Prince Philip Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

The British Thoracic Society (BTS) Home Oxygen Guideline provides detailed evidence-based guidance for the use of home oxygen for patients out of hospital. Although the majority of evidence comes from the use of oxygen in patients with chronic obstructive pulmonary disease, the scope of the guidance includes patients with a variety of long-term respiratory illnesses and other groups in whom oxygen is currently ordered, such as those with cardiac failure, cancer and end-stage cardiorespiratory disease, terminal illness or cluster headache. It explores the evidence base for the use of different modalities of oxygen therapy and patient-related outcomes such as mortality, symptoms and quality of life. The guideline also makes recommendations for assessment and follow-up protocols, and risk assessments, particularly in the clinically challenging area of home oxygen users who smoke. The guideline development group is aware of the potential for confusion sometimes caused by the current nomenclature for different types of home oxygen, and rather than renaming them, has adopted the approach of clarifying those definitions, and in particular emphasising what is meant by long-term oxygen therapy and palliative oxygen therapy. The home oxygen guideline provides expert consensus opinion in areas where clinical evidence is lacking, and seeks to deliver improved prescribing practice, leading to improved compliance and improved patient outcomes, with consequent increased value to the health service.

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: Over the last two decades, progress in prevention and treatment of caries and periodontal diseases has been translated to better oral health and improved tooth retention in the adult population. The ageing population and the increasing expectations of good oral health-related quality of life in older age pose formidable challenges to clinical care and healthcare systems. AIMS: The objective of this workshop was to critically review scientific evidence and develop specific recommendations to: (i) prevent tooth loss and retain oral function through prevention and treatment of caries and periodontal diseases later in life and (ii) increase awareness of the health benefits of oral health as an essential component of healthy ageing. METHODS: Discussions were initiated by three systematic reviews covering aspects of epidemiology of caries and periodontal diseases in elders, the impact of senescence on caries and periodontal diseases and the effectiveness of interventions. Recommendations were developed based on evidence from the systematic reviews and expert opinion. RESULTS: Key messages included: (i) the ageing population, trends in risk factors and improved tooth retention point towards an expected increase in the total burden of disease posed by caries and periodontal diseases in the older population; (ii) specific surveillance is required to monitor changes in oral health in the older population; (iii) senescence impacts oral health including periodontitis and possibly caries susceptibility; (iv) evidence indicates that caries and periodontal diseases can be prevented and treated also in older adults; (v) oral health and functional tooth retention later in life provides benefits both in terms of oral and general quality of life and in terms of preventing physical decline and dependency by fostering a healthy diet; (vi) oral healthcare professionals and individuals should not base decisions impacting tooth retention on chronological age but on level of dependency, life expectancy, frailty, comfort and quality of life; and (vii) health policy should remove barriers to oral health care for vulnerable elders. CONCLUSIONS: Consensus was reached on specific actionable priorities for public health officials, oral healthcare professionals, educators and workforce planners, caregivers and relatives as well as for the public and ageing patients. Some priorities have major implications for policymakers as health systems need to adapt to the challenge by systemwide changes to enable (promote) tooth retention later in life and management of deteriorating oral health in increasingly dependent elders.

STUDY OBJECTIVES: To identify factors before a trial of nasal continuous positive airway pressure (CPAP) treatment that are associated with lower compliance. DESIGN: A prospective cohort study. Initial Hospital Anxiety and Depression Scale scores and other demographic data were noted. Machine use was recorded by clock timer after a 1-month trial of treatment. SETTING: District General Hospital sleep-disordered breathing clinic. PATIENTS OR PARTICIPANTS: Eighty consecutive patients with symptoms of sleep apnea-hypopnea syndrome and a 4% Sao2 desaturation index greater than 10 events per hour. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Those reporting 'initial problems' with CPAP went on to have an average of 2.4 hours of on time per night, while those not reporting initial problems had an on time of 5.0 hours per night (P < .001). Those living alone had a machine on time of 3.2 hours compared with 4.5 hours for those with partners (P = .04). Pearson's correlations between hours on time were -0.08 (P = .48) for initial Anxiety score and 0.10 (P = .37) for initial Depression score. CONCLUSIONS: There was no association between baseline anxiety and depression scores, as measured by the Hospital Anxiety and Depression Scale, and subsequent machine use. Other factors observable prior to commencing treatment, in particular, 'initial problems' (reported at autotitration), 'recent life-events' and 'living alone' were associated with lower machine use. Regarding all initial variables, reporting problems after the first night of nCPAP seems the most important predictor of ensuing machine use. A single screening question immediately after autotitration is useful in identifying those at high risk of treatment failure.

BACKGROUND AND OBJECTIVES: Skin resurfacing and wrinkle removal is a large medical laser market. However, the rate of undesirable side effects is high and sometimes is not warranted by the aesthetic improvement observed. The authors have evaluated the potential benefits of an approach to selective non-ablative wrinkle reduction. MATERIALS AND METHODS: This technique selectively targets the microvasculature which plays a key role in the stimulation of enhanced collagen production. RESULTS: The study reported shows that application of the laser parameters described enhances collagen production by an average of 84%, measured 72 hours after a single laser treatment. This is achieved whilst leaving the skin barrier intact and with no adverse pigmentary changes. The study further shows that a cosmetic improvement is observed with an average value of 1.88 reduction in wrinkle appearance as measured on the Fitzpatrick Wrinkle Severity scale. This improvement was achieved with one brief treatment and no reported incidence of side effects. CONCLUSION: In conclusion, the treatment modality described may be a new approach to the treatment of wrinkles.

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 ).

Chronic obstructive pulmonary disease (COPD), lung cancer, asthma and pulmonary tuberculosis are common pulmonary diseases that are caused or worsened by tobacco smoking. Growing observational evidence suggests that symptoms and prognosis of these conditions improve upon smoking cessation. Despite increasing numbers of (small) randomised controlled trials suggesting intensive smoking cessation treatments work in people with pulmonary diseases many patients are not given specific advice on the benefits or referred for intensive cessation treatments and, therefore, continue smoking.This is a qualitative review regarding smoking cessation in patients with COPD and other pulmonary disorders, written by a group of European Respiratory Society experts. We describe the epidemiological links between smoking and pulmonary disorders, the evidence for benefits of stopping smoking, how best to assess tobacco dependence and what interventions currently work best to help pulmonary patients quit. Finally, we describe characteristics and management of any "hardcore" smoker who finds it difficult to quit with standard approaches.

BACKGROUND: Survival time for lung cancer is poor with over 90% of patients dying within five years of diagnosis primarily due to detection at late stage. The main objective of this study was to evaluate Fourier transform infrared spectroscopy (FTIR) as a high throughput and cost effective method for identifying biochemical changes in sputum as biomarkers for detection of lung cancer. METHODS: Sputum was collected from 25 lung cancer patients in the Medlung observational study and 25 healthy controls. FTIR spectra were generated from sputum cell pellets using infrared wavenumbers within the 1800 to 950 cm-1 "fingerprint" region. RESULTS: A panel of 92 infrared wavenumbers had absorbances significantly different between cancer and normal sputum spectra and were associated with putative changes in protein, nucleic acid and glycogen levels in tumours. Five prominent significant wavenumbers at 964 cm-1, 1024 cm-1, 1411 cm-1, 1577 cm-1 and 1656 cm-1 separated cancer spectra from normal spectra into two distinct groups using multivariate analysis (group 1: 100% cancer cases; group 2: 92% normal cases). Principal components analysis revealed that these wavenumbers were also able to distinguish lung cancer patients who had previously been diagnosed with breast cancer. No patterns of spectra groupings were associated with inflammation or other diseases of the airways. CONCLUSIONS: Our results suggest that FTIR applied to sputum might have high sensitivity and specificity in diagnosing lung cancer with potential as a non-invasive, cost-effective and high-throughput method for screening. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00899262.

Obesity is associated with significant morbidity and mortality and is increasing in prevalence worldwide. Associated conditions include insulin resistance (IR), diabetes, hypertension and dyslipidaemia; a clustering of these has recently been termed as metabolic syndrome. Weight gain is a major predictor of the metabolic syndrome with waist circumference being a more sensitive indicator than body mass index as it reflects both abdominal subcutaneous adipose tissue and visceral adipose tissue (VAT). VAT has more metabolic activity and secretes a number of hormones and pro-inflammatory cytokines which are linked with the metabolic abnormalities listed above. Central obesity also increases the risk of obstructive sleep apnoea syndrome (OSAS), where the sleep disordered breathing may also independently lead to/or exacerbate IR, diabetes and cardiovascular risk. The contribution of OSAS to the metabolic syndrome has been under-recognized. The putative mechanisms by which OSAS causes or exacerbates these other abnormalities are discussed. We propose that activation of nuclear factor kappa B by stress hypoxia and/or by increased adipokines and free fatty acids released by excess adipose tissue is the final common inflammatory pathway linking obesity, OSAS and the metabolic syndrome both individually and, in many cases, synergistically.

Previous studies in acquired haemophilia A have reported on cohorts of patients referred to specialist centres or were retrospective surveys of specialist centre experience. This may have resulted in the literature representing a more severe group of patients than seen in routine haematological practice. We report on a consecutive, unselected cohort of all patients in south and west Wales who presented with acquired haemophilia A between 1996 and 2002. There were 18 patients, an incidence of 1.34/million/year. Compared with previously reported cohorts our patients were older, with a median age of 70 years, and less likely to have an underlying diagnosis (27%). The bleeding phenotype was less severe, with only 27% having life or limb threatening bleeds and 41% required no haemostatic treatment. One patient died of bleeding, but three died of complications related to immunosuppression. Response to immunosuppression was high compared with other series, with 88% of treated patients attaining an undetectable inhibitor and normal factor VIII level. These data suggest that previously reported cohorts may represent more severely affected patients and, whilst guidelines for treatment based on these assumptions may be valid for severely affected patients, they may not be universally applicable.

The mouse mutant curly tail (ct) provides a model system for studies of neurulation mechanisms. 60% of ct/ct embryos develop spinal neural tube defects (NTD) as a result of delayed neurulation at the posterior neuropore whereas the remaining 40% of embryos develop normally. In order to investigate the role of cell proliferation during mouse neurulation, cell cycle parameters were studied in curly tail embryos developing spinal NTD and in their normally developing litter-mates. Measurements were made of mitotic index, median length of S-phase and percent reduction of labelling index during a [3H]thymidine pulse-chase experiment. These independent measures of cell proliferation rate indicate a reduced rate of proliferation of gut endoderm and notochord cells in the neuropore region of embryos developing spinal NTD compared with normally developing controls. The incidence of cell death and the relative frequency of mitotic spindle orientations does not differ consistently between normal and abnormal embryos. These results suggest a mechanism of spinal NTD pathogenesis in curly tail embryos based on failure of normal cell proliferation in gut endoderm and notochord.

In the first part, the following mechanisms involved in different forms of cell death are considered, with a view to identifying potential therapeutic targets: tumour necrosis factor receptors (TNFRs) and their engagement by tumour necrosis factor-alpha (TNF-); poly [ADP-ribose] polymerase (PARP)-1 cleavage; the apoptosis signalling kinase (ASK)-c-Jun N-terminal kinase (JNK) axis; lysosomal permeability; activation of programmed necrotic cell death; oxidative stress, caspase-3 inhibition and parthanatos; activation of inflammasomes by reactive oxygen species and the development of pyroptosis; oxidative stress, calcium dyshomeostasis and iron in the development of lysosomal-mediated necrosis and lysosomal membrane permeability; and oxidative stress, lipid peroxidation, iron dyshomeostasis and ferroptosis. In the second part, there is a consideration of the role of lethal and sub-lethal activation of these pathways in the pathogenesis and pathophysiology of neurodegenerative and neuroprogressive disorders, with particular reference to the TNF--TNFR signalling axis; dysregulation of ASK-1-JNK signalling; prolonged or chronic PARP-1 activation; the role of pyroptosis and chronic inflammasome activation; and the roles of lysosomal permeabilisation, necroptosis and ferroptosis. Finally, it is suggested that, in addition to targeting oxidative stress and inflammatory processes generally, neuropsychiatric disorders may respond to therapeutic targeting of TNF-, PARP-1, the Nod-like receptor NLRP3 inflammasome and the necrosomal molecular switch receptor-interacting protein kinase-3, since their widespread activation can drive and/or exacerbate peripheral inflammation and neuroinflammation even in the absence of cell death. To this end, the use is proposed of a combination of the tetracycline derivative minocycline and N-acetylcysteine as adjunctive treatment for a range of neuropsychiatric disorders.

This study assessed the positional and temporal movement patterns of professional rugby union players during competition using global positioning system (GPS) units. GPS data were collected from 33 professional rugby players from 13 matches throughout the 2012-2013 season sampling at 10 Hz. Players wore GPS units from which information on distances, velocities, accelerations, exertion index, player load, contacts, sprinting and repeated high-intensity efforts (RHIE) were derived. Data files from players who played over 60 min (n = 112) were separated into five positional groups (tight and loose forwards; half, inside and outside backs) for match analysis. A further comparison of temporal changes in movement patterns was also performed using data files from those who played full games (n = 71). Significant positional differences were found for movement characteristics during performance (P < 0.05). Results demonstrate that inside and outside backs have greatest high-speed running demands; however, RHIE and contact demands are greatest in loose forwards during match play. Temporal analysis of all players displayed significant differences in player load, cruising and striding between halves, with measures of low- and high-intensity movement and acceleration/deceleration significantly declining throughout each half. Our data demonstrate significant positional differences for a number of key movement variables which provide a greater understanding of positional requirements of performance. This in turn may be used to develop progressive position-specific drills that elicit specific adaptations and provide objective measures of preparedness. Knowledge of performance changes may be used when developing drills and should be considered when monitoring and evaluating performance.

BACKGROUND: The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all-cause 30-day readmissions and complications in a prospective population-based cohort. METHODS: Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all-cause 30-day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two-level hierarchical structure with patients (level 1) nested within hospitals (level 2). RESULTS: Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. CONCLUSION: Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics.

There is a close relationship between the abnormal microcirculation in diabetic subjects and diabetic neuropathy. Neurogenic factors play a prominent role in the regulation of the microcirculation. In diabetic neuropathy, damage to these mechanisms results in a profound haemodynamic disturbance with increased arteriovenous shunting, abnormal postural regulation of blood flow, and abnormal inflammatory responses to tissue injury. Abnormal neurogenic regulation of microvascular haemodynamics may contribute to the development of microangiopathy manifest as increased basement thickening and both are undoubtedly implicated in the pathogenesis of diabetic foot ulceration. In turn it is now recognized that microvascular abnormalities may contribute to the ischaemic aetiology of diabetic neuropathy.

Many children with Down syndrome (DS) are capable of developing some reading and writing abilities. The purpose of this study was to further the knowledge of literacy learning and factors that influence that learning in children with DS. Twelve elementary school children with DS were followed over a 4.5-year period. All the children attended regular education classrooms with personal aides and resource rooms as support. Measures of the children’s reading, language, cognitive, and phonological awareness abilities were collected three times. Analyses demonstrated that some reading ability was present in all but one of the children by the end of the study. Phonological awareness and word attack skills did not keep pace with word recognition abilities in these children. When age and mental age (i.e., the mean of the age-equivalent scores from the Pattern Analysis and Bead Memory subtests of the Stanford Binet Intelligence Scale, 4 th edition) were partialled out, word attack skill was uniquely predicted by measures of phoneme segmentation and auditory memory as well. Clinical implications of the findings are discussed.

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

BACKGROUND: Loop diuretics, when given as intermittent bolus injections in acutely decompensated heart failure, may cause fluctuations in intravascular volume, increased toxicity and development of tolerance. Continuous infusion has been proposed to avoid these complications and result in greater diuresis, hopefully leading to faster symptom resolution, decrease in morbidity and possibly, mortality. OBJECTIVES: To compare the effects and adverse effects of continuous intravenous infusion of loop diuretics with those of bolus intravenous administration among patients with congestive heart failure Class III-IV. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2003), MEDLINE (1966 to 2003), EMBASE (1980 to 2003) and the HERDIN database. We also contacted pharmaceutical companies. SELECTION CRITERIA: Randomized controlled trials comparing the efficacy of continuous intravenous infusion versus bolus intravenous administration of loop diuretics in congestive heart failure were included DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study eligibility, methodological quality and did data extraction. Included studies were assessed for validity. Authors were contacted when feasible. Adverse effects information was collected from the trials. MAIN RESULTS: Eight trials involving 254 patients were included. In seven studies which reported on urine output, the output (as measured in cc/24 hours) was noted to be greater in patients given continuous infusion with a weighted mean difference (WMD) of 271 cc/24 hour (95%CI 93.1 to 449; p<0.01). Electrolyte disturbances (hypokalemia, hypomagnesemia) were not significantly different in the two treatment groups with a relative risk (RR) of 1.47 (95%CI 0.52 to 4.15; p=0.5). Less adverse effects (tinnitus and hearing loss) were noted when continuous infusion was given, RR 0.06 (95%CI 0.01 to 0.44; p=0.005). Based on a single study, the duration of hospital stay was significantly shortened by 3.1days with continuous infusion WMD -3.1 (95%CI -4.06 to -2.20; p<0.0001) while cardiac mortality was not significantly different in the two treatment groups, RR 0.47 (95% CI 0.33 to 0.69; p<0.0001). Based on two studies, all cause mortality was not significantly different in the two treatment groups, RR 0.52 (95%CI 0.38 to 0.71; p<0.0001). REVIEWER'S CONCLUSIONS: Currently available data are insufficient to confidently assess the merits of the two methods of giving intravenous diuretics. Based on small and relatively heterogenous studies, this review showed greater diuresis and a better safety profile when loop diuretics were given as continuous infusion. The existing data still does not allow definitive recommendations for clinical practice and larger studies should be done to more adequately settle this issue.