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The prevalence of diabetes in Birmingham is 11% but it is 22% in hospital inpatients. Queen Elizabeth Hospital in Birmingham (QEHB) serves a multi-ethnic population with 6% Afro-Caribbean, 19% South Asian and 70% White European. A clinical audit of 18,965 emergency admissions to QEHB showed that 5% were undiagnosed but had admission glucose in the ‘diabetes’ range and 16% were in the ‘at risk’ range. The proportion of Afro-Caribbeans (7%) and South Asians (8%) in the ‘diabetes’ range was higher than White Europeans (5%). Given the magnitude of the problem, this paper explores the issues concerning the use of reflex HbA1c testing in the UK for diagnosis of diabetes in hospital admissions. HbA1c testing is suitable for most patients but conditions affecting red blood cell turnover invalidate the results in a small number of people. However, there are pertinent questions relating to the introduction of such testing in the NHS on a routine basis. Literature searches on a topical question ‘Is hyperglycaemia identified during emergency admission/attendance acted upon?’, were performed from 2016 to 2021 and 2016 to 2022. They identified 21 different, relevant, research papers - 5 from Australia, 9 from Europe including 4 from the UK, 5 from America and 1 each from Canada and Africa. These papers revealed an absence of established procedures for the management and follow-up of routinely detected hyperglycaemia using HbA1c when no previous diabetes diagnosis was recorded. Further work is required to determine the role of reflex HbA1c testing for diagnosis of diabetes in admissions with hyperglycaemia, and the cost-effectiveness and role of point-of-care HbA1c testing.

Background Patients with chronic kidney disease (CKD) are more prone to severe infection. Vaccination is a key strategy to reduce this risk. Some studies suggest vaccine efficacy may be reduced in patients with CKD, despite preserved maintenance of long-term responses to some pathogens and vaccines. Here, we investigated immune responses to 2 vaccines in patients with CKD to identify predictors of immunological responsiveness. Methods Individuals >65 years old, with or without nondialysis CKD (n = 36 and 29, respectively), were vaccinated with a nonadjuvanted seasonal influenza vaccine (T-dependent) and Pneumovax23 (23-valent pneumococcal polysaccharide [PPV23], T-independent). Humoral responses were measured at baseline, day 28, and 6 months. Lymphocyte subset and plasma cell/blast analyses were performed using flow cytometry. Cytomegalovirus (CMV) serotyping was assessed by enzyme-linked immunosorbent assay. Results Only modest responsiveness was observed to both vaccines, independent of CKD status (25% adequate response in controls vs. 12%–18% in the CKD group). Unexpectedly, previous immunization with PPV23 (median 10-year interval) and CMV seropositivity were associated with poor PPV23 responsiveness in both study groups (P < .001 and .003, respectively; multivariable linear regression model). Patients with CKD displayed expanded circulating populations of T helper 2 and regulatory T cells, which were unrelated to vaccine responses. Despite fewer circulating B cells, patients with CKD were able to mount a similar day 7 plasma cell/blast response to controls. Conclusion Patients with nondialysis CKD can respond similarly to vaccines as age- and sex-matched healthy individuals. CKD patients display an immune signature that is independent of vaccine responsiveness. Prior PPV23 immunization and CMV infection may influence responsiveness to vaccination. Clinical Trials Registration. NCT02535052, Patients with nondialysis Chronic Kidney Disease (CKD) can mount similar responses to vaccination as controls. Subtle changes in lymphocyte phenotype are seen in CKD when controlled for effect of Cytomegalovirus (CMV). Latent CMV infection and previous PPV23 vaccination are associated with poorer vaccine responses.

Funding: Engineering and Physical Sciences Research Council (EP/V027182/1, EP/P015638/1), Royal Society (URF/R/180015). When solving a combinatorial problem, the formulation or model of the problem is critical to the efficiency of the solver. Automating the modelling process has long been of interest because of the expertise and time required to produce an effective model of a given problem. We describe a method to automatically produce constraint models from a problem specification written in the abstract constraint specification language Essence. Our approach is to incrementally refine the specification into a concrete model by applying a chosen refinement rule at each step. Any non-trivial specification may be refined in multiple ways, creating a space of models to choose from. The handling of symmetries is a particularly important aspect of automated modelling. Many combinatorial optimisation problems contain symmetry, which can lead to redundant search. If a partial assignment is shown to be invalid, we are wasting time if we ever consider a symmetric equivalent of it. A particularly important class of symmetries are those introduced by the constraint modelling process: modelling symmetries. We show how modelling symmetries may be broken automatically as they enter a model during refinement, obviating the need for an expensive symmetry detection step following model formulation. Our approach is implemented in a system called Conjure. We compare the models produced by Conjure to constraint models from the literature that are known to be effective. Our empirical results confirm that Conjure can reproduce successfully the kernels of the constraint models of 42 benchmark problems found in the literature. Publisher PDF

Neutrophil dysfunction has been described with age, appears exaggerated in infection, with altered phosphoinositol signaling a potential mechanism. However, functional aging is heterogeneous. Frailty is a negative health status and is more common in older adults. We hypothesized that neutrophil migration may be compromised in frailty, associated with the degree of frailty experienced by the older person. We compared measures of frailty, neutrophil function, and systemic inflammation in 40 young and 77 older community-dwelling adults in the United Kingdom. Systemic neutrophils exhibited an age-associated reduction in the accuracy of migration (chemotaxis) which was further blunted with frailty. The degree of migratory inaccuracy correlated with physical (adjusted hand grip strength) and cognitive (Stroop test) markers of frailty. Regression analysis demonstrated that age, Charlson comorbidity index, and frailty index were able to predict neutrophil chemotaxis. Reduced chemotaxis of neutrophils from frail adults could be reversed using selective PI3K inhibitors. Exposure of neutrophils from young adults to plasma from chronically inflamed frail older adults could not recapitulate the migratory deficit in vitro, and there were no relationships with systemic inflammation and neutrophil dysfunction. Frailty exaggerated the neutrophil deficits seen with advanced age but aspects of the frailty-associated deficit in neutrophil function are rescuable and thus potentially form a therapeutic target to improve outcomes from infection in older adults.

BACKGROUND: Infections remain a part of the natural course of cancer, and lung cancer patients often present with some form of respiratory infection that can lead to their ultimate demise. METHODS: Data was gathered concerning all unplanned hospital admissions (UHAs) to our centre from three separate patient cohorts; non-small cell lung cancer (NSCLC) patients (cohort 1), “other cancer” patients (breast, prostate, colon) (cohort 2) and all non-cancer patients (cohort 3). RESULTS: Across the three cohorts, there were 455, 1,190 and 54,158 individual patient UHAs to our centre respectively. Within the NSCLC cohort, 164 UHAs were as a direct result of pneumonia (36.0%), compared to 1.3% and 2.2% in the other two cohorts (P

When solving a combinatorial problem using propositional satisfiability (SAT), the encoding of the problem is of vital importance. We study encodings of Pseudo-Boolean (PB) constraints, a common type of arithmetic constraint that appears in a wide variety of combinatorial problems such as timetabling, scheduling, and resource allocation. In some cases PB constraints occur together with at-most-one (AMO) constraints over subsets of their variables (forming PB(AMO) constraints). Recent work has shown that taking account of AMOs when encoding PB constraints using decision diagrams can produce a dramatic improvement in solver efficiency. In this paper we extend the approach to other state-of-the-art encodings of PB constraints, developing several new encodings for PB(AMO) constraints. Also, we present a more compact and efficient version of the popular Generalized Totalizer encoding, named Reduced Generalized Totalizer. This new encoding is also adapted for PB(AMO) constraints for a further gain. Our experiments show that the encodings of PB(AMO) constraints can be substantially smaller than those of PB constraints. PB(AMO) encodings allow many more instances to be solved within a time limit, and solving time is improved by more than one order of magnitude in some cases. We also observed that there is no single overall winner among the considered encodings, but efficiency of each encoding may depend on PB(AMO) characteristics such as the magnitude of coefficient values.

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 Conclusions Active cancer diagnosis has a threefold increase in risk of hospitalisation with COVID-19. Increased age, urea and CRP predict mortality in patients with cancer. MLA complements traditional statistical analysis in identifying prognostic variables for outcomes of COVID-19 infection in patients with cancer. This study provides proof of concept for MLA in risk prediction for COVID-19 in patients with cancer and should inform a redesign of cancer services to ensure safe delivery of cancer care.

Objective:Vitamin A (VA) deficiency, more common in low- and middle-income countries (LMIC) secondary to malnutrition, is associated with increased morbidity and mortality. The prevalence and impact of VA deficiency in high-income countries (HIC) where chronic conditions may predispose is less well understood.Design:Interpretation of serum retinol may be affected by inflammation, so C-reactive protein (CRP) levels were sought. Binary logistic regression and generalised estimating equations were performed to review the relationship between CRP and VA.Setting:We examined the scale of low and deficient VA status in our tertiary University Teaching Hospital (HIC).Participants:Patients undergoing serum retinol concentrations 2012–2016 were identified from laboratory records, and records examined.Results:Totally, 628 assays were requested, with eighty-two patients VA low (0·7–0·99 Umol/l) or deficient (Conclusion:The majority of patients tested either were replete or likely to have abnormal VA levels due to concomitant inflammation. A minority of patients had signs and symptoms of VA deficiency and was a cause of significant morbidity, but aetiology differs from LMIC, overwhelmingly malabsorption, most commonly secondary to surgery or hepatobiliary disease. A correlation between inflammation and low VA levels exists, which raises the possibility that requesting a VA level in an asymptomatic patient with active inflammation may be of questionable benefit.

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

Ethnic differences in intact parathyroid hormone (iPTH) at similar total 25 hydroxyvitamin D [25(OH)D] concentrations have been reported between US resident Whites, Blacks, and Hispanics, but this has not been studied between South Asians and Whites. We, therefore, compared the iPTH relationship to 25(OH)D in UK resident South Asians and Whites. A comparative, cross-sectional observational study in which demographic and laboratory data on South Asian and White residents of Wolverhampton, UK were analyzed. Log-log models measured the association between 25(OH)D and the interaction term of ethnicity and iPTH. Seven hundred and seventy-two patients consisting of 315 white subjects (208 women) and 457 South Asian subjects (331 women) were studied. Compared to South Asians, White subjects were older, had higher serum concentrations of 25(OH)D, creatinine (lower eGFR), adjusted calcium and magnesium, but similar concentrations of iPTH and phosphate. In an adjusted model, variables significantly associated with 25(OH)D included age, creatinine, adjusted calcium and ethnicity; but not iPTH and the interaction term of ethnicity and iPTH (beta coefficient –0.071, 95% CI –0.209, 0.067, p=0.32). In our study cohort, iPTH was not, per se, influenced by 25 (OH)D. We found no ethnic differences in the association between iPTH and 25(OH)D between South Asians and White UK residents

Background Laparoscopic liver resection (LLR) requires training in both hepatobiliary surgery and advanced laparoscopy. Available data on LLR learning curves are derived from pioneer surgeons. The aims of this study were to evaluate the LLR learning curve for second generation surgeons, and to compare different CUSUM methodology with and without risk adjustment. Methods Retrospective analysis of a prospective database of 111 consecutive patients who underwent LLR by two surgeons at a single centre between 2011 and 2016. The LLR learning curve for minor hepatectomy (MH) was evaluated for each surgeon using standard CUSUM before and after risk-adjusting for operative difficulty using the Iwate index, and compared with Learning Curve (LC) CUSUM. The end points were operative time and conversion rate. Results Standard CUSUM analysis identified a learning curve of 50–60 MH procedures. The corresponding learning curve reduced to 25–30 after risk-adjusting for operative difficulty, whilst LC-CUSUM identified a learning curve of 17–25 procedures. Conclusions The learning curve for laparoscopic minor liver resection by second generation surgeons is shorter than that for pioneer surgeons. Laparoscopic HPB fellowship programmes may further shorten the learning curve, facilitating safe expansion of LLR. The LC-CUSUM method is an alternative technique that warrants further study.

Rationale: Population studies suggest improved sepsis outcomes with statins, but the results of randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly been negative. In vitro data suggest that statins modulate age-related neutrophil functions, improving neutrophil responses to infection, but only in older patients and at high doses. Objectives: To determine if high-dose simvastatin improves neutrophil functions and is safe and tolerated in hospitalized older adults with community-acquired pneumonia with sepsis (CAP + S) not admitted to critical care. Methods: We conducted a randomized, double-blind, placebo-controlled pilot study of simvastatin 80 mg or placebo for 7 days for patients with CAP + S aged 55 years or older admitted to a secondary care hospital. The Day 4 primary endpoint was change in neutrophil extracellular trap formation (NETosis). Day 4 secondary endpoints included neutrophil chemotaxis, safety and tolerability, Sequential Organ Failure Assessment score, mortality, readmission, and markers of tissue degradation/inflammation. Measurements and Main Results: Four days of simvastatin adjuvant therapy in patients with CAP + S was associated with improvements in systemic neutrophil function (NETosis and chemotaxis), a reduction in systemic neutrophil elastase burden, and improved Sequential Organ Failure Assessment scores compared with placebo. A post hoc analysis demonstrated that simvastatin therapy was associated with improved hospitalization-free survival compared with placebo. Simvastatin was well tolerated in this elderly and multimorbid patient group with common coprescription of macrolide antibiotics. Conclusions: This pilot study supports high-dose simvastatin as an adjuvant therapy for CAP + S in an older and milder disease cohort than assessed previously. A definitive multicenter study is now warranted in this population to assess the likelihood of benefit and harm. Clinical trial registered with EudraCT (2012-00343-29).

ObjectiveTo evaluate the effectiveness of reminder letters informed by social normative theory (a type of ‘nudge theory’) on uptake of seasonal influenza vaccination by front-line hospital staff.DesignIndividually randomised controlled trial.SettingA large acute care hospital in England.ParticipantsFront-line staff employed by the hospital (n=7540) were randomly allocated to one of four reminder types in a factorial design.InterventionsThe standard letter included only general information directing the staff to take up the vaccine. A second letter highlighted a type of social norm based on peer comparisons. A third letter highlighted a type of social norm based on an appeal to authority. A fourth letter included a combination of the social norms.Main outcome measureThe proportion of hospital staff vaccinated on-site.ResultsVaccine coverage was 43% (812/1885) in the standard letter group, 43% (818/1885) in the descriptive norms group, 43% (814/1885) in the injunctive norms group and 43% (812/1885) in the combination group. There were no statistically significant effects of either norm or the interaction. The OR for the descriptive norms factor is 1.01 (0.89–1.15) in the absence of the injunctive norms factor and 1.00 (0.88–1.13) in its presence. The OR for the injunctive norms factor is 1.00 (0.88–1.14) in the absence of the descriptive norms factor and 0.99 (0.87–1.12) in its presence.ConclusionsWe find no evidence that the uptake of the seasonal influenza vaccination is affected by reminders using social norms to motivate uptake.

Patient selection for combined liver-kidney transplantation (CLKT) is a current issue on the background of organ shortage. This study aimed to compare outcomes and post-transplant renal function for patients receiving CLKT and liver transplantation alone (LTA) based on native renal function using estimated glomerular filtration rate (eGFR) stratification. Using the UK National transplant database (NHSBT) 6035 patients receiving a LTA (N = 5912; 98%) or CLKT (N = 123; 2%) [2001-2013] were analysed, and stratified by KDIGO stages of eGFR at transplant (eGFR group-strata). There was no difference in patient/graft survival between LTA and CLKT in eGFR group-strata (P > 0.05). Of 377 patients undergoing renal replacement therapy (RRT) at time of transplantation, 305 (81%) and 72 (19%) patients received LTA and CLKT respectively. A significantly greater proportion of CLKT patients had severe end-stage renal disease (eGFR < 30 ml/min/1.73 m2 ) at 1 year post-transplant compared to LTA (9.5% vs. 5.7%, P = 0.001). Patient and graft survival benefit for patients on RRT at transplantation was favouring CLKT versus LTA (P = 0.038 and P = 0.018, respectively) but the renal function of the long-term survivors was not superior following CLKT. The data does not support CLKT approach based on eGFR alone, and the advantage of CLKT appear to benefit only those who are on established RRT at the time of transplant.

BackgroundThis study assesses COVID-19 hospitalised patient demography and outcomes during wave 1 and wave 2, prior to new variants of the virus.MethodsAll patients with a positive SARS-CoV-2 swab between 10th March 2020 and 5th July 2020 (wave 1) and 1st September 2020 and 16th November 2020 (wave 2) admitted to University Hospitals Birmingham NHS Foundation Trust were included (n=4856), followed for 28 days.ResultsWave 2 patients were younger, more ethnically diverse, had less co-morbidities and disease presentation was milder on presentation. After matching for these factors, mortality was reduced, but without differences in intensive care admissions.ConclusionPrior to new SARS-CoV-2 variants, outcomes for hospitalised patients with COVID-19 were improving but with similar intensive care needs.

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.This cross-sectional study included observations from KMCH-NNCD-II (2017) study (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.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.This study is funded by KMCH Research Foundation, India.

We thank M.M. Speeckaert and co-workers for their interest in our paper about vitamin D status and seroconversion for coronavirus disease 2019 (COVID-19) in UK healthcare workers [1]. We agree with the authors that vitamin D binding protein (DBP) is important in determining serum 25(OH)D3 levels. The majority of vitamin D in the circulation is bound to DBP, also known as gc-globulin, which has actin-binding and immunomodulatory functions independent of vitamin D carriage [2]. DBP levels may be particularly relevant to determining 25(OH)D3 levels in severely ill COVID-19 patients with acute respiratory distress syndrome (ARDS), as we have previously demonstrated that DBP is a negative acute phase protein with levels dropping by about a third in patients with ARDS [3]. This tends to lower circulating total vitamin D but releases free 25(OH)D that can be taken up by cells of the immune system and epithelial cells. The consequences of changes in serum 25(OH)D during illness are, therefore, complex and difficult to interpret [4]. Genome-wide association analyses have shown that single nucleotide polymorphisms (SNPs) in the gene for DBP (GC) are important contributors to the genetic component of circulating 25D concentrations, but this is still a relatively small proportion of overall serum 25D levels, and it is unclear how these SNPs impact DBP/25D homeostasis in the setting of disease., This work outlines the potential importance of vitamin D binding protein and vitamin D in immune function and COVID-19 infection https://bit.ly/3byTaO5

BackgroundPirfenidone 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.MethodsThis 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.Results104 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).ConclusionsThis 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.

Objectives Relapses affect 30–50% of patients with ANCA-associated vasculitis (AAV) over 5 years, necessitating long-term treatment. Although there have been studies looking at predictors of relapse in AAV, this research has yet to translate clinically into guidance on tailored therapy. The aim of this systematic review was to identify and meta-analyse existing risk factors from the literature and produce a model to calculate individualised patient risk of relapse. Method A search strategy was developed to include all studies identifying predictors of AAV relapse using multivariate analysis. Individual risk factors were extracted and pooled hazard ratios (HRs) calculated. A model to predict the time to first relapse based on identified risk factors was tested retrospectively using a cohort of patients with AAV. Results The review of 2674 abstracts identified 117 papers for full text review, with 16 eligible for inclusion. Pooled HRs were calculated from significant risk factors, including anti-PR3 ANCA positivity [HR 1.69 (95% CI 1.46, 1.94)], cardiovascular involvement [HR 1.78 (95% CI 1.26, 2.53)], creatinine >200 µmol/l (relative to creatinine ≤100) [HR 0.39 (95% CI 0.22, 0.69)] and creatinine 101–200 µmol/l [HR 0.81 (95% CI 0.77, 0.85)]. Using data from 182 AAV patients to validate the model gave a C-statistic of 0.61. Conclusion Anti-PR3 ANCA positivity, lower serum creatinine and cardiovascular system involvement are all associated with an increased risk of relapse, and a combination of these risk factors can be used to predict the individualised risk of relapse. In order to produce a clinically useful model to stratify risk, we need to identify more risk factors, with a focus on robust biomarkers.

BACKGROUNDVenous thromboembolism (VTE) causes significant mortality and morbidity in hospitalised patients. In England, reporting the percentage of patients with a completed VTE risk assessment is mandated, but this does not include whether that risk assessment resulted in appropriate prescribing. Full guideline compliance (an assessment and action) is rarely reported. Education, audit and feedback enhance guideline compliance but electronic prescribing systems(EPS) can mandate guideline-compliant actions. We hypothesised that EPS-based interventions would increase full VTE guideline compliance more than other interventions.METHODSAll admitted patients within University Hospitals Birmingham NHS Foundation Trust were included for analysis between 2011-2020. The proportion of patients who received a fully compliant risk assessment and action was assessed over time. Interventions included face-to-face feedback based on measured performance (an individual approach) and mandatory risk assessment and prescribing rules into an EPS (a systems approach).RESULTSData from all 235,005 admissions and all 5503 prescribers were included in the analysis. Face-to-face feedback improved full VTE guideline concordance from 70% to 77% (p=DISCUSSION/ CONCLUSIONAn EPS-systems approach was more effective in improving sustained guideline-compliant VTE prevention. Non-compliance was still not eradicated despite this mandated system and requires further research.FUNDINGHDR-UK Hub PIONEERSummary BoxWhat is already known?Hospitalised patients are at an increased risk of venous thromboembolism (VTE), which can lead to significant morbidity and mortality. Risk factors for VTE are well known, there are established screening criteria and there is an effective prophylactic therapy, using low molecular weight heparin where indicated. Since 2010, NHS England has mandated the reporting of the percentage of patients with a completed VTE risk assessment. However, it does not automatically follow that completing a risk assessment leads to the appropriate action (prescribing and administering VTE prophylaxis where indicated). Currently it is unclear what percentage of patients have a guideline compliant VTE risk assessment and an associated action, or how full guideline compliance can be improved.What does this paper add?First, this paper describes that a VTE risk assessment does not always lead to full VTE guideline compliance (an appropriate prescription and administration of heparin where indicated). This is currently not part of mandated reporting but potentially could lead to patient harm. Second, that Electronic Health Systems (EHS) can capture and interrogate guideline-associated risk assessments and prescribing, and be used to improve full guideline compliance, through a combination of individual feedback to prescribing outliers and mandated prescribing rules. These EPS-assisted systems are robust, and sustain guideline compliance through personnel and formulary changes.

Funding: This work was part-funded by the Royal Society of New Zealand Marsden grant UOA-1418, Leverhulme grant RF-2018-213\9 and EPSRC IAA grant ‘High Definition digital aerial survey software’. We anticipate that unmanned aerial vehicles will become popular wildlife survey platforms. Because detecting animals from the air is imperfect, we develop a mark‐recapture line transect method using two digital cameras, possibly mounted on one aircraft, which cover the same area with a short time delay between them. Animal movement between the passage of the cameras introduces uncertainty in individual identity, so individual capture histories are unobservable and are treated as latent variables. We obtain the likelihood for mark‐recapture line transects without capture histories by automatically enumerating all possibilities within segments of the transect that contain ambiguous identities, instead of attempting to decide identities in a prior step. We call this method “Latent Capture‐history Enumeration” (LCE). We include an availability model for species that are periodically unavailable for detection, such as cetaceans that are undetectable while diving. External data are needed to estimate the availability cycle length, but not the mean availability rate, if the full availability model is employed. We compare the LCE method with the recently developed cluster capture‐recapture method (CCR), which uses a Palm likelihood approximation, providing the first comparison of CCR with maximum likelihood. The LCE estimator has slightly lower variance, more so as sample size increases, and close to nominal coverage probabilities. Both methods are approximately unbiased. We illustrate with semisynthetic data from a harbor porpoise survey. Postprint

SummaryBackgroundIt is clear that in UK healthcare workers, COVID-19 infections and deaths were more likely to be in staff who were of BAME origin. This has led to much speculation about the role of vitamin D in healthcare worker COVID-19 infections. We aimed to determine the prevalence of vitamin D deficiency in NHS staff who have isolated with symptoms suggestive of COVID-19 and relate this to vitamin D status.MethodsWe recruited NHS healthcare workers between 12thto 22ndMay 2020 as part of the COVID-19 convalescent immunity study (COCO). We measured anti-SARS-Cov-2 antibodies using a combined IgG, IgA and IgM ELISA (The Binding Site). Vitamin D status was determined by measurement of serum 25(OH)D3using the AB SCIEX Triple Quad 4500 mass spectrometry system.FindingsOf the 392 NHS healthcare workers, 214 (55%) had seroconverted for COVID-19. A total of 61 (15.6%) members of staff were vitamin D deficient (30 kg/m2), and were male. Multivariate analysis revealed that BAME and COVID-19 seroconversion were independent predictors of vitamin D deficiency. Staff who were vitamin D deficient were more likely to self-report symptoms of body aches and pains but importantly not the respiratory symptoms of cough and breathlessness. Vitamin D levels were lower in those COVID-19 positive staff who reported fever, but this did not reach statistical significance. Within the whole cohort there was an increase in seroconversion in staff with vitamin D deficiency compared to those without vitamin D deficiency (n=44/61, 72%vsn=170/331, 51%; p=0·003); this was particularly marked in the proportion of BAME males who were vitamin D deficient compared to non-vitamin D deficient BAME males (n=17/18, 94%vsn=12/23, 52%; p=0·005). Multivariate analysis revealed that vitamin D deficiency was an independent risk factor for seroconversion (OR 2·6, 95%CI 1·41–4·80; p=0·002).InterpretationIn those healthcare workers who have isolated due to symptoms of COVID-19, those of BAME ethnicity are at the highest risk of vitamin D deficiency. Vitamin D deficiency is a risk factor for COVID-19 seroconversion for NHS healthcare workers especially in BAME male staff.FundingThis study was funded internally by the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust and supported by the National Institute for Health Research (NIHR)/Wellcome Trust Birmingham Clinical Research Facility. AAF and DRT are funded by the Medical Research Council (MR/S002782/1). The Binding Site (Edgbaston, UK) have provided reagents and plates for the SARS-CoV-2 ELISA free of charge.Research in contextEvidence before this studyThe ongoing COVID-19 pandemic has raised several questions, one of which is whether individuals with vitamin D deficiency were at a greater risk of being infected or having a severe outcome if infected. Among UK healthcare workers, and indeed the general population, individuals of BAME ethnicity are disproportionately affected by COVID-19. It is well established that individuals of BAME ethnicity have a higher prevalence of vitamin D deficiency, but it is unknown if vitamin D deficiency among UK NHS workers was connected to the risk of COVID-19 infection. Our search of the literature revealed no previous studies have established the prevalence of vitamin D deficiency within a UK NHS trust. Unsurprisingly, there is also no evidence to suggest if vitamin D deficiency was connected to the risk of infection among UK healthcare workers.Added value of this studyIn this study of healthcare workers who had isolated for COVID-19 symptoms towards the end of UK surge within a large UK NHS trust, 15.6% were vitamin D deficient. Our data also reveal that healthcare workers of BAME ethnicity and those who had seroconverted for COVID-19 were more likely to be vitamin D deficient. Multivariate analysis also show that vitamin D deficiency was the only predictor of COVID-19 seroconversion. Vitamin D deficient healthcare workers that are BAME and male had a 94% seroconversion for COVID-19 compared to non-deficient BAME males suggesting they are more at risk of COVID-19 if vitamin D deficient.Implications of all the available evidenceThere is an increased risk of COVID-19 infection in healthcare workers with vitamin D deficiency. Our data adds to the emerging evidence from studies in the UK and across the globe that individuals with severe COVID-19 are more vitamin D deficient than those with mild disease. Finally, ours and the available evidence demonstrate vitamin D supplementation in individuals at risk of vitamin D deficiency or shown to be deficient may help alleviate the impact of COVID-19.

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 Conclusion Patients of South Asians origin with RA from both countries had limited knowledge about CVD risk. There is a need to educate them about CVD risk during consultation, as this will result in better outcomes.

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 IPF patients 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 to the control group (56.3%) (p=0.012). PFS was not significant at 12 or 18 months. The 12-month post-treatment mean decline in FVC% predicted (-4.6±6.2%) was significantly less than the 12-month pre-treatment 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 BMI≤25, baseline DLco% predicted ≤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).Conclusion 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.

Funding: This work is supported by EPSRC grants DTG1796157 and EP/P015638/1. Problems such as timetabling or personnel allocation can be modeled and solved using discrete constraint programming languages. However, while existing constraint solving software solves such problems quickly in many cases, these systems involve specialized languages that require significant time and effort to learn and apply. These languages are typically text-based and often difficult to interpret and understand quickly, especially for people without engineering or mathematics backgrounds. Visualization could provide an alternative way to model and understand such problems. Although many visual programming languages exist for procedural languages, visual encoding of problem specifications has not received much attention. Future problem visualization languages could represent problem elements and their constraints unambiguously, but without unnecessary cognitive burdens for those needing to translate their problem's mental representation into diagrams. As a first step towards such languages, we executed a study that catalogs how people represent constraint problems graphically. We studied three groups with different expertise: non-computer scientists, computer scientists and constraint programmers and analyzed their marks on paper (e.g., arrows), gestures (e.g., pointing) and the mappings to problem concepts (e.g., containers, sets). We provide foundations to guide future tool designs allowing people to effectively grasp, model and solve problems through visual representations. Postprint

Background Aspirin forms a cornerstone of management in patients with established cardiovascular disease (CVD). Despite proven efficacy, variability of aspirin response has long been recognised, with early studies suggesting rates of high on treatment platelet reactivity (HTPR) as ranging between 5 and 45%. Whether aspirin responsiveness relates to long-term prognosis in patients with CVD is unknown. Methods A prospective, single-centre analysis of 224 troponin positive non-ST elevation myocardial infarction (NSTEMI) patients undergoing coronary angiography. Aspirin-naive patients were loaded with 300 mg aspirin and maintained on 75 mg daily. Blood samples were obtained at the time of angiography and the VerifyNow Aspirin assay utilised to determine aspirin effect. The primary end point was all-cause mortality at 10 years. Results Time from aspirin loading (or admission on aspirin) to angiography was 4.9 ± 2.7 days. Platelet aggregation results, expressed as aspirin reaction units (ARU) were divided into tertiles: T1 (ARU 363–405) (n = 76), T2 (ARU 406–436) (n = 76), T3 (ARU 437–596) (n = 72). Higher ARU values were associated with increased mortality (log rank, p = 0.009), with those in the T3 having a 3-fold higher rate of events than those in the T1 (HR 3.03 [95% CI 1.33–6.99], p = 0.009) over a 10-year follow up. Conclusion Our study demonstrates that aspirin responsiveness is directly related to 10-year survival and may identify patients who may benefit from additional antithrombotic therapy. Further, ARU values less than the previously defined cut off 550 are associated with reduced survival at 10 years.

Background South Asians have a higher risk of cardiovascular disease (CVD). Rheumatoid arthritis (RA) increases the risk of premature atherosclerosis. Therefore, we compared 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 < 0.01). Regarding modifiable risk factors for CVD only 44.6% from India and 45.4% in the UK were aware of them (p=ns). However, awareness of the link between RA and increased risk of CVD was even more limited (38.1% in India and 40.7% in UK (p=ns). Conclusion Patients of South Asians origin with RA from both countries had limited knowledge about CVD risk. There is a need to educate them about CVD risk during consultation, as this will result in better outcomes. Disclosures K. Kumar None. S. Arya None. P. Nightingale None. T. Sheeran None. A. Aggarwal None.

Introduction Sarcopenia is a progressive loss in muscle mass, strength and function, the adverse consequences of which are severe, affecting quality of life and placing an increasing burden on social and healthcare systems. Vitamin D status is known to be associated with markers of sarcopenia, namely muscle mass, strength and function. Also, resistance exercise training (RET) is currently the only proven intervention to treat sarcopenia. However, very little data exist on the influence of combining the two interventions of vitamin D supplementation and resistance exercise training, although a recent systematic review provides tentative support for the current study’s hypothesis that the combined intervention may further improve musculoskeletal function above exercise training alone. The aim of the present study is to determine whether vitamin D3 supplementation is any more effective in improving musculoskeletal function when combined with RET compared with exercise training alone in older adults. Methods and analysis This double-blinded randomised placebo-controlled trial will recruit a target of 127 eligible men and women aged ≥65 years living independently or in sheltered housing within the Birmingham area to two groups: (1) 6 months RET and placebo or (2) 6 months RET and 800 IU/d vitamin D3. Measures of muscle power (Nottingham Power Rig), body composition (dual energy X-ray absorptiometry), muscle function (short physical performance battery, timed up and go), falls and fractures as events will be assessed. Assessments will take place at baseline and postintervention, with intermittent monitoring of bone turnover, calcium and vitamin D. The primary outcome will be lower limb extensor power output. Analyses of within-group changes and between-group differences in outcome measures are planned. Ethics and dissemination The EXVITD study has ethical approval granted by the Black Country National Health Service Research Ethics Committee (14/WM/1220). Results of this trial will be submitted for publication in peer-reviewed journals and presented at conferences. The study is being conducted according to the principles of the Declaration of Helsinki. Trial registration number NCT02467153; Post-results.

IntroductionSarcopenia is a progressive loss in muscle mass, strength and function, the adverse consequences of which are severe, affecting quality of life and placing an increasing burden on social and healthcare systems. Vitamin D status is known to be associated with markers of sarcopenia, namely muscle mass, strength and function. Also, resistance exercise training (RET) is currently the only proven intervention to treat sarcopenia. However, very little data exist on the influence of combining the two interventions of vitamin D supplementation and resistance exercise training, although a recent systematic review provides tentative support for the current study’s hypothesis that the combined intervention may further improve musculoskeletal function above exercise training alone. The aim of the present study is to determine whether vitamin D3supplementation is any more effective in improving musculoskeletal function when combined with RET compared with exercise training alone in older adults.Methods and analysisThis double-blinded randomised placebo-controlled trial will recruit a target of 127 eligible men and women aged ≥65 years living independently or in sheltered housing within the Birmingham area to two groups: (1) 6 months RET and placebo or (2) 6 months RET and 800 IU/d vitamin D3. Measures of muscle power (Nottingham Power Rig), body composition (dual energy X-ray absorptiometry), muscle function (short physical performance battery, timed up and go), falls and fractures as events will be assessed. Assessments will take place at baseline and postintervention, with intermittent monitoring of bone turnover, calcium and vitamin D. The primary outcome will be lower limb extensor power output. Analyses of within-group changes and between-group differences in outcome measures are planned.Ethics and disseminationThe EXVITD study has ethical approval granted by the Black Country National Health Service Research Ethics Committee (14/WM/1220). Results of this trial will be submitted for publication in peer-reviewed journals and presented at conferences. The study is being conducted according to the principles of the Declaration of Helsinki.Trial registration numberNCT02467153; Post-results.

Background: Studies during the COVID-19 pandemic have suggested patient characteristics with increased risk of death. Most studies have not included populations which reflect an urban UK demographic but emerging case reports have suggested poorer outcomes in certain ethnic groups. It was hypothesised that people from South Asian ethnic groups would be more susceptible to severe manifestations of COVID-19. Methods: Patients with confirmed SARS-CoV-2 infection by positive polymerase chain reaction testing and requiring admission to University Hospitals Birmingham NHS Foundation Trust in Birmingham UK between 10th March 2020 and 17th April 2020 were included. Demographics, ethnicity, baseline co-morbidities, social deprivation index and outcome (death within the censor date) were assessed and Cox regression analysis conducted. Using observed sex-specific age distributions of COVID-19 admissions/deaths and 2011 census data for Birmingham/Solihull, expected numbers of admissions and deaths were estimated and ratios of observed to expected numbers calculated, providing standardised admission ratios (SAR) and standardised mortality ratios (SMR). Results: 2217 patients admitted to UHB with a proven diagnosis of COVID-19 were included. 58.2% were male, 69.5% White and the majority (80.2%) had co-morbidities. 18.5% were of South Asian ethnicity, and these patients were more likely to be younger (median age 61 vs.77), have no co-morbidities (27.8% vs. 16.6%) but a higher prevalence of diabetes mellitus (48.1% vs 28.2%) than White patients. SAR and SMR suggested more admissions and deaths in South Asian patients than would be predicted. These patients were more likely to present with severe disease. South Asian ethnicity was associated with an increased risk of death (Hazard Ratio 1.67 (95%CI 1.34 – 2.10)) after adjusting for age, sex, deprivation and comorbidities. Interpretation: Current evidence suggests those of South Asian ethnicity may be at risk of worse COVID019 outcomes, further studies needs to establish the underlying mechanistic pathways. Funding Statement: HDRUK Hub PIONEER Declaration of Interests: S Gallier, C Mainey, P Nightingale, D McNulty, A Kolesnyk, M Ahmed, H Crothers, F Evison, A Liaqat, L Irshad, M. Harris, T Nabavi, P Cockwell, D Pagano, report no conflicts of interest. S Ballreports funding support from the HDFR-UK, K Reeves reports funding support from the NIHR, E Sapey reports funding support from the MRC, Wellcome Trust, NIHR and British Lung Foundation. K. Nirantharakumar reports funding from MRC, Wellcome Trust, NIHR, Vifor and AstraZeneca. A.K Dennistonreports funding from HDR-UK, Wellcome Trust and Fight for Sight. Ethics Approval Statement: This retrospective cohort study, using prospectively collected data was conducted as part of DECOVID, an HRA and London - City & East Research Ethics Committee approved research database (Ethics number 20/HRA/1689).

Funding: UK EPSRC grant EP/P015638/1. Satisfiability Modulo Theories (SMT) is a well-established methodology that generalises propositional satisfiability (SAT) by adding support for a variety of theories such as integer arithmetic and bit-vector operations. SMT solvers have made rapid progress in recent years. In part, the efficiency of modern SMT solvers derives from the use of specialised decision procedures for each theory. In this paper we explore how the Essence Prime constraint modelling language can be translated to the standard SMT-LIB language. We target four theories: bit-vectors (QF_BV), linear integer arithmetic (QF_LIA), non-linear integer arithmetic (QF_NIA), and integer difference logic (QF_IDL). The encodings are implemented in the constraint modelling tool Savile Row. In an extensive set of experiments, we compare our encodings for the four theories, showing some notable differences and complementary strengths. We also compare our new encodings to the existing work targeting SMT and SAT, and to a well-established learning CP solver. Our two proposed encodings targeting the theory of bit-vectors (QF_BV) both substantially outperform earlier work on encoding to QF_BV on a large and diverse set of problem classes. Postprint

Aims To establish the prevalence of admission plasma glucose in 'diabetes' and 'at risk' ranges in emergency hospital admissions with no prior diagnosis of diabetes; characteristics of people with hyperglycaemia; and factors influencing glucose measurement. Methods Electronic patient records for 113 097 hospital admissions over 1 year from 2014 to 2015 included 43 201 emergencies with glucose available for 31 927 (74%) admissions, comprising 22 045 people. Data are presented for 18 965 people with no prior diagnosis of diabetes and glucose available on first attendance. Results Three quarters (14 214) were White Europeans aged 62 (43‐78) years, median (IQ range); 12% (2241) South Asians 46 (32‐64) years; 9% (1726) Unknown/Other ethnicities 43 (29‐61) years; and 4% (784) Afro‐Caribbeans 49 (33‐63) years, P 24 hours. Conclusions Hyperglycaemia was evident in 21% of adults admitted as an emergency; various aspects related to follow‐up and initial testing, age and ethnicity need to be considered by professional bodies addressing undiagnosed diabetes in hospital admissions., Glucose needs to be measured in all adults admitted as an emergency not just those over 40/30 years old, as younger people particularly South Asians and Afro‐Caribbeans are at risk of being admitted with undiagnosed diabetes. Overall, 5% of emergency admissions had glucose in the ‘diabetes’ range, 8% if South Asian and Afro‐Caribbean, with 16% of people in the ‘at risk’ range. One third of all emergency admissions were for 24 hours.