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Summary: Background: Liver disease is the only major chronic disease and mortality is increasing. Earlier detection of liver fibrosis can reduce progression to cirrhosis and hepatocellular carcinoma. Many studies have reported an increased prevalence in liver fibrosis among adults in urban regions but there are few data in physically active rural populations without attributable metabolic risk factors. This aim of this study is to investigate the prevalence of abnormal liver functions tests (LFTs) and liver fibrosis among adults in a rural population. Methods: This cross-sectional study included observations from KMCH-NNCD-II (2017) study (n = 907) from a farming village, Nallampatti, located in South India. We assessed lifestyle (occupation, tobacco use and alcohol consumption using AUDIT-C questionnaire), markers for metabolic diseases (obesity, hypertension, diabetes, hypercholesterolemia), LFTs and markers for hepatitis viruses B and C. 901 participants had transient elastography to assess fibrosis. Participants with abnormal LFTs and significant liver fibrosis (F2-F4) underwent additional liver screening (caeruloplasmin, iron studies and autoimmune hepatitis panel). Multiple logistic regression analyses were performed to understand the association of liver fibrosis with lifestyle and metabolic risk factors after adjustment for co-variates. Findings: Significant liver fibrosis (F2-F4) was observed in 14.4%, and cirrhosis in 0.8%. There was an association of liver fibrosis with abnormal LFTs but no association between alcohol consumption, viral hepatitis, hepatic liver screening and liver fibrosis. Among metabolic risk factors, no association was observed for hypertension and hypercholesterolemia but diabetes [OR – 3.206 (95% CI: 1.792 – 5.736)], obesity [1.987 (1.341 – 2.944)] and metabolic syndrome [2.539 (1.680 – 3.836)] showed association with significant liver fibrosis (F2-F4) after adjustment for confounding factors. Interpretation: Our results suggest that the prevalence of liver fibrosis in rural population is similar to urban counterparts. The association of metabolic risk factors with liver fibrosis in physically active rural population warrants further investigations in future studies. Funding: This study is funded by KMCH Research Foundation, India.

Abstract Background South Asians have a higher risk of cardiovascular disease (CVD). Rheumatoid arthritis (RA) increases the risk of premature atherosclerosis. We investigated whether there was a substantial difference in the level of CVD risk knowledge among patients of South Asian origin with RA in India and in the UK. Methods In this cross-sectional survey, patients of South Asian origin with RA from India and the UK were recruited from secondary care settings. Data were collected via Heart Disease Fact Questionnaire-Rheumatoid Arthritis (HDFQ-RA), a validated self-completion questionnaire. The HDFQ-RA was translated into Hindi and piloted among patients from South Asian background before use. Additionally, clinical and demographic data was collected. Results Among 118 patients from each country, 84% were female and they had similar age, education level, employment status and co-morbidities. Patients from India had longer disease duration (5.5 years versus 4.1 years (p = 0.012) whereas those from the UK had higher disease activity score (4.0 + 0.8 versus 3.1 + 0.7, p

Objective Susceptibility of patients with cancer to COVID-19 pneumonitis has been variable. We aim to quantify the risk of hospitalisation in patients with active cancer and use a machine learning algorithm (MLA) and traditional statistics to predict clinical outcomes and mortality.Design Retrospective cohort study.Setting A single UK district general hospital.Participants Data on total hospital admissions between March 2018 and June 2020, all active cancer diagnoses between March 2019 and June 2020 and clinical parameters of COVID-19-positive admissions between March 2020 and June 2020 were collected. 526 COVID-19 admissions without an active cancer diagnosis were compared with 87 COVID-19 admissions with an active cancer diagnosis.Primary and secondary outcome measures 30-day and 90-day post-COVID-19 survival.Results In total, 613 patients were enrolled with male to female ratio of 1:6 and median age of 77 years. The estimated infection rate of COVID-19 was 87 of 22 729 (0.4%) in the patients with cancer and 526 of 404 379 (0.1%) in the population without cancer (OR of being hospitalised with COVID-19 if having cancer is 2.942671 (95% CI: 2.344522 to 3.693425); p

Data were collected on patients admitted to the Queen Elizabeth Hospital Birmingham with type-1 myocardial infarction during 2016 and 2017 inclusively, who were treated by percutaneous intervention and had pre-discharge transthoracic echocardiography. The data were obtained from prospectively maintained hospital databases and records. Echocardiography was performed and reported contemporaneously by accredited echocardiographers. The purpose was to understand the prevalence and characteristics of mitral regurgitation (MR) after acute MI, including patients with ST-elevation (STEMI) and non-ST elevation MI (NSTEMI). MR was observed in 294/1000 patients with the following relative severities: mild = 76%, moderate = 21%, severe = 3% [1]. MR was graded by multiparametric quantification including proximal isolvelocity surface area (PISA), vena contracta (VC), effective regurgitant orifice area (EROA) and regurgitant volume (RVol). Amongst all patients with MR (n=294), PISA was performed in 89/294 (30%), VC 75/294 (26%), EROA in 53/294 (18%) and RVol in 26/294 (9%). Amongst patients with moderate or severe MR (n=70), PISA was performed in 57/70 (81%), VC in 55/70 (79%), EROA in 46/70 (66%) and RVol in 25/70 (36%). Characteristics of MR following acute MI were also assessed including frequency of reported leaflet thickness (259/294 = 88%) and mitral annular calcification (102/294 = 35%). Furthermore, the effect of MI on pre-existing MR was investigated and patients with pre-existing MR who continue to have MR after acute MI were found to have progression of MR by one grade in approximately 25% of cases. Finally, using Cox proportional hazards univariate analysis, significant factors associated with mortality in patients with MR post-MI include age (HR 1.065; 95% CI 1.035-1.096; p

Background: Lung resection remains the gold standard treatment for early stage lung cancer; prediction of postoperative lung function is a key selection criterion for surgery with the aim of determining risk of postoperative dyspnoea. We aimed to identify the different prediction techniques used, and compare their accuracy. Methods: A systematic review and meta-analysis sought to synthesise studies conducted that assess prediction of postoperative lung function up to 18/02/2018 (n = 135). PROBAST was used to assess risk of bias in studies, 17 studies were judged to be at low risk of bias. Findings: Meta-analysis revealed CT volume and density measurement to be the most accurate (mean difference 71 ml) and precise (standard deviation 207 ml) of the reported techniques used for predicting FEV1; evidence for predicting gas transfer was lacking. Interpretation: The evidence suggests using CT volume and density is the preferred technique in the prediction of postoperative FEV1. Further studies are required to ensure that the methods and thresholds we propose are linked to patient reported outcomes. Funding: Salary support for NKO, RM, PN, BN, and AMT was provided by University Hospitals Birmingham NHS Foundation Trust. Keywords: Thoracic surgery, Lung cancer, Lung function, Operability

Abstract Background Intravenous pulse methylprednisolone (MP) is commonly included in the management of severe ANCA associated vasculitis (AAV) despite limited evidence of benefit. We aimed to evaluate outcomes in patients who had, or had not received MP, along with standard therapy for remission induction in severe AAV. Methods We retrospectively studied 114 consecutive patients from five centres in Europe and the United States with a new diagnosis of severe AAV (creatinine > 500 μmol/L or dialysis dependency) and that received standard therapy (plasma exchange, cyclophosphamide and high-dose oral corticosteroids) for remission induction with or without pulse MP between 2000 and 2013. We evaluated survival, renal recovery, relapses, and adverse events over the first 12 months. Results Fifty-two patients received pulse MP in addition to standard therapy compared to 62 patients that did not. There was no difference in survival, renal recovery or relapses. Treatment with MP associated with higher risk of infection during the first 3 months (hazard ratio (HR) 2.7, 95%CI [1.4–5.3], p = 0.004) and higher incidence of diabetes (HR 6.33 [1.94–20.63], p = 0.002), after adjustment for confounding factors. Conclusions The results of this study suggest that addition of pulse intravenous MP to standard therapy for remission induction in severe AAV may not confer clinical benefit and may be associated with more episodes of infection and higher incidence of diabetes.

Background Pirfenidone and nintedanib are the only disease-modifying treatments available for idiopathic pulmonary fibrosis (IPF). Our aim was to test their effectiveness and safety in clinical practice.Methods This is a single-centre retrospective observational study undertaken at a specialised interstitial lung disease centre in England. Data including progression-free survival (PFS), mortality and drug tolerability were compared between patients with IPF on antifibrotic therapies and an untreated control group who had a forced vital capacity percentage (FVC %) predicted within the licensed antifibrotic treatment range.Results 104 patients received antifibrotic therapies and 64 control patients were identified. PFS at 6 months was significantly greater in the antifibrotic group (75.0%) compared with the control group (56.3%) (p=0.012). PFS was not significant at 12 or 18 months when comparing the antifibrotic group with the control group. The 12-month post-treatment mean decline in FVC % predicted (−4.6±6.2%) was significantly less than the 12-month pretreatment decline (−10.4±11.8%) (p=0.039). The 12-month mortality rate was not significantly different between the antifibrotic group (25.3%) and the control group (35.5%) (p=0.132). Baseline Body Mass Index of≤25, baseline diffusion capacity for carbon monoxide percentage predicted of ≤35 and antifibrotic discontinuation within 3 months were independent predictors of 12-month mortality. Antifibrotic discontinuation was significantly higher by 3 and 6 months for patients on pirfenidone than those on nintedanib (p=0.006 and p=0.044, respectively). Discontinuation at 12 months was not significantly different (p=0.381).Conclusions This real-world study revealed that antifibrotics are having promising effects on PFS, lung function and mortality. These findings may favour commencement of nintedanib as first-line antifibrotic therapy, given the lower rates of early treatment discontinuation, although further studies are required to investigate this.

Background Studies suggest that certain black and Asian minority ethnic groups experience poorer outcomes from COVID-19, but these studies have not provided insight into potential reasons for this. We hypothesised that outcomes would be poorer for those of South Asian ethnicity hospitalised from a confirmed SARS-CoV-2 infection, once confounding factors, health-seeking behaviours and community demographics were considered, and that this might reflect a more aggressive disease course in these patients.Methods Patients with confirmed SARS-CoV-2 infection requiring admission to University Hospitals Birmingham NHS Foundation Trust (UHB) in Birmingham, UK between 10 March 2020 and 17 April 2020 were included. Standardised admission ratio (SAR) and standardised mortality ratio (SMR) were calculated using observed COVID-19 admissions/deaths and 2011 census data. Adjusted HR for mortality was estimated using Cox proportional hazard model adjusting and propensity score matching.Results All patients admitted to UHB with COVID-19 during the study period were included (2217 in total). 58% were male, 69.5% were white and the majority (80.2%) had comorbidities. 18.5% were of South Asian ethnicity, and these patients were more likely to be younger and have no comorbidities, but twice the prevalence of diabetes than white patients. SAR and SMR suggested more admissions and deaths in South Asian patients than would be predicted and they were more likely to present with severe disease despite no delay in presentation since symptom onset. South Asian ethnicity was associated with an increased risk of death, both by Cox regression (HR 1.4, 95% CI 1.2 to 1.8), after adjusting for age, sex, deprivation and comorbidities, and by propensity score matching, matching for the same factors but categorising ethnicity into South Asian or not (HR 1.3, 95% CI 1.0 to 1.6).Conclusions Those of South Asian ethnicity appear at risk of worse COVID-19 outcomes. Further studies need to establish the underlying mechanistic pathways.

Abstract Background There is a need for a large, contemporary, multi-centre series of measured glomerular filtration rates (mGFR) from healthy individuals to determine age- and gender-specific reference ranges for GFR. We aimed to address this and to use the ranges to provide age- and gender-specific advisory GFR thresholds considered acceptable for living kidney donation. Methods Individual-level data including pre-donation mGFR from 2974 prospective living kidney donors from 18 UK renal centres performed between 2003 and 2015 were amalgamated. Age- and gender-specific GFR reference ranges were determined by segmented multiple linear regression and presented as means ± two standard deviations. Results Males had a higher GFR than females (92.0 vs 88.1 mL/min/1.73m2, P 60 years had a GFR

Abstract Background Cardiovascular disease is a leading cause of death in ANCA-associated vasculitis (AAV). An expansion of CD4+CD28null T cells is seen mainly in cytomegalovirus (CMV)-seropositive individuals and has been linked to increased cardiovascular disease risk in other conditions. The aims of this study were to phenotype CD4+CD28null T cells in AAV with respect to their pro-inflammatory capacity and ability to target and damage the endothelium and to investigate their relationship to arterial stiffness, a marker of cardiovascular mortality. Methods CD4+CD28null T cells were phenotyped in 53 CMV-seropositive AAV patients in stable remission and 30 age-matched CMV-seropositive healthy volunteers by flow cytometry following stimulation with CMV lysate. The expression of endothelial homing markers and cytotoxic molecules was evaluated in unstimulated CD4+CD28null T cells. Arterial stiffness was measured by carotid-to-femoral pulse wave velocity (PWV) in patients with AAV. Results CD4+CD28null T cells were CMV-specific and expressed a T helper 1 (Th1) phenotype with high levels of interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) secretion. They also co-expressed the endothelial homing markers CX3CR1, CD49d and CD11b and cytotoxic molecules perforin and granzyme B. CD4+CD28null T cells were phenotypically similar in patients with AAV and healthy volunteers but their proportion was almost twice as high in patients with AAV (11.3% [3.7–19.7] versus 6.7 [2.4–8.8]; P = 0.022). The size of the CD4+CD28null T-cell subset was independently linked to increased PWV in AAV (0.66 m/s increase per 10% increase in CD4+CD28null cells, 95% confidence interval 0.13–1.19; P = 0.016). Conclusion The host cellular immune response to CMV leads to the expansion of cytotoxic CD4+CD28null T cells that express endothelial homing markers and are independently linked to increased arterial stiffness, a marker of cardiovascular mortality. Suppression of CMV in AAV may be of therapeutic value in reducing the risk of cardiovascular disease.

Abstract Background The optimal decontamination method for needle-free connectors is still unresolved. The objective of this study was to determine if a continuous passive disinfection cap is as effective as standard cleaning for the microbial decontamination of injection ports of two types of needle-free connectors. Methods The injection ports of needle-free connectors were inoculated with Staphylococcus aureus and allowed to dry. Disinfection caps containing 70% (v/v) isopropyl alcohol (IPA) were attached to the connectors for one, three or 7 days and were compared with needle-free connectors cleaned with 2% (w/v) chlorhexidine gluconate (CHG) in 70% (v/v) IPA. The number of S. aureus remaining on the injection ports was evaluated. Median log10 reductions and 95% confidence interval (CI) were calculated and data analyzed using the Mann-Whitney test. Results The application of the disinfection cap resulted in a significantly higher reduction in S. aureus than the 2% (w/v) CHG in 70% (v/v) IPA wipe, achieving a > 5 Log10 reduction in CFU at each time point. Conclusions The disinfection caps resulted in a significantly higher reduction in S.aureus on the injection ports when compared to the use of a 2% (w/v) CHG in 70% (v/v) IPA wipe. This offers an explanation for the lower rates of central-line associated bloodstream infection (CLABSI) associated with the use of disinfection caps reported in clinical studies.

Abstract Background Acute Kidney Injury (AKI) has evoked much interest over the past decade and is reported to be associated with high inpatient mortality. Preventable death and increased readmission rates related to AKI have been the focus of considerable interest. Methods We studied hospital acquired AKI in all emergency hospital admissions, except transfers from ICU to ICU or patients known to renal services, to ascertain mortality and readmission rates, and trackable modifiable factors for death, using cox regression and Kaplan Meier survival curves. Data was extracted from the electronic patient records and a series of case notes reviewed. Admissions were included between April 2006 and March 2010 (and patients followed up until September 2011). Results Overall incidence of AKI was 2.2%, (AKI stage 1, 61%, stage 2,27% and stage 3, 12%). In patients who sustain in-hospital AKI, 34% die in hospital, 42% are dead at 90 days and 48% at 1 year post discharge, compared to 12% 1 year mortality in patients without AKI. In multivariable analyses, AKI is an independent risk factor for in-hospital mortality (Hazard Ratio 1.6: 95% confidence intervals 1.43–1.75: P

Background Community-acquired pneumonia (CAP) is a leading cause of sepsis worldwide. Prompt identification of those at high risk of adverse outcomes improves survival by enabling early escalation of care. There are multiple severity assessment tools recommended for risk stratification; however, there is no consensus as to which tool should be used for those with CAP. We sought to assess whether pneumonia-specific, generic sepsis or early warning scores were most accurate at predicting adverse outcomes.Methods We performed a retrospective analysis of all cases of CAP admitted to a large, adult tertiary hospital in the UK between October 2014 and January 2016. All cases of CAP were eligible for inclusion and were reviewed by a senior respiratory physician to confirm the diagnosis. The association between the CURB65, Lac-CURB-65, quick Sequential (Sepsis-related) Organ Failure Assessment tool (qSOFA) score and National Early Warning Score (NEWS) at the time of admission and outcome measures including intensive care admission, length of hospital stay, in-hospital, 30-day, 90-day and 365-day all-cause mortality was assessed.Results 1545 cases were included with 30-day mortality of 19%. Increasing score was significantly associated with increased risk of poor outcomes for all four tools. Overall accuracy assessed by receiver operating characteristic curve analysis was significantly greater for the CURB65 and Lac-CURB-65 scores than qSOFA. At admission, a CURB65 ≥2, Lac-CURB-65 ≥moderate, qSOFA ≥2 and NEWS ≥medium identified 85.0%, 96.4%, 40.3% and 79.0% of those who died within 30 days, respectively. A Lac-CURB-65 ≥moderate had the highest negative predictive value: 95.6%.Conclusion All four scoring systems can stratify according to increasing risk in CAP; however, when a confident diagnosis of pneumonia can be made, these data support the use of pneumonia-specific tools rather than generic sepsis or early warning scores.

Summary: Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR. : Elhassan et al. show that oral nicotinamide riboside increases the NAD+ metabolome in aged human skeletal muscle, without apparently altering mitochondrial bioenergetics. Measures of muscle and whole-body metabolism are also unchanged. Nicotinamide riboside reduces the levels of circulating inflammatory cytokines. Studies in relevant human disease models are warranted. Keywords: nicotinamide adenine dinucleotide, metabolism, aging, inflammation, cell adhesion

Kidneys from non-white donors have inferior outcomes, but it is unclear if ethnicity matching between donors and recipients achieves better post kidney transplant outcomes.We undertook a retrospective, population cohort study utilising UK Transplant Registry data. The cohort comprised adult, kidney-alone, transplant recipients receiving their first kidney transplant between 2003-2015, with data censored at 1st October 2016. We included 27,970 recipients stratified into white (n = 23,215), black (n = 1,679) and south Asian (n = 3,076) ethnicity, with median post-transplant follow-up of 1,676 days (IQR 716-2,869 days). Unadjusted and adjusted Cox regression survival analyses were performed to investigate ethnicity effect on risk for graft loss and mortality.In unadjusted analyses, matched ethnicity between donors-recipients resulted in better outcomes for delayed graft function, one-year creatinine, graft and patient survival but these differed by ethnicity matches. Compared to white-to-white transplants, risk for death-censored graft loss was higher in black-to-black and similar among Asian-to-Asian transplants, but mortality risk was lower for both black-to-black and Asian-to-Asian transplants. In Cox regression models, compared to white donors, we observed higher risk for graft loss with both south Asian (HR 1.38, 95%CI 1.12-1.70, p = 0.003) and black (HR 1.66, 95%CI 1.30-2.11, p

Network-based diffusion analysis (NBDA) is a statistical method that allows the researcher to identify and quantify a social influence on the spread of behaviour through a population. Hitherto, NBDA analyses have not directly modelled spatial population structure. Here we present a spatial extension of NBDA, applicable to diffusion data where the spatial locations of individuals in the population, or of their home bases or nest sites, are available. The method is based on the estimation of inter-individual associations (for association matrix construction) from the mean inter-point distances as represented on a spatial point pattern of individuals, nests or home bases. We illustrate the method using a simulated dataset, and show how environmental covariates (such as that obtained from a satellite image, or from direct observations in the study area) can also be included in the analysis. The analysis is conducted in a Bayesian framework, which has the advantage that prior knowledge of the rate at which the individuals acquire a given task can be incorporated into the analysis. This method is especially valuable for studies for which detailed spatially structured data, but no other association data, is available. Technological advances are making the collection of such data in the wild more feasible: for example, bio-logging facilitates the collection of a wide range of variables from animal populations in the wild. We provide an R package, spatialnbda, which is hosted on the Comprehensive R Archive Network (CRAN). This package facilitates the construction of association matrices with the spatial x and y coordinates as the input arguments, and spatial NBDA analyses.