factors relating to rehearsal/re-consolidation may have enabled SenseCam images to improve Mrs B's autobiographical recollection.

PURPOSE: We compared the safety and efficacy of Aquablation and transurethral prostate resection for the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. MATERIALS AND METHODS: In a double-blind, multicenter, prospective, randomized, controlled trial 181 patients with moderate to severe lower urinary tract symptoms related to benign prostatic hyperplasia underwent transurethral prostate resection or Aquablation. The primary efficacy end point was the reduction in International Prostate Symptom Score at 6 months. The primary safety end point was the development of Clavien-Dindo persistent grade 1, or 2 or higher operative complications. RESULTS: Mean total operative time was similar for Aquablation and transurethral prostate resection (33 vs 36 minutes, p = 0.2752) but resection time was lower for Aquablation (4 vs 27 minutes, p <0.0001). At month 6 patients treated with Aquablation and transurethral prostate resection experienced large I-PSS improvements. The prespecified study noninferiority hypothesis was satisfied (p <0.0001). Of the patients who underwent Aquablation and transurethral prostate resection 26% and 42%, respectively, experienced a primary safety end point, which met the study primary noninferiority safety hypothesis and subsequently demonstrated superiority (p = 0.0149). Among sexually active men the rate of anejaculation was lower in those treated with Aquablation (10% vs 36%, p = 0.0003). CONCLUSIONS: Surgical prostate resection using Aquablation showed noninferior symptom relief compared to transurethral prostate resection but with a lower risk of sexual dysfunction. Larger prostates (50 to 80 ml) demonstrated a more pronounced superior safety and efficacy benefit. Longer term followup would help assess the clinical value of Aquablation.

In 2017, the British Association for Cardiovascular Prevention and Rehabilitation published its official document detailing standards and core components for cardiovascular prevention and rehabilitation. Building on the success of previous editions of this document (published in 2007 and 2012), the 2017 update aims to further emphasise to commissioners, clinicians, politicians and the public the importance of robust, quality indicators of cardiac rehabilitation (CR) service delivery. Otherwise, its overall aim remains consistent with the previous publications-to provide a precedent on which all effective cardiovascular prevention and rehabilitation programmes are based and a framework for use in assessment of variation in service delivery quality. In this 2017 edition, the previously described seven standards and core components have both been revised to six, with a greater focus on measurable clinical outcomes, audit and certification. The principles within the updated document underpin the six-stage pathway of care for CR, and reflect the extensive evidence base now available within the field. To help improve current services, close collaboration between commissioners and CR providers is advocated, with use of the CR costing tool in financial planning of programmes. The document specifies how quality assurance can be facilitated through local audit, and advocates routine upload of individual-level data to the annual British Heart Foundation National Audit of Cardiac Rehabilitation, and application for national certification ensuring attainment of a minimum quality standard. Although developed for the UK, these standards and core components may be applicable to other countries.

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 ).