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Background: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear. Methods: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aβ2GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I β2GPI (aD1β2GPI) IgG. Findings: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p

Background Beta-blockers are widely used for many cardiovascular conditions; however, their efficacy in contemporary clinical practice remains uncertain. Methods We performed a prospectively designed, umbrella review of meta-analyses of randomised controlled trials (RCTs) investigating the evidence of beta-blockers in the contemporary management of coronary artery disease (CAD), heart failure (HF), patients undergoing surgery or hypertension (registration: PROSPERO CRD42016038375). We searched MEDLINE, EMBASE and the Cochrane Library from inception until December 2018. Outcomes were analysed as beta-blockers versus control for all-cause mortality, myocardial infarction (MI), incident HF or stroke. Two independent investigators abstracted the data, assessed the quality of the evidence and rated the certainty of evidence. Results We identified 98 meta-analyses, including 284 unique RCTs and 1,617,523 patient-years of follow-up. In CAD, 12 meta-analyses (93 RCTs, 103,481 patients) showed that beta-blockers reduced mortality in analyses before routine reperfusion, but there was a lack of benefit in contemporary studies where ≥ 50% of patients received thrombolytics or intervention. Beta-blockers reduced incident MI at the expense of increased HF. In HF with reduced ejection fraction, 34 meta-analyses (66 RCTs, 35,383 patients) demonstrated a reduction in mortality and HF hospitalisation with beta-blockers in sinus rhythm, but not in atrial fibrillation. In patients undergoing surgery, 23 meta-analyses (89 RCTs, 19,211 patients) showed no effect of beta-blockers on mortality for cardiac surgery, but increased mortality in non-cardiac surgery. In non-cardiac surgery, beta-blockers reduced MI after surgery but increased the risk of stroke. In hypertension, 27 meta-analyses (36 RCTs, 260,549 patients) identified no benefit versus placebo, but beta-blockers were inferior to other agents for preventing mortality and stroke. Conclusions Beta-blockers substantially reduce mortality in HF patients in sinus rhythm, but for other conditions, clinicians need to weigh up both benefit and potential risk.

There is concern that the development of heart failure and atrial fibrillation has a detrimental influence on clinical outcomes. The aim of this study was to assess all-cause mortality and length of hospital stay in patients with chronic and new-onset concomitant AF and HF.Using the ACALM registry, we analysed adults hospitalised between 2000 and 2013 with AF and HF and assessed prevalence, mortality and length of hospital stay. Patients with HF and/or AF at baseline (study-entry) were compared with patients who developed new-onset disease during follow-up.Of 929,552 patients, 31,695 (3.4%) were in AF without HF, 20,768 (2.2%) had HF in sinus rhythm, and 10,992 (1.2%) had HF in AF. Patients with HF in AF had the greatest all-cause mortality (70.8%), followed by HF in sinus rhythm (64.1%) and AF alone (45.1%, p0.0001). Patients that developed new-onset AF, HF or both had significantly worse mortality (58.5%, 70.7% and 74.8% respectively) compared to those already with the condition at baseline (48.5%, 63.7% and 67.2% respectively, p0.0001). Patients with HF in AF had the longest length of hospital stay (9.41days, 95% CI 8.90-9.92), followed by HF in sinus rhythm (7.67, 95% CI 7.34-8.00) and AF alone (6.05, 95% CI 5.78-6.31).Patients with HF in AF are at a greater risk of mortality and longer hospital stay compared to patients without the combination. New-onset AF or HF is associated with significantly worse prognosis than long-standing disease.

Current myocarditis guidelines do not advocate treatment to prevent myocardial injury and scar deposition in patients with myocarditis and normal left ventricular ejection fraction. We aimed to ascertain the utility of beta blockers, calcium channel blockers and antagonists of the renin–angiotensin system in ameliorating myocardial injury, scar formation and calcification in animal in vivo models of myocarditis. The project was prospectively registered with the PROSPERO database of systematic reviews (CRD42018089336). Primary outcomes (necrosis, fibrosis and calcification) were meta-analysed with random-effects modelling. 52 studies were systematically reviewed. Meta-analysis was performed compared with untreated controls. In each study, we identified all independent comparisons of treatment versus control groups. The pooled weighted mean difference (WMD) indicated treatment reduced necrosis by 16.9% (71 controlled analyses, 95% CI 13.2–20.7%; P

Background: Renal transplant recipients (RTRs) are often Vitamin D (VitD) depleted as a result of both chronic kidney disease and mandated sun avoidance behaviours. Repleting VitD may be warranted, but how, and for how long, is unknown, as is the impact of seasonality on the success of repletion. We investigated the impact of seasonality on VitD status following VitD repletion in a large cohort of stable, long-term RTRs. Methods: Serum 25-hydroxyvitamin D [25(OH)D] concentrations and bone biochemistry parameters were analysed from 102 VitD repletion courses in 98 RTRs that had undergone VitD repletion. Repletion was delivered over 6 months with either 240 000 IU colecalciferol if pre-repletion serum VitD was between 20 and 50 nmol/L, or with 360 000 IU if VitD was

Overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of heart failure (HF) and chronic kidney disease (CKD). RAAS antagonists can significantly improve clinical outcomes, but monotherapy blocks but one step of the RAAS and can be bypassed through compensatory mechanisms. Providing more complete RAAS blockade by deploying drugs with complementary actions seemed logical - hence the practice of using dual (or triple) RAAS inhibitors. However, RAAS antagonists also exhibit dose-limiting side effects, including acute kidney injury, hyperkalaemia and hypotension, which blunt their overall effectiveness. Despite achieving better RAAS blockade, several trials failed to show clinical outcome improvements. Patients with concomitant CKD and HF (cardiorenal syndrome) are at the greatest risk of these adverse events and therefore the least able to benefit, yet they also have the worst prognosis. This paradox, where those most in need have fewest therapeutic options, poses three questions which are the focus of this review: whether (i) novel therapies that prevent adverse effects can restore therapeutic benefits to patients who would otherwise be RAAS-therapy intolerant, (ii) there are any validated alternatives to their use and (iii) newer approaches to the detection of fluid congestion are ready for implementation.

ObjectiveWhether statins increase the risk of intracerebral haemorrhage (ICH) in patients with a previous stroke remains uncertain. This study addresses the evidence of statin therapy on ICH and other clinical outcomes in patients with previous ischaemic stroke (IS) or ICH.MethodsA systematic literature review and meta-analysis was performed in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to assess observational and randomised studies comparing statin therapy with control (placebo or no treatment) in patients with a previous ICH or IS. The risk ratios (RR) for the primary outcome (ICH) and secondary outcomes (IS, any stroke, mortality and function) were pooled using random effects meta-analysis according to stroke subtype.ResultsForty-three studies with a combined total of 317 291 patient-years of follow-up were included. In patients with previous ICH, statins had no significant impact on the pooled RR for recurrent ICH (1.04, 95% CI 0.86 to 1.25; n=23 695); however, statins were associated with significant reductions in mortality (RR 0.49, 95% CI 0.36 to 0.67; n=89 976) and poor functional outcome (RR 0.71, 95% CI 0.67 to 0.75; n=9113). In patients with previous IS, statins were associated with a non-significant increase in ICH (RR 1.36, 95% CI 0.96 to 1.91; n=103 525), but significantly lower risks of recurrent IS (RR 0.74, 95% CI 0.66 to 0.83; n=53 162), any stroke (RR 0.82, 95% CI 0.67 to 0.99; n=55 260), mortality (RR 0.68, 95% CI 0.50 to 0.92; n=74 648) and poor functional outcome (RR 0.83, 95% CI 0.76 to 0.91; n=34 700).ConclusionsIrrespective of stroke subtype, there were non-significant trends towards future ICH with statins. However, this risk was overshadowed by substantial and significant improvements in mortality and functional outcome among statin users.Trial registration numberCRD42017079863.

Islet transplantation is an effective means of treating severe type 1 diabetes in patients with life-threatening hypoglycemia. Improvements in glycemic control with correction of HbA1C enhance quality of life irrespective of insulin independence. By antagonizing the Natural Killer Group 2, member D (NKG2D) receptor expression on NK and CD8+ T cells, in combination with blocking CTLA-4 binding sites, we demonstrate a significant delay of graft rejection in islet allotransplant. Anti-NKG2D combined with CTLA-4 Ig (n = 15) results in prolonged allograft survival, with 84.6 ± 10% of the recipients displaying insulin independence compared to controls (n = 10, p

Chronic catecholamine production is associated with desensitisation and down-regulation of adrenergic receptors and occurs in conditions, such as heart failure and myocardial infarction. The effects of further acute adrenergic stimulation, which may occur during exercise, and their subsequent effects on chemosensitivity and ventilation are unclear. Chronic isoprenaline (ISO) increased ventilation by 50 % (P

Since the initial reporting of the successful reversal of hyperglycemia through the transplantation of pancreatic islets, significant research efforts have been conducted in elucidating the process of revascularization and the influence of engraftment site on graft function and survival. During the isolation process the intrinsic islet vascular networks are destroyed, leading to impaired revascularization after transplant. As a result, in some cases a significant quantity of the beta cell mass transplanted dies acutely following the infusion into the portal vein, the most clinically used site of engraftment. Subsequently, despite the majority of patients achieving insulin independence after transplant, a proportion of them recommence small, supplemental exogenous insulin over time. Herein, this review considers the process of islet revascularization after transplant, its limiting factors, and potential strategies to improve this critical step. Furthermore, we provide a characterization of alternative transplant sites, analyzing the historical evolution and their role towards advancing transplant outcomes in both the experimental and clinical settings.

Background Atrial Fibrillation (AF) and Heart Failure (HF) frequently co-exist conferring considerable morbidity and mortality, yet current treatment options remain limited. Recent meta-analyses of patients with concomitant AF and HF have suggested no prognostic benefit of beta-blockers or digoxin, creating a paradox whereby those most in need have the fewest therapeutic choices. We sought to investigate the association between HF and AF and their impact on mortality from a large 14-year naturalistic follow-up study. Methods Anonymous data of adult patients aged ≥18 with all types of HF and AF admitted to several hospitals in the North of England between 2000 and 2013 was obtained and processed using the ACALM (Algorithm for Co-morbidity, Associations, Length of stay and Mortality) study protocol. ACALM uses the ICD-10 and OPCS-4 coding systems to identify patients and the methodology has been published widely. Analyses were performed comparing mortality between patients with HF, AF and combined HF and AF at baseline and their development during follow-up. Results At baseline, of 929,552 adult patients 29,164 (3.1%) had AF, 19,474 (2.1%) had HF, and 5,728 (0.6%) had both HF and AF. Of those with AF at baseline, 1,647 (5.6%) developed HF during follow-up, and of those with HF at baseline, 824 (4.2%) developed AF during follow-up. Demographics and crude mortality rates are shown; see Table. Patients with combined AF and HF at baseline had increased mortality than patients with AF or HF alone. Patients with AF at baseline that developed HF, and patients with HF at baseline that developed AF, experienced a greater mortality compared to those with combined HF and AF at baseline; see Figure. Conclusion Concomitant AF and HF is associated with substantial mortality and risk of death, irrespective of which disease develops first. In light of limited current treatment for these patients, future therapies to specifically target the combined HF and AF group are required.

Objective To clarify the impact of digoxin on death and clinical outcomes across all observational and randomised controlled trials, accounting for study designs and methods. Data sources and study selection Comprehensive literature search of Medline, Embase, the Cochrane Library, reference lists, and ongoing studies according to a prospectively registered design (PROSPERO: CRD42014010783), including all studies published from 1960 to July 2014 that examined treatment with digoxin compared with control (placebo or no treatment). Data extraction and synthesis Unadjusted and adjusted data pooled according to study design, analysis method, and risk of bias. Main outcome measures Primary outcome (all cause mortality) and secondary outcomes (including admission to hospital) were meta-analysed with random effects modelling. Results 52 studies were systematically reviewed, comprising 621 845 patients. Digoxin users were 2.4 years older than control (weighted difference 95% confidence interval 1.3 to 3.6), with lower ejection fraction (33% v 42%), more diabetes, and greater use of diuretics and anti-arrhythmic drugs. Meta-analysis included 75 study analyses, with a combined total of 4 006 210 patient years of follow-up. Compared with control, the pooled risk ratio for death with digoxin was 1.76 in unadjusted analyses (1.57 to 1.97), 1.61 in adjusted analyses (1.31 to 1.97), 1.18 in propensity matched studies (1.09 to 1.26), and 0.99 in randomised controlled trials (0.93 to 1.05). Meta-regression confirmed that baseline differences between treatment groups had a significant impact on mortality associated with digoxin, including markers of heart failure severity such as use of diuretics (P=0.004). Studies with better methods and lower risk of bias were more likely to report a neutral association of digoxin with mortality (P

Background Digoxin use in heart failure and atrial fibrillation are common but declining, and remain the subject of conflicting clinical viewpoints. Recent observational studies have suggested increased mortality in patients receiving digoxin. We sought to clarify the impact of digoxin on clinical events, accounting for study designs, methodology and potential bias, regardless of clinical indication. Methods A comprehensive search of Medline, Embase and Cochrane from 1960 onwards identified 59 studies. 40 studies were suitable for meta-analysis with 67 study analyses comparing digoxin with either placebo or no treatment: 34 unadjusted, 19 adjusted, 10 propensity-matched and 4 randomised controlled trials (RCTs). All-cause mortality was meta-analysed using a random effects model according to study design and the review was prospectively registered (PROSPERO: CRD42014010783). Results 467,273 patients were included for meta-analysis. Those treated with digoxin were 2.4 years older than control (weighted difference; 95% CI 1.3–3.5) with lower ejection fraction (33% vs. 42%) and more diabetes. Concomitant use of diuretics and anti-arrhythmic drugs (AAD) was also greater with digoxin therapy (see Table 1). Compared to control, the pooled risk ratio for death in digoxin-treated patients was 1.7 in unadjusted observational analysis (95% CI 1.5–2.0), 1.9 in adjusted observational analyses (95% CI 1.5–2.3), 1.1 in propensity-matched analyses (95% CI 1.0–1.4) and 1.0 in RCTs (95% CI 0.9–1.1); see Figure 1. Meta-regression of observational studies confirmed that differences between treatment arms had a significant impact on the risk associated with digoxin use, including diabetes (p = 0.01), diuretics (p = 0.001), and AAD (p = 0.01); see Figure 2. Conclusion Digoxin is not associated with increased mortality in RCTs. The impact of digoxin on clinical outcomes should not be assessed in observational studies due to fundamental differences in patients receiving treatment. Future RCTs are crucial to accurately estimate the clinical value of digoxin therapy on clinical outcomes.