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Background Acute kidney injury (AKI) is common after liver transplantation (LT). Induction with interleukin-2 receptor antagonists is often used as a “renal-sparing” strategy. The aim of this study was to assess this approach in a real-world setting in an LT center. Methods A retrospective cohort analysis of LTs between 2011 and 2018 was performed to assess the impact of a renal-sparing strategy using basiliximab in conjunction with mycophenolate mofetil and corticosteroids from day 0 post-LT along with delayed introduction of tacrolimus. This was compared with a group receiving tacrolimus, mycophenolate mofetil, and corticosteroids from the outset. Results The renal-sparing regimen was associated with significantly lower incidence of all-stage AKI at day 7 post-LT (36% vs 55%, P = .006) and less decline in renal function at 3 months (39% vs 57%, P = .01). No further significant differences in renal outcomes were observed at other time points on follow-up to 1 year post-LT. There was no significant difference in the incidence of acute cellular rejection, inpatient length of stay or graft survival. The decision to adopt a renal-sparing regimen was predominantly made on a clinically reactive basis within the first 24 hours post-LT in 77%, and was preordained in 23%. Cost-effectiveness analysis did not find evidence of a significant cost saving when using a renal-sparing strategy. Conclusion This study provides real-world analysis of the use of a renal-sparing immunosuppression regimen in LT. Although improvements in incidence of AKI in the short term were demonstrated, this did not translate to cost savings or improved renal outcomes after 3 months.

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.

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.

Systemic autoimmune inflammatory disorders confer a higher risk of cardiovascular (CV) disease leading to increased morbidity and mortality and reduced life expectancy compared to the general population. CV risk in systemic sclerosis (SSc) has not been studied extensively but surrogate markers of atherosclerosis namely carotid intima media thickness (cIMT) and pulse wave velocity (PWV) are impaired in some but not all studies in SSc patients. The aim of this study was to investigate the prevalence of subclinical atherosclerosis assessed by cIMT and PWV between two well-characterized SSc and Rheumatoid Arthritis (RA) cohorts. Consecutive SSc patients attending the Scleroderma Clinic were compared with RA patients recruited in the Dudley Rheumatoid Arthritis Co-morbidity Cohort (DRACCO), a prospective study examining CV burden in RA. Augmentation Index (Aix75) and cIMT were measured in all participants. Propensity score matching was utilised to select patients from the two cohorts with similar demographic characteristics, CV risk factors and inflammatory load. Unpaired analysis was performed using unpaired t test for continuous variables and χ2 test for dichotomous variables. Statistical analysis was repeated using paired t test for continuous normal variables and McNemar’s test for dichotomous variables. Fifty five age- and sex-matched SSc and RA patients were included in the analysis. No difference was demonstrated between SSc and RA subjects regarding cIMT (0.66 mm vs 0.63 mm, respectively) and Aix75% measurements (33.4 vs 31.7, respectively) neither in paired (p = 0.623 for cIMT and p = 0.204 for Aix%) nor in unpaired t test analysis (p = 0.137 for cIMT and p = 0.397 for AIx%). The results of this comparative study show that subclinical atherosclerosis is comparable between SSc and RA, a systemic disease with well-defined high atherosclerotic burden. Such findings underscore the importance of CV risk management in SSc in parallel with other disease-related manifestations.

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.

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.

Chronic gastroesophageal reflux predisposes to the development of esophageal adenocarcinoma (EAC). Asthma and medication to treat it are associated with gastroesophageal reflux and EAC. We studied subjects with chronic obstructive pulmonary disease (COPD) to examine the relationship between COPD and medication used to treat it, and the risk of reflux esophagitis, Barrett's esophagus, and EAC.A case-control study from the UK General Practice Research Database was conducted. Cases were aged 50 or above with a diagnosis of COPD and were matched with controls without a diagnosis of COPD by age, general practitioners practice, and time on the database. EAC was confirmed by cross-referencing cancer registry data. Cox-regression analysis was performed to assess the relationship between COPD, reflux esophagitis, Barrett's esophagus, and EAC.A total of 45,141 cases were studied [24,464 male, age 75 (50 to 100) years]. Among COPD cases there were 55 esophageal cancers (30 EAC) and 506 Barrett's esophagus, compared with 62 (34 EAC) and 329 Barrett's esophagus among controls. COPD was not associated with EAC on univariable [0.92 (0.56 to 1.50), P=0.73] and multivariable analysis [0.85 (0.52 to 1.40), P=0.53]. COPD was however, associated with Barrett's esophagus on univariable [0.92 (0.56 to 1.50), P=0.73] and multivariable [1.53 (1.31 to 1.78), P0.001] analysis and reflux esophagitis on univariable [1.41 (1.36 to 1.48), P0.001] and multivariable [1.33 (1.27 to 1.40), P0.001] analysis.COPD is associated with an increased risk of reflux esophagitis and Barrett's esophagus but not EAC.

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.

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

Mitral regurgitation (MR) following acute myocardial infarction (AMI) worsens prognosis and reports of prevalence vary significantly. The objective was to determine prevalence, risk factors, and outcomes related to MR following AMI. We identified 1000 consecutive patients admitted with AMI in 2016/17 treated by percutaneous coronary intervention with pre-discharge transthoracic echocardiography. MR was observed in 294 of 1000 (29%), graded as mild (n = 224 [76%]), moderate (n = 61 [21%]) and severe (n = 9 [3%]). Compared with patients without MR, patients with MR were older (70 ± 12 vs 63 ± 13 years; p0.001), with worse left ventricular ejection fraction (LVEF) (52 ± 15% vs 55 ± 11%; p0.001) and creatinine clearance (69 ± 33 ml/min vs 90 ± 39 ml/min; p0.001). They also had higher rates of hypertension (64% vs 55%; p = 0.012), heart failure (3.4% vs 1.1%; p = 0.014), previous MI (28% vs 20%; p = 0.005) and severe flow-limitation in the circumflex (50% vs 33%; p0.001) or right coronary artery (51% vs 42%; p = 0.014). Prevalence and severity of MR were unaffected by AMI subtype. Revascularization later than 72 hours from symptom-onset was associated with increased likelihood of MR (33% vs 25%; p = 0.036) in patients with non-ST elevation myocardial infarction (NSTEMI). After a mean of 3.2 years, 56 of 288 (19%) patients with untreated MR died. Age and LVEF independently predicted mortality. The presence of even mild MR was associated with increased mortality (p = 0.029), despite accounting for confounders. In conclusion, MR is observed in over one-quarter of patients after AMI and associated with lower survival, even when mild. Prevalence and severity are independent of MI subtype, but MR was more common with delayed revascularization following NSTEMI.

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.

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.

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.

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.

Objectives To estimate the cumulative effective dose of radiation (E) and additional lifetime attributable risk (LAR) of cancer from ionizing radiation in children with osteogenesis imperfecta (OI), who require frequent imaging for fractures and bone densitometry (DXA) surveillance. Also, to evaluate the pattern of long bone fractures. Methods We reviewed all imaging (x-rays, DXA and computed tomography [CT]) conducted in a cohort of children with OI with a minimum observation period of 5 years. For each image, E was estimated using age-dependent local data, and LAR of cancer was extrapolated. LAR and fracture data were compared among children with mild, moderate and severe OI. LAR was allocated to cancer risk categories, and the moderate risk group (1 in 1000 to 1 in 100) was evaluated further. Results Results from 106 children with OI (50% females, 5747 images) are presented, with a median (range) observation period of 11.7 (5.2–15.6) years. CT accounted for 0.8% of total imaging procedures but contributed to 66% of total E. The overall LAR of cancer was minimal, averaging an additional 8.8 cases per 100,000 exposed patients (0.8–403). LAR was significantly lower in children with mild OI compared to those with moderate (p = 0.006) and severe OI (p = 0.001). All patients with a moderate LAR of cancer (n = 8) had undergone CT scans and 88% had scoliosis or vertebral fractures. The cohort experienced 412 long bone fractures, with the most common site being the femur (26.5%). OI severity correlated positively with long bone fracture rates (p Conclusions When compared to baseline LAR of cancer (50%) the additional cancer risk from ionizing radiation imaging in our paediatric OI cohort was small (0.0088%). To reduce additional cancer risk, we recommend replacing spinal x-rays with vertebral fracture assessments on DXA and exercising caution with CT imaging.

This study aimed to evaluate the prevalence of glucocorticoid-induced adrenal insufficiency in a cohort of patients with brain and skull base tumours and to identify factors which may predict its occurrence. Patients with brain or skull base tumours attending for a short synacthen test (SST) (adrenocorticotropin hormone (ACTH) stimulation test) at a single institution over a 3-year period were retrospectively identified. Baseline demographics and dexamethasone exposure were examined. Only patients with dexamethasone exposure were included in the final analysis looking at the primary end point of SST failure. Fisher’s exact test, Student’s t test, Mann-Whitney test and the Kendall’s tau-b test were used to evaluate the influence of age, gender, diagnosis and mean pituitary radiation dose on the primary endpoint. Receiver operating characteristic (ROC) curves were generated to explore the impact of duration and total exposure to dexamethasone on likelihood of SST failure. Thirty-one of 51 patients with previous dexamethasone exposure failed their first SST (61%). No significant relationship was demonstrated between age, gender, diagnosis or mean pituitary radiation dose and SST failure. Duration of and total exposure to dexamethasone were significantly associated with SST failure (p = 0.001 and p = 0.007, respectively). ROC curves generated values of 78 days and 171 mg days to give a sensitivity of 94 and 97%, respectively, to detect SST failure. Duration of dexamethasone use and total exposure predict for adrenal insufficiency in patients with brain and skull base tumours. Values derived from this study may be useful to identify patients at higher risk of adrenal suppression who require empirical hydrocortisone pending formal testing of the hypothalamic-pituitary-adrenal axis.

Dysregulated neutrophil functions with age and sepsis are described. Statins are associated with improved infection survival in some observational studies, but trials in critically ill patients have not shown benefit. Statins also alter neutrophil responses in vitro.To assess neutrophil migratory accuracy with age during respiratory infections and determine if and how a statin intervention could alter these blunted responses.The migratory accuracy of blood neutrophils from young (aged35 yr) and old (aged60 yr) patients in health and during a lower respiratory tract infection, community-acquired pneumonia, and pneumonia associated with sepsis was assessed with and without simvastatin. In vitro results were confirmed in a double-blind randomized clinical trial in healthy elders. Cell adhesion markers were assessed.In vitro neutrophil migratory accuracy in the elderly deteriorated as the severity of the infectious pulmonary insult increased, without recovery at 6 weeks. Simvastatin rescued neutrophil migration with age and during mild to moderate infection, at high dose in older adults, but not during more severe sepsis. Confirming in vitro results, high-dose (80-mg) simvastatin improved neutrophil migratory accuracy without impeding other neutrophil functions in a double-blind randomized clinical trial in healthy elders. Simvastatin modified surface adhesion molecule expression and activity, facilitating accurate migration in the elderly.Infections in older adults are associated with prolonged, impaired neutrophil migration, potentially contributing to poor outcomes. Statins improve neutrophil migration in vivo in health and in vitro in milder infective events, but not in severe sepsis, supporting their potential utility as an early intervention during pulmonary infections. Clinical trial registered with www.clinicaltrialsregister.eu (2011-002082-38).

Community-acquired pneumonia (CAP) is the leading cause of death from infection in developed countries. There is evidence of an association between improved survival from infection and statin use. The possible beneficial effects of statins are complicated by the common use of macrolide antibiotics for pneumonia, with current guidance suggesting that concurrent macrolide and statin use is contraindicated.We conducted an observational study of statin use in patients with CAP. Of 2,067 patients with CAP, 30.4% were on statin therapy at admission. Statin users were more likely to survive the admission (p

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

Context Osteogenesis imperfecta (OI) is associated with reduced muscle size, dynamic muscle function, and mobility. Objective To assess the effect of whole body vibration (WBV) on bone density and geometry, muscle size and function, mobility, and balance in children with OI. Design Randomized controlled pilot trial. Setting Tertiary pediatric research center. Participants Twenty-four children (5 to 16 years) with OI types 1, 4, and limited mobility [Child Health Assessment Questionnaire (CHAQ) score ≥ 0.13] recruited in sex- and pubertal stage-matched pairs. Incident fractures in two boys (WBV arm) led to exclusion of two prepubertal pairs. Intervention Five months of WBV training (3 × 3 minutes twice daily) or regular care. Main Outcome Measures Bone and muscle variables measured by dual-energy X-ray absorptiometry (spine, hip, total body) and peripheral quantitative computed tomography (tibia). Mobility assessed by 6-minute walk tests and CHAQ; dynamic muscle function by mechanography. Results All participants had reduced walking distances and muscle function (P < 0.001). Body mass index z score was associated with higher CHAQ scores (ρ + 0.552; P = 0.005) and lower walking and two-leg jumping performance (ρ − 0.405 to −0.654, P < 0.05). The WBV and control groups did not differ in the 5-month changes in bone. Total lean mass increased more in the WBV group [+1119 g (+224 to +1744)] compared with controls [+635 g (−951 to +1006)], P = 0.01, without improving mobility, muscle function, or balance. Conclusions The increase in lean mass without changes in muscle function or bone mass suggests reduced biomechanical responsiveness of the muscle-bone unit in children with OI.

Aim To estimate the proportion of type 2 diabetes mellitus and abnormal glucose homeostasis in childhood obesity and assess the predictive role of HbA1c as a diagnostic marker compared with oral glucose tolerance testing (OGTT). Methods A retrospective study in a tertiary paediatric hospital. Data were collected on all overweight or obese children who underwent routine OGTT between 2012 and 2016. Ethnicity, anthropometry, comorbidities and other risk factors associated with diabetes were recorded systematically. Fasting venous glucose, insulin and HbA1c values, along with 120-min venous glucose were recorded. Receiver operating characteristic (ROC) curve analysis was performed to derive optimum thresholds of HbA1c for detection of type 2 diabetes, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Predictive HbA1c thresholds for the detection of abnormal glucose homeostasis in children with obesity were calculated. Results Of 156 children, 13 (8%, 10 female, 10 Asian) had type 2 diabetes, 95 (61%) had normal glucose tolerance, 18 (12%) had isolated IFG, 19 (12%) had isolated IGT, and another 11 (7%) had both IFG and IGT. The proportion of abnormal glucose homeostasis was 39%. ROC curve analysis demonstrated that HbA1c ≥ 42 mmol/mol (6.0%) predicted type 2 diabetes (specificity 95%, sensitivity 85%) but performed moderately for IFG (specificity 46%, sensitivity 78%) and IGT (specificity 78%, sensitivity 55%). Conclusion Despite HbA1c being a less-sensitive diagnostic tool compared with OGTT for children with IFG and IGT, it is reliable in detecting type 2 diabetes in asymptomatic children with obesity, instead of the labour- and cost-intensive OGTT.

Background. The long-term use of calcineurin inhibitors (CNIs) after liver transplantation (LT) is associated with nephrotoxicity. Methods. Five-year follow-up data were retrieved from the randomized controlled multicenter SiLVER trial. Standard CNI-based mammalian target of rapamycin-free immunosuppression (group A, n = 264) was compared with a 50% reduction of CNI and introduction of the mammalian target of rapamycin inhibitor Sirolimus (SIR) within 4-6 weeks after LT (group B, n = 261). Results. Median MELD at LT was low with 10 (7-15) (group A) and 11 (8-15) (group B) in the intention-to-treat approach. CNI dose and CNI trough were reduced by 20% and 8% (group A) versus 55% and 56% (group B) at 3 months posttransplantation. Renal function was preserved at 3 months after LT in the SIR arm (estimated glomerular filtration rate 74 [57-95] versus 67 [55-85] mL/min/1.73m2 P = 0.004) but was similarly impaired thereafter compared with group A. The per protocol analysis identified LT recipients in group B with concomitant early CNI minimization and SIR treatment >= year 1 with significantly superior estimated glomerular filtration rate and lowest rate of chronic kidney disease (>= stage 3) from year 1 onwards until study end. Competing risk factors for renal disease (arterial hypertension, fat metabolism disorder, and hyperglycemia) were not associated with worse kidney function. Conclusions. Prevention of CNI nephrotoxicity by SIR-based early CNI minimization protects renal function only short-term after LT in the intention-to-treat analysis of this low MELD cohort. Yet, selected LT recipients compliant with early CNI minimization and SIR maintenance achieved better long-term renal outcomes compared with real-world practice.

Objectives: Tunnelled central venous catheters dysfunction can be defined as failure to provide blood flow above 200 mL/min during dialysis often caused by thrombosis. Although urokinase is used routinely for thrombolysis, there is wide variation in dose regimens. A multidisciplinary group was formed to address this issue and offer guidance. Methods: Dialysis centres that used urokinase in the United Kingdom took part in a prospective study to determine the safety and outcomes of thrombolysis using agreed protocols. Data were collected anonymously from September 2017 until February 2018. Catheter blood flow was measured before and after the following interventions: catheter dwell or push locks with 12,500–50,000 IU or catheter infusion with 100,000–250,000 IU of urokinase. Interventions were repeated if the blood flow remained below 200 mL/min. Results: 10 centres took part and recruited 200 patients; 45.5% were female and 54.5% were male with mean age of 63.6 (±15.2) years. The cumulative success rate for thrombolysis was 90.5% after first intervention, 97% after second intervention, and 99% after more than 2 interventions. Although there was trend towards benefit with dose increments, the success rate between push/dwell locks and high-dose infusion of urokinase was not significantly different (p = 0.069). Seventeen (8.5%) tunnelled central venous catheters were removed due to failure of treatment. No urokinase-related adverse events were reported. Conclusion: In this study, urokinase was safe and efficacious; there was no difference between dwell and push locks. There was some benefit with high-dose infusion of urokinase compared to the dwell and push lock.

Background Delirium is a common severe neuropsychiatric condition secondary to physical illness, which predominantly affects older adults in hospital. Prior to this study, the UK point prevalence of delirium was unknown. We set out to ascertain the point prevalence of delirium across UK hospitals and how this relates to adverse outcomes. Methods We conducted a prospective observational study across 45 UK acute care hospitals. Older adults aged 65 years and older were screened and assessed for evidence of delirium on World Delirium Awareness Day (14th March 2018). We included patients admitted within the previous 48 h, excluding critical care admissions. Results The point prevalence of Diagnostic and Statistical Manual on Mental Disorders, Fifth Edition (DSM-5) delirium diagnosis was 14.7% (222/1507). Delirium presence was associated with higher Clinical Frailty Scale (CFS): CFS 4–6 (frail) (OR 4.80, CI 2.63–8.74), 7–9 (very frail) (OR 9.33, CI 4.79–18.17), compared to 1–3 (fit). However, higher CFS was associated with reduced delirium recognition (7–9 compared to 1–3; OR 0.16, CI 0.04–0.77). In multivariable analyses, delirium was associated with increased length of stay (+ 3.45 days, CI 1.75–5.07) and increased mortality (OR 2.43, CI 1.44–4.09) at 1 month. Screening for delirium was associated with an increased chance of recognition (OR 5.47, CI 2.67–11.21). Conclusions Delirium is prevalent in older adults in UK hospitals but remains under-recognised. Frailty is strongly associated with the development of delirium, but delirium is less likely to be recognised in frail patients. The presence of delirium is associated with increased mortality and length of stay at one month. A national programme to increase screening has the potential to improve recognition.

BackgroundCommunity-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.MethodsWe 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.Results1545 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%.ConclusionAll 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.

ObjectiveTo investigate delays from symptom onset to rheumatology assessment for patients with a new onset of rheumatoid arthritis (RA) or unclassified arthritis.MethodsNewly presenting adults with either RA or unclassified arthritis were recruited from rheumatology clinics. Data on the length of time between symptom onset and first seeing a GP (patient delay), between first seeing a general practitioner (GP) and being referred to a rheumatologist (general practitioner delay) and being seen by a rheumatologist following referral (hospital delay) were captured.Results822 patients participated (563 female, mean age 55 years). The median time between symptom onset and seeing a rheumatologist was 27.2 weeks (IQR 14.1–66 weeks); only 20% of patients were seen within the first 3 months following symptom onset. The median patient delay was 5.4 weeks (IQR 1.4–26.3 weeks). Patients who purchased over-the-counter medications or used ice/heat packs took longer to seek help than those who did not. In addition, those with a palindromic or an insidious symptom onset delayed for longer than those with a non-palindromic or acute onset. The median general practitioner delay was 6.9 weeks (IQR 2.3–20.3 weeks). Patients made a mean of 4 GP visits before being referred. The median hospital delay was 4.7 weeks (IQR 2.9–7.5 weeks).ConclusionThis study identified delays at all levels in the pathway towards assessment by a rheumatologist. However, delays in primary care were particularly long. Patient delay was driven by the nature of symptom onset. Complex multi-faceted interventions to promote rapid help seeking and to facilitate prompt onward referral from primary care should be developed.

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. Electronic supplementary material The online version of this article (10.1186/s12882-019-1226-0) contains supplementary material, which is available to authorized users.

BackgroundStudies 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.MethodsPatients with confirmed SARS-CoV-2 infection requiring admission to University Hospitals Birmingham NHS Foundation Trust(UHB) in Birmingham UK between 10thMarch 2020-17thApril 2020 were included. Standardised Admission Ratio(SAR) and Standardised Mortality Ratio(SMR) were calculated using observed COVID-19 admissions/deaths and 2011 census data. Hazard Ratio (aHR) for mortality was estimated using Cox proportional hazard model adjusting and propensity score matching.ResultsAll patients admitted to UHB with COVID-19 during the study period were included (2217 in total). Fifty-eight percent were male, 69.5% White and the majority (80.2%) had co-morbidities. Eighteen and a half percent were of South Asian ethnicity, and these patients were more likely to be younger, have no co-morbidities 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 (Hazard Ratio 1.4 (95%CI 1.2–1.8) 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 (Hazard ratio 1.3 (1.0-1.6)).ConclusionsThose of South Asian ethnicity appear at risk of worse COVID-19 outcomes, further studies need to establish the underlying mechanistic pathways.

BACKGROUND Cardiac dysfunction is frequently observed in patients with cirrhosis. There remains a paucity of data from routine clinical practice regarding the role of echocardiography in the pre-assessment of transjugular intrahepatic portosystemic stent-shunt. AIM Our study aimed to investigate if echocardiography parameters predict outcomes after transjugular intrahepatic portosystemic stent-shunt insertion in cirrhosis. METHODS Patients who underwent echocardiography and transjugular intrahepatic portosystemic stent-shunt insertion at the liver unit (Birmingham, UK) between 1999 and 2016 were included. All echocardiography measures (including left ventricle ejection fraction; early maximal ventricular filling/late filling velocity ratio, diastolic dysfunction as per British Society of Echocardiography guidelines) were independently reviewed by a cardiologist. Predictors of 30-day and overall transplant free-survival were assessed. RESULTS One Hundred and Seventeen patients with cirrhosis (median age 56 years; 54% alcohol; Child-Pugh B/C 71/14.5%; Model For End-Stage Liver Disease 12) underwent transjugular intrahepatic portosystemic stent-shunt for ascites (n = 78) and variceal haemorrhage (n = 39). Thirty-day and overall transplant-free survival was 90% (n = 105) and 31% (n = 36), respectively, over a median 663 (IQR 385-2368) days follow-up. Model for End-Stage Liver Disease (P

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., Graphical Abstract, Highlights • NR supplementation in aged subjects augments the skeletal muscle NAD+ metabolome • NR supplementation does not affect skeletal muscle mitochondrial bioenergetics • NR supplementation reduces levels of circulating inflammatory cytokines, 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.

Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVEs in RA patients.A randomized, double-blind, placebo-controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P0.05. RA patients age50 years or with a disease duration of10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety.A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range [IQR] 1.90, 3.49 years) (7,827 patient-years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio [HR] 0.66 [95% confidence interval (95% CI) 0.39, 1.11]; P = 0.115 and adjusted HR 0.60 [95% CI 0.32, 1.15]; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low-density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P0.0001). C-reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter [IQR 0.94, 6.08] versus 3.60 mg/liter [IQR 1.47, 7.49]; P0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI -14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 [19.8%]) and placebo group (n = 292 [19.5%]) were similar.Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists' Collaboration meta-analysis of statin effects in other populations.

Headache is disabling and prevalent in idiopathic intracranial hypertension. Therapeutic lumbar punctures may be considered to manage headache. This study evaluated the acute effect of lumbar punctures on headache severity. Additionally, the effect of lumbar puncture pressure on post-lumbar puncture headache was evaluated.Active idiopathic intracranial hypertension patients were prospectively recruited to a cohort study, lumbar puncture pressure and papilloedema grade were noted. Headache severity was recorded using a numeric rating scale (NRS) 0-10, pre-lumbar puncture and following lumbar puncture at 1, 4 and 6 hours and daily for 7 days.Fifty two patients were recruited (mean lumbar puncture opening pressure 32 (28-37 cmCSF). At any point in the week post-lumbar puncture, headache severity improved in 71% (but a small reduction of -1.1 ± 2.6 numeric rating scale) and exacerbated in 64%, with 30% experiencing a severe exacerbation ≥ 4 numeric rating scale. Therapeutic lumbar punctures are typically considered in idiopathic intracranial hypertension patients with severe headaches (numeric rating scale ≥ 7). In this cohort, the likelihood of improvement was 92% (a modest reduction of headache pain by -3.0 ± 2.8 numeric rating scale, p = 0.012, day 7), while 33% deteriorated. Idiopathic intracranial hypertension patients with mild (numeric rating scale 1-3) or no headache (on the day of lumbar puncture, prior to lumbar puncture) had a high risk of post- lumbar puncture headache exacerbation (81% and 67% respectively). Importantly, there was no relationship between lumbar puncture opening pressure and headache response after lumbar puncture.Following lumbar puncture, the majority of idiopathic intracranial hypertension patients experience some improvement, but the benefit is small and post-lumbar puncture headache exacerbation is common, and in some prolonged and severe. Lumbar puncture pressure does not influence the post-lumbar puncture headache.

Infection is a leading cause of death in antineutrophil cytoplasmic antibody–associated vasculitis. Here we show that suppression of subclinical reactivation of cytomegalovirus limits CD4+CD28null T-cell expansion and that this is associated with improved immune response to a T-cell–dependent pneumococcal vaccine challenge., Background Infection is the leading cause of death in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Expansion of CD4+CD28null T cells is associated with increased risk of infection and mortality, but is only present in cytomegalovirus (CMV)–seropositive individuals. We hypothesized that subclinical CMV reactivation drives CD4+CD28null T-cell expansion, that this is associated with impaired immune response to heterologous antigens, and that antiviral therapy may ameliorate this. Methods In a proof-of-concept open-label clinical trial, 38 CMV-seropositive AAV patients were randomized to receive valacyclovir for 6 months or no intervention. CMV reactivation was measured monthly in plasma and urine. CD4+CD28null T cells were enumerated at baseline and at 6 months. At 6 months, 36 patients were vaccinated with a 13-valent pneumococcal vaccine. Serotype-specific immunoglobulin G was assayed before and 4 weeks postvaccination to calculate the antibody response ratio. Results Valacyclovir treatment suppressed subclinical CMV reactivation and reduced CD4+CD28null T-cell proportion. CD4+CD28null T-cell reduction correlated with improved vaccine response, whereas CMV reactivation associated with reduced response to vaccination. Furthermore, expansion of CD4+CD28null T cells was associated with a reduction in the functional capacity of the CD4 compartment. Conclusions Suppression of CMV may improve the immune response to a T-cell–dependent pneumococcal vaccination in patients with AAV, thus offering potential clinical benefit. Clinical Trials Registration NCT01633476.

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

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.

Background: needle-free connectors are widely used in clinical practice. The aim of this study was to identify any differences between microbial ingress into six different connectors (three neutral-displacement, one negative-displacement and two anti-reflux connectors). Methods: each connector underwent a 7-day clinical simulation involving repeated microbial contamination of the connector's injection ports with Staphylococcus aureus followed by decontamination and then saline flushes through each connector. The simulation was designed to be a surrogate marker for the potential risk of contamination in clinical practice. Results: increasing numbers of S. aureus were detected in the flushes over the 7 days of sampling despite adherence to a rigorous decontamination programme. Significant differences in the number of S. aureus recovered from the saline flush of some types of connectors were also detected. Two different durations (5- and 15-second) of decontamination of the injection ports with 70% isopropyl alcohol (IPA) wipes were also investigated. There was no significant difference between the median number of S. aureus recovered in the saline flushes following a 5-second (165.5, 95% CI=93-260) or a 15-second decontamination regimen (75, 10–190). Conclusions: The findings suggest that there may be differences in the risk of internal microbial contamination with different types of connectors and that even 15 seconds of decontamination may not fully eradicate microorganisms from the injection ports of some devices.

To assess the reliability of patellotrochlear Index (PTI) in patellar height assessment on successive MRI scans in asymptomatic patients. Sixty-four patients with two successive MRI scans (128 studies) of the same knee for non-patellofemoral joint symptoms were identified retrospectively. PTI and knee flexion angle were assessed independently by three observers to assess interobserver reliability. The effect of knee flexion on PTI was assessed by comparing the change in values of PTI in each patient correlated with change in knee flexion. Sixty-four MRIs of patients (M:F) aged between 18 and 35 years (mean 24.6) years were assessed. The mean PTI for initial scan group was 0.33% (95% CI: 0.29–0.37; SD: 0.15) and consecutive scan group was 0.30% (CI: 0.27–0.33; SD: 0.3). The difference was not significant (p = 0.097 using a paired t test) with high inter-observer correlation (0.9) in both sets. Spearman’s rho for knee flexion angle and PTI was found to be positive and statistically significant (0.41; p = 0.001). A linear regression model was derived using a scatter chart of change in PTI with change in knee flexion for each patient. The gradient of the linear regression line was used to estimate a cPTI (corrected PTI) value (corrected to 0 degrees of knee flexion), defined as cPTI = PTI – 1.3a (a = knee flexion angle). This study demonstrates high inter-observer correlation of PTI on MRI and high test–retest reliability indicating unconscious quadriceps contraction does not change the index sufficiently. Knee flexion significantly alters PTI, increased patellotrochlear engagement with flexion increases the index. We propose use of the formula cPTI = PTI -1.3a to correct the index to 0 degree knee flexion in clinical practice.

Outcomes after burn have continued to improve over the last 70 years in all age groups including the elderly. However, concerns have been raised that survival gains have not been to the same magnitude in elderly patients compared to younger age groups. The aims of this study were to analyze the recent outcomes of elderly burn injured patients admitted to the Birmingham Burn Centre, compare data with a historical cohort and published data from other burn centres worldwide. A retrospective review was conducted of all patients ≥65 years of age, admitted to our centre with cutaneous burns, between 2004 and 2012. Data was compared to a previously published historical cohort (1999-2003). 228 patients were included. The observed mortality for the study group was 14.9%. The median age of the study group was 79 years, the male to female ratio was 1:1 and median Total Body Surface Area (TBSA) burned was 5%. The incidence of inhalation injury was 13%. Median length of stay per TBSA burned for survivors was 2.4 days/% TBSA. Mortality has improved in all burn size groups, but differences were highly statistically significant in the medium burn size group (10-20% TBSA, p≤0.001). Burn outcomes in the elderly have improved over the last decade. This reduction has been impacted by a reduction in overall injury severity but is also likely due to general improvements in burn care, improved infrastructure, implementation of clinical guidelines and increased multi-disciplinary support, including Geriatric physicians.

Objectives The Fontan procedure provides palliation for patients with complex congenital heart disease. A late complication is the development of a pro-arrhythmogenic environment. Modifications to the surgical technique try and reduce the incidence of late arrhythmia. This study aims to establish incidence and outcome of arrhythmias in Fontan patients with long-term follow-up. Methods Retrospective analysis of adult patients with a Fontan circulation cared for by University Hospitals Birmingham between 2001 and 2013. Results 166 patients, mean age 29.1 years, were identified (63% atriopulmonary (AP) Fontan, 13% lateral tunnel (LT), 24% extracardiac total cavopulmonary connection (TCPC)). The mean follow-up since Fontan surgery was 18.6 years. 42% (70 patients) had suffered at least one tachyarrhythmia, with 100% incidence of arrhythmia in AP Fontan patients surviving at least 26 years following surgery. The most common arrhythmia was intra-atrial re-entrant tachycardia (66%). There was also a significant incidence of arrhythmia in the LT and TCPC groups (23% at mean follow-up of 19.6 years and 13.6 years, respectively). 44 patients had undergone electrical cardioversion, 30 had ablations and 10 had undergone Fontan conversion surgery. Survival analysis showed only age at the time of Fontan as a significant predictor for arrhythmia onset (p Conclusions There is a significant, increasing arrhythmia burden in adult patients with a Fontan circulation. Arrhythmia development could be regarded as an inevitable consequence of an AP Fontan. There remains a high incidence of arrhythmia with more modern surgical approaches. The long-term future of these patients is unclear and their care poses significant challenges.

Objectives The antimicrobial efficacy of an iodine-impregnated incise drape against MRSA was evaluated in a skin model. The permeation of iodine from this drape into the skin was also assessed. Methods The antimicrobial efficacy was evaluated in ex vivo studies following application of the surgical incise drape for various times on the surface of donor skin, which was inoculated with either 1 × 103 or 1 × 106 cfu MRSA/cm2 skin and mounted on Franz diffusion cells. In some experiments the MRSA-inoculated skin was pre-incubated for 18 h at room temperature prior to applying the drape. Permeation of iodine into the skin using this model was also determined following application of the incise drape for 6 h. Results The iodine-impregnated drape demonstrated antimicrobial activity compared with the non-use of drape. This reached significance when a high inoculum of MRSA was applied with no pre-incubation period and when a low inoculum of MRSA was applied with a pre-incubation period (P = 0.002 and P = 0.014, respectively). Furthermore, in experiments wherein a high inoculum of MRSA was applied with no pre-incubation period, the iodine-impregnated drape demonstrated superior antimicrobial activity compared with the use of a non-antimicrobial drape (P Conclusions The iodine-impregnated surgical incise drape had detectable antimicrobial activity. Furthermore, iodine penetrated into the deeper layers of the skin. This property should suppress microbial regrowth at and around a surgical incision site, making its use preferable to the use of a standard drape or non-use of a drape.

BACKGROUND The impact of ethnicity on outcomes after orthotopic liver transplantation (OLT) is unclear. The British Indo-Asian population has a high incidence of liver disease but its contribution to the national deceased donor pool is small. We evaluated access to and outcomes of OLT in Indo-Asians. METHODS We compared 182 Indo-Asians with white patients undergoing OLT. Matching criteria were transplantation year, liver disease, age, sex. Donor and recipient characteristics, postoperative outcomes, including patient and graft survival, OLT era (early, 1987-2001; late, 2002-2011) were compared. Survival was also analyzed by underlying disease-acute liver failure (ALF) and chronic liver failure. RESULTS Indo-Asians had higher diabetes incidence. There were no differences in waiting time for transplantation, despite smaller body size and more uncommon blood groups (B, AB) among Indo-Asians. In the early era, patient survival for Indo-Asians with ALF was worse when compared to whites. In the late era, graft and patient survival at 1, 2, and 5 years were similar between groups. CONCLUSION This study demonstrates that Indo-Asian patients have equal access to OLT and comparable outcomes to whites in the United Kingdom. Survival has improved among Indo-Asian patients; this may be attributable to careful patient selection in case of ALF, though improvement of patient management may have contributed.

This service evaluation analysed the long-term clinical outcomes, as measured by the Pain Self-Efficacy Questionnaire (PSEQ) and Oswestry Disability Index (ODI), of a 12-h group-based, multidisciplinary, combined physical and psychological treatment programme for patients with persistent back pain in a secondary care setting. Between April 2012 and December 2015, 373 patients attended the programme, with outcome measures obtained for 272 patients post-treatment. We randomly selected 120 patients who had completed treatment, for long-term outcome measurement follow-up, and gained outcome measures for 40 patients in total. At a median follow-up of 27 months post-treatment, the results demonstrated significant improvements in both clinical outcome measures. We conclude that a brief combined physical and psychological treatment programme appears to be effective at reducing back disability and pain self-efficacy, with improvements maintained in the longer term.

Background\ud Chlorhexidine (CHG) penetrates poorly into skin. The purpose of this study was to compare the depth of CHG skin permeation from solutions containing either 2% (w/v) CHG and 70% (v/v) isopropyl alcohol (IPA) or 2% (w/v) CHG, 70% (v/v) IPA and 2% (v/v) 1,8-cineole.\ud \ud Methods\ud An ex-vivo study using Franz diffusion cells was carried out. Full thickness human skin was mounted onto the cells and a CHG solution, with or without 2% (v/v) 1,8-cineole was applied to the skin surface. After twenty-four hours the skin was sectioned horizontally in 100 μm slices to a depth of 2000 μm and the concentration of CHG in each section quantified using high performance liquid chromatography (HPLC). The data were analysed with repeated measures analysis of variance.\ud \ud Results\ud The concentration of CHG in the skin on average was significantly higher (33.3% [95%, CI 1.5% - 74.9%]) when a CHG solution which contained 1,8-cineole was applied to the skin compared to a CHG solution which did not contain this terpene (P = 0.042).\ud \ud Conclusions\ud Enhanced delivery of CHG can be achieved in the presence of 1,8-cineole, which is the major component of eucalyptus oil. This may reduce the numbers of microorganisms located in the deeper layers of the skin which potentially could decrease the risk of surgical site infection.

Aims Peer review of contour volume is a priority in the radiotherapy treatment quality assurance process for head and neck cancer. It is essential that incorporation of peer review activity does not introduce additional delays. An on-demand peer review process was piloted to assess the feasibility and efficiency of this approach, as compared with a historic scheduled weekly approach. Materials and methods Between November 2016 and April 2017 four head and neck clinicians in one centre took part in an on-demand peer review process. Cases were of radical or adjuvant intent of any histology and submitted on a voluntary basis. The outcome of contour peer review would be one of unchanged (UC), unchanged with variation or discretion noted (UV), minor change (M) or significant change (S). The time difference between the completion of the on-demand peer review was compared with the time difference to a hypothetical next Monday or Tuesday weekly peer review meeting. The time taken to review each case was also documented in the latter period of the pilot project. Results In total, 62 cases underwent peer review. Peer review on-demand provided dosimetrists with an average of an extra two working days available per case to meet treatment start dates. The proportion of cases with outcomes UC, UV, M and S were 45%, 16%, 26% and 13%, respectively. The mean peer review time spent per case was 17 min (12 cases). The main reason for S was discrepancy in imaging interpretation (4/8 cases). A lower proportion of oropharyngeal cases were submitted and had S outcomes. A higher proportion of complex cases, e.g. sinonasal/nasopharynx location or previous downstaging chemotherapy had S outcomes. The distribution of S outcomes appears to be similar regardless of clinician experience. The level of peer review activity among individuals differed by workload and job timetable. Conclusion On-demand peer review of the head and neck contour volume is feasible, reduces delay to the start of dosimetry planning and bypasses the logistical barriers of weekly meetings. An audit of participation will be required to ensure successful implementation.