West Middlesex University 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.

A longitudinal study, based on interviews with 308 middle-class, preponderantly white mothers, provided an opportunity to evaluate the continuity, predictive factors, and behavioral correlates of sleep problems in young children. When their children were 8 months old, 10% of the mothers reported that their babies woke three or more times per night, 8% reported that the babies took an hour or more to settle after waking, 5% complained that their own sleep was severely disrupted by the child, and 18% reported at least one of these problems. At 3 years of age, 29% of the children had difficulty getting to bed and/or falling asleep or staying asleep. Of children with a sleep problem at 8 months of age, 41% still had a problem at 3 years of age, whereas only 26% of children without a problem at 8 months of age had a problem at 3 years of age (P less than .001). Among children with sleep problems at 8 months of age, mothers' depressed feelings were the only measured demographic or psychosocial factor associated with persistent sleep problems (P = .02). A separate analysis indicated that these depressed feelings did not appear to be a consequence of the child's sleep problem. Future studies should evaluate how maternal depression interacts with other factors to result in persistent sleep problems. Children with persistent sleep problems were more likely to have behavior problems, especially tantrums (P less than .02) and behavior management problems (P less than .01), than were children without persistent sleep problems (P less than .02).(ABSTRACT TRUNCATED AT 250 WORDS)

The families of 29 patients with systemic lupus erythematosus and 42 normal subjects were studied to determine the inheritance of the HLA-A, B, C, and DR antigens and also the complement polymorphisms for C2, C4A, C4B, and Bf, which are encoded in the same region of the sixth chromosome. Null (silent) alleles for C4A, C4B, or C2 were found in 24 of the 29 (83%) patients compared with 18 of the 42 (43%) normal controls. HLA-DR3 was present in 20 (69%) of the patients and seven out of 39 (18%) of the normal controls. There was strong linkage disequilibrium between DR3 and the null alleles for C4A and C4B. The data did not permit the relative contributions of DR3 and null factors of C4A and C4B as genetic risk factors to be distinguished. The known association of systemic lupus erythematosus with uncommon inherited and acquired deficiencies of complement components suggests, however, that the presence of null alleles for C4A and C4B, as well as C2, found in most of the patients, is relevant to their genetic susceptibility to this disease.

This is the peer reviewed version of the following article: Pavord, S. , Myers, B. , Robinson, S. , Allard, S. , Strong, J. , Oppenheimer, C. and , (2012), UK guidelines on the management of iron deficiency in pregnancy. British Journal of Haematology, 156: 588-600. doi:10.1111/j.1365-2141.2011.09012.x, which has been published in final form at https://doi.org/10.1111/j.1365-2141.2011.09012.x This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions

These consensus guidelines were jointly commissioned by the British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE). They provide an evidence-based framework for the use of surveillance colonoscopy and non-colonoscopic colorectal imaging in people aged 18 years and over. They are the first guidelines that take into account the introduction of national bowel cancer screening. For the first time, they also incorporate surveillance of patients following resection of either adenomatous or serrated polyps and also post-colorectal cancer resection. They are primarily aimed at healthcare professionals, and aim to address: Which patients should commence surveillance post-polypectomy and post-cancer resection? What is the appropriate surveillance interval? When can surveillance be stopped? two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument provided a methodological framework for the guidelines. The BSG’s guideline development process was used, which is National Institute for Health and Care Excellence (NICE) compliant. two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps The key recommendations are that the high-risk criteria for future colorectal cancer (CRC) following polypectomy comprise either : two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps This cohort should undergo a one-off surveillance colonoscopy at 3 years. Post-CRC resection patients should undergo a 1 year clearance colonoscopy, then a surveillance colonoscopy after 3 more years.

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.

BACKGROUND: Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS: We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 μg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS: The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS: The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.).

Abstract Although some attention has been paid to the idea that seismic migration is equivalent to a type of deconvolution (of the spatial wavelet), less thought has been given to the opposite perspective: that deconvolution (of the earth Q filter) might itself be equivalent to a form of migration. The key point raised in this paper is that a dispersive 1-D backward propagation can form the basis of a number of different algorithms for inverse Q filtering, each of which is akin to a particular migration algorithm. An especially efficient algorithm can be derived by means of a coordinate transformation equivalent to that in the Stolt frequency-wavenumber migration.This fast algorithm, valid for Q constant with depth, can be extended to accommodate depth-variable Q by cascading a series of constant Q compensations, as in cascaded migration. By combining a cascaded phase compensation with a windowed approach to amplitude compensation, we obtain an algorithm that is sufficiently efficient to be used routinely for prestack data processing. Data examples compare the results of conventional processing with the more stable phase treatment that can be obtained by including prestack inverse Q filtering in the processing.

1. Sialic acid has been found to interfere with three colorimetric reactions used for the estimation of DNA: a modified diphenylamine reaction at 100 degrees (Dische, 1930), the nitrophenylhydrazine method (Webb & Levy, 1955) and the diphenylamine reaction at 30 degrees (Burton, 1956). 2. Evidence is presented that sialic acid is present in hydrolysates obtained from gastric wash-out material. 3. A mathematical method for correcting for interference from sialic acid in the diphenylamine reaction at 30 degrees is described. 4. The diphenylamine reaction has been modified to make it suitable for the estimation of DNA in the presence of sialic acid. The modifications are to increase the concentration of diphenylamine to 2% and to perform the reaction at 6-13 degrees for 48hr. These modifications increase the sensitivity 25% above Burton's (1956) modification of the diphenylamine reaction. 5. The precipitation, extraction and recovery of DNA from gastric wash-out material have been investigated.

BACKGROUND: The aim of this study was first to analyze the stability of Antonovsky's Sense of Coherence (SOC) as a measure of a person's world view over time; secondly, to investigate its relationship with depression and anxiety. METHODS: Data from two longitudinal studies were used: a study of severely injured accident victims (n = 96), and a study of patients suffering from rheumatoid arthritis (RA, n = 60). The 13 items short version of the SOC scale and measures of depression and anxiety (Symptom Checklist, Hospital Anxiety and Depression Scale) were administered repeatedly over 6-12 months in both studies. RESULTS: In the sample of accident victims, a significant decrease in the SOC mean score was observed during the first half year after the accident. During the same time period, symptoms of anxiety and depression decreased significantly. In the second half year after the accident, SOC as well as measures of psychopathology remained stable. RA patients showed high stability of SOC and measures of anxiety and depression over time. In both samples, between-time correlations of SOC scores were high (r > or = 0. 70, p<0.01), indicating a high test-retest stability of SOC. Furthermore, in both samples, significant negative correlations of a moderate to high degree (r = -0.28 to -0.73, p<0.01) were found between SOC and measures of anxiety and depression. CONCLUSIONS: SOC can be seen as a relatively stable (trait) measure. However, traumatic events such as life-threatening accidents may change a person's world view and thus their SOC, even if psychiatric symptoms abate. This suggests that SOC is not merely a proxy measure of psychopathology, but rather a partially independent, general measure of a person's world view.

OBJECTIVE: To determine the nature and outcome of obstetric cholestasis in a United Kingdom population. DESIGN: Prospective analysis of clinical outcome in women diagnosed with obstetric cholestasis that is actively managed. SETTING: Antenatal population of three London hospitals between August 1999 and April 2001. POPULATION: Seventy women with obstetric cholestasis defined as abnormal liver function (one or more abnormality in gamma-glutamyl transpeptidase, alanine amino-transferase, aspartate amino-transferase and total bile acids) in a pregnant woman with pruritus, in the absence of other pathology. METHODS: All women were interviewed weekly regarding their symptoms. All were actively managed according to a standardised protocol, which included early delivery before 38 weeks. Obstetric outcome was recorded. RESULTS: Seventy women of mean age 30 (6) years delivered 73 infants. The median gestation at onset of pruritus was 30 (range 4-39) weeks and at diagnosis of obstetric cholestasis was 33.7 (range 21-40.7) weeks. Asian women were more likely to be diagnosed with obstetric cholestasis. Pruritus was usually severe and generalised, and commonly worst on the palms and/or soles of the feet. There were no stillbirths or perinatal deaths. Twenty-five women required caesarean section (36%); only four (16%) were for fetal distress. Twelve women (17%) delivered before 37 weeks, of which eight (67%) were iatrogenic. Ten (14%) infants required admission to the special care baby unit of which four (40%) were ventilated. CONCLUSIONS: Policies of active management result in increased intervention and associated complications. This must be balanced against possible reductions in perinatal mortality.

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 ).

Abstract Objective : To examine the prognostic significance and role in risk stratification of the biochemical marker troponin T in patients admitted with unstable angina. Design : Single centre, blinded, prospective study of patients admitted with chest pain. Setting : Coronary care unit of a district general hospital. Subjects : 460 patients admitted with chest pain and followed up for a median of three years. 183 patients had a final diagnosis of unstable angina. Main outcome measures : Cardiac death, need for coronary revascularisation, or readmission with non-fatal myocardial infarction as first events. Results : 62 (34%) unstable angina patients were troponin T positive. This group had significantly increased incidence rates of subsequent cardiac death (12 cases (19%) v 14 (12%)), coronary revascularisation (22 (35%) v 26 (21%)), death or revascularisation (33 (53%) v 40 (33%)), and death or non-fatal myocardial infarction (18 (29%) v 21 (17%)) compared with the troponin T negative group. In multiple logistic regression troponin T status was a highly significant predictor for the end points coronary revascularisation and cardiac death or revascularisation as first events. Conclusion : Troponin T in the serum of patients with unstable angina identifies a subgroup at higher risk of subsequent cardiac events and its measurement aids in risk factor stratification. The increased risk extends to two years after admission. Prospective randomised trials are required to identify optimum therapeutic strategies for this subgroup. Key messages Stratifying patients with unstable angina for risk remains a difficult clinical problem A new cardiac specific protein, troponin T, can now be measured in serum The detection of troponin T 12-24 hours after admission identifies a high risk subgroup of patients with unstable angina Prospective trials are required to identify optimum therapeutic strategies for this subgroup

The epidemiology of recurrent stomachache and headache was studied in a community sample of 308 preschool children, most of whom were white. When the children were 3 years old, interviews with their mothers indicated that 3% had recurrent headaches and 9% had recurrent stomachaches. Children with recurrent stomachaches were more likely than those without recurrent stomachaches to have mothers who were emotionally depressed (P less than .01), had marital problems (P less than .05), and perceived their own health as poor (P less than .05). When maternal poor health was controlled, depression was still associated with their children having stomachaches (P less than .05). Prospectively collected data demonstrate that children with recurrent stomachaches did not have bowel difficulties when they were infants. Other psychosocial stresses and demographic factors were not associated with stomachaches. The only variable associated with recurrent headache was maternal depression. Children with recurrent headaches or stomachaches were more likely to have behavior problems, as measured by the Behavior Screening Questionnaire, than were children without these symptoms. The analysis presents new data on these common symptoms of childhood.

This study examined the efficacy of a cognitive and behavioural intervention (CBT) for patients with recent onset, seropositive rheumatoid arthritis. Fifty-three participants with a diagnosis of classical or definite rheumatoid arthritis, who were seropositive and had less than 2 years of disease history were recruited into the trial. All participants received routine medical management during the study, although half were randomly allocated to receive an adjunctive psychological intervention. All pre- and post-treatment assessments were conducted blind to the allocation. Analyses were conducted of treatment completers and also by intention-to-treat. Significant differences were found between the groups at both post-treatment and 6-month follow-up in depressive symptoms. While the CBT group showed a reduction in depressive symptoms, the same symptoms increased in the Standard group. At outcome but not follow-up, the CBT group also showed reduction in C-reactive protein levels. However, the CBT group did show significant improvement in joint involvement at 6-month follow-up compared with the Standard group, indicating physical improvements above those achieved with standard care. These results indicate that cognitive-behavioural intervention offered as an adjunct to standard clinical management early in the course of RA is efficacious in producing reductions in both psychological and physical morbidity

Fifty-eight patients with uncomplicated diverticular disease of the colon took bran crispbread, ispaghula drink, and placebo for four months each in a randomised, cross-over, double-blind controlled trial. Assessments were made subjectively, using a monthly self-administered questionnaire, and objectively, by examining a seven-day stool collection at the end of each treatment period. In terms of a pain score, lower bowel symptom score (the pain score and sensation of incomplete emptying, straining, stool consistency, flatus, and aperients taken), and total symptom score (belching, nausea, vomiting, dyspepsia, and abdominal distension) fibre supplementation conferred no benefit. Symptoms of constipation, however, when assessed alone, were significantly relieved. Both fibre regimens produced the expected changes in stool weight, consistency, and frequency. It is concluded that dietary fibre supplements in the commonly used doses do no more than relieve constipation. Perhaps the impression that fibre helps diverticular disease is simply a manifestation of Western civilisation's obsession with the need for regular frequent defecation.

Journal Article THE NATURAL HISTORY OF TRANSIENT ISCHAEMIC CEREBRO-VASCULAR ATTACKS Get access JOHN MARSHALL JOHN MARSHALL From the National Hospital for Nervous Diseases, the West Middlesex Hospital, and the Institute of Neurology, Queen SquanceLondon, W.C.I Search for other works by this author on: Oxford Academic PubMed Google Scholar QJM: An International Journal of Medicine, Volume 33, Issue 3, July 1964, Pages 309–324, https://doi.org/10.1093/oxfordjournals.qjmed.a067022 Published: 01 July 1964 Article history Received: 07 December 1963 Published: 01 July 1964

cases, and the side-effects seen in the course of their treatment, are discussed.

BACKGROUND: Tackling tuberculosis requires testing and treatment of latent tuberculosis in high-risk groups. The aim of this study was to estimate the predictive values of the tuberculin skin test (TST) and two interferon-γ release assays (IGRAs) for the development of active tuberculosis in high-risk groups-ie, people in recent contact with active tuberculosis cases and from high-burden countries. METHOD: In this prospective cohort study, we recruited participants from 54 centres (eg, clinics, community settings) in London, Birmingham, and Leicester in the UK. Participants were eligible if they were aged 16 years or older and at high risk for latent tuberculosis infection (ie, recent contact with someone with active tuberculosis [contacts] or a migrant who had arrived in the UK in the past 5 years from-or who frequently travelled to-a country with a high burden of tuberculosis [migrants]). Exclusion criteria included prevalent cases of tuberculosis, and participants who were treated for latent tuberculosis after a positive test result in this study. Each participant received three tests (QuantiFERON-TB Gold-In Tube, T-SPOT.TB, and a Mantoux TST). A positive TST result was reported using three thresholds: 5 mm (TST-5), 10 mm (TST-10), and greater than 5 mm in BCG-naive or 15 mm in BCG-vaccinated (TST-15) participants. Participants were followed up from recruitment to development of tuberculosis or censoring. Incident tuberculosis cases were identified by national tuberculosis databases, telephone interview, and review of medical notes. Our primary objective was to estimate the prognostic value of IGRAs compared with TST, assessed by the ratio of incidence rate ratios and predictive values for tuberculosis development. The study was registered with ClinicalTrials.gov, NCT01162265, and is now complete. FINDINGS: Between May 4, 2010, and June 1, 2015, 10 045 people were recruited, of whom 9610 were eligible for inclusion. Of this cohort, 4861 (50·6%) were contacts and 4749 (49·4%) were migrants. Participants were followed up for a median of 2·9 years (range 21 days to 5·9 years). 97 (1·0%) of 9610 participants developed active tuberculosis (77 [1·2%] of 6380 with results for all three tests). In all tests, annual incidence of tuberculosis was very low in those who tested negatively (ranging from 1·2 per 1000 person-years, 95% CI 0·6-2·0 for TST-5 to 1·9 per 1000 person-years, 95% CI 1·3-2·7, for QuantiFERON-TB Gold In-Tube). Annual incidence in participants who tested positively were highest for T-SPOT.TB (13·2 per 1000 person-years, 95% CI 9·9-17·4), TST-15 (11·1 per 1000 person-years, 8·3-14·6), and QuantiFERON-TB Gold In-Tube (10·1 per 1000 person-years, 7·4-13·4). Positive results for these tests were significantly better predictors of progression than TST-10 and TST-5 (eg, ratio of test positivity rates in those progressing to tuberculosis compared with those not progressing T-SPOT.TB vs TST-5: 1·99, 95% CI 1·68-2·34; p<0·0001). However, TST-5 identified a higher proportion of participants who progressed to active tuberculosis (64 [83%] of 77 tested) than all other tests and TST thresholds (≤75%). INTERPRETATION: IGRA-based or BCG-stratified TST strategies appear most suited to screening for potential disease progression among high-risk groups. Further work will be needed to assess country-specific cost-effectiveness of each screening test, and in the absence of highly specific diagnostic tests, cheap non-toxic treatments need to be developed that could be given to larger groups of people at potential risk. FUNDING: National Institute for Health Research Health Technology Assessment Programme 08-68-01.