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SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1β, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPβ (p = 0.03) as well as amyloid β (Aβ) 40 (p = 5.2 × 10

Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response.

We recently described aberrantly increased cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as new hallmarks of amyotrophic lateral sclerosis (ALS). However, the generalizability and potential roles of cytoplasmic IRTs in health and disease remain unclear. Here, using time-resolved deep sequencing of nuclear and cytoplasmic fractions of human induced pluripotent stem cells undergoing motor neurogenesis, we reveal that ALS-causing VCP gene mutations lead to compartment-specific aberrant accumulation of IRTs. Specifically, we identify >100 IRTs with increased cytoplasmic abundance in ALS samples. Furthermore, these aberrant cytoplasmic IRTs possess sequence-specific attributes and differential predicted binding affinity to RNA binding proteins. Remarkably, TDP-43, SFPQ and FUS—RNA binding proteins known for nuclear-to-cytoplasmic mislocalization in ALS—abundantly and specifically bind to this aberrant cytoplasmic pool of IRTs. Our data are therefore consistent with a novel role for cytoplasmic IRTs in regulating compartment-specific protein abundance. This study provides new molecular insight into potential pathomechanisms underlying ALS and highlights aberrant cytoplasmic IRTs as potential therapeutic targets., Aberrant cytoplasmic SFPQ intron-retaining transcripts (IRTs) have recently been described in ALS, but their roles remained unclear. Tyzack, Neeves et al. now identify >100 cytoplasmic IRTs and show that they are ‘blueprints’ for ALS-related RNA binding protein mislocalization, as well as potential therapeutic targets.

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

Astrocytes contribute to motor neuron death in amyotrophic lateral sclerosis (ALS), but whether they adopt deleterious features consistent with inflammatory reactive states remains incompletely resolved. To identify inflammatory reactive features in ALS human induced pluripotent stem cell (hiPSC)–derived astrocytes, we examined transcriptomics, proteomics, and glutamate uptake in VCP-mutant astrocytes. We complemented this by examining other ALS mutations and models using a systematic meta-analysis of all publicly-available ALS astrocyte sequencing data, which included hiPSC-derived astrocytes carrying SOD1, C9orf72, and FUS gene mutations as well as mouse ALS astrocyte models with SOD1G93A mutation, Tardbp deletion, and Tmem259 (also known as membralin) deletion. ALS astrocytes were characterized by up-regulation of genes involved in the extracellular matrix, endoplasmic reticulum stress, and the immune response and down-regulation of synaptic integrity, glutamate uptake, and other neuronal support processes. We identify activation of the TGFB, Wnt, and hypoxia signaling pathways in both hiPSC and mouse ALS astrocytes. ALS changes positively correlate with TNF, IL1A, and complement pathway component C1q-treated inflammatory reactive astrocytes, with significant overlap of differentially expressed genes. By contrasting ALS changes with models of protective reactive astrocytes, including middle cerebral artery occlusion and spinal cord injury, we uncover a cluster of genes changing in opposing directions, which may represent down-regulated homeostatic genes and up-regulated deleterious genes in ALS astrocytes. These observations indicate that ALS astrocytes augment inflammatory processes while concomitantly suppressing neuronal supporting mechanisms, thus resembling inflammatory reactive states and offering potential therapeutic targets.

Reactive astrocytes are implicated in amyotrophic lateral sclerosis (ALS), although the mechanisms controlling reactive transformation are unknown. We show that decreased intron retention (IR) is common to human-induced pluripotent stem cell (hiPSC)-derived astrocytes carrying ALS-causing mutations in VCP, SOD1 and C9orf72. Notably, transcripts with decreased IR and increased expression are overrepresented in reactivity processes including cell adhesion, stress response and immune activation. This was recapitulated in public-datasets for (i) hiPSC-derived astrocytes stimulated with cytokines to undergo reactive transformation and (ii) in vivo astrocytes following selective deletion of TDP-43. We also re-examined public translatome sequencing (TRAP-seq) of astrocytes from a SOD1 mouse model, which revealed that transcripts upregulated in translation significantly overlap with transcripts exhibiting decreased IR. Using nucleocytoplasmic fractionation of VCP mutant astrocytes coupled with mRNA sequencing and proteomics, we identify that decreased IR in nuclear transcripts is associated with enhanced nonsense mediated decay and increased cytoplasmic expression of transcripts and proteins regulating reactive transformation. These findings are consistent with a molecular model for reactive transformation in astrocytes whereby poised nuclear reactivity-related IR transcripts are spliced, undergo nuclear-to-cytoplasmic translocation and translation. Our study therefore provides new insights into the molecular regulation of reactive transformation in astrocytes., Graphical Abstract Graphical abstractHealthy astrocytes (left, blue) have prevalent nuclear intron retention in reactivity transcripts, promoting their nuclear confinement (introns shown as red rectangles). Conversely, ALS astrocytes (right, red) exhibit decreased intron retention in reactivity transcripts, enabling cytoplasmic translocation and translation upon engaging ribosomes, underlying their reactive transformation. A small number of intron retaining transcripts escape to the cytoplasm where they are degraded by nonsense mediated decay (NMD), which is enhanced in ALS astrocytes.

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterised neurological syndromes involving the peripheral and central nervous system (n = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with (n = 94) and without (n = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with central nervous system inflammation (encephalitis and acute disseminated encephalomyelitis) (14800pg/mL [400, 32400]), compared to those with encephalopathy (1410pg/mL [756, 1446], peripheral syndromes (GBS) (740pg/mL [507, 881]) and controls (872pg/mL [654,1200]). Serum neurofilament light levels were elevated across patients hospitalised with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19., Graphical Abstract Graphical Abstract

SUMMARYWe recently described aberrant cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as a new hallmark of amyotrophic lateral sclerosis (ALS). However the generalizability and potential roles of cytoplasmic IRTs in health and disease remain unclear. Here, using time-resolved deep-sequencing of nuclear and cytoplasmic fractions of hiPSCs undergoing motor neurogenesis, we reveal that ALS-causing VCP gene mutations lead to compartment-specific aberrant accumulation of IRTs. Specifically, we identify >100 IRTs with increased cytoplasmic (but not nuclear) abundance in ALS samples. Furthermore, these aberrant cytoplasmic IRTs possess sequence-specific attributes and differential predicted binding affinity to RNA binding proteins (RBPs). Remarkably, TDP-43, SFPQ and FUS – RBPs known for nuclear-to-cytoplasmic mislocalization in ALS – avidly and specifically bind to this aberrant cytoplasmic pool of IRTs, as opposed to any individual IRT. Our data are therefore consistent with a novel role for cytoplasmic IRTs in regulating compartment-specific protein abundance. This study provides new molecular insight into potential pathomechanisms underlying ALS and highlights aberrant cytoplasmic IRTs as potential therapeutic targets.Abstract Figure

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome is a rare multisystem disease associated with a plasma-cell dyscrasia. Although pachymeningeal involvement has occasionally been described, MRI of the central nervous system (CNS) has not yet been extensively investigated. We retrospectively evaluated CNS MRI in Europe’s largest single-center cohort of POEMS syndrome. Of 77 patients who have been formally diagnosed with POEMS, 41 had MRI brain and 29 had MRI spine. A control group of 33 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) was used as this is the major differential diagnosis. Of these CIDP patients, 12 underwent both MRI brain and spine, 7 had solely MRI brain and 14 had MRI spine. In 41 POEMS patients with MRI brain, we identified frequent smooth, diffuse meningeal thickening of the cerebral convexities and falx (n = 29, 71%), of which 4 had meningeal collections. 17 (41%) had vascular abnormalities including white-matter disease, of which 4 had established infarcts. Of 29 patients with MRI spine, 17 (59%) had thickening of the brachial and lumbosacral plexus. Conversely in 19 CIDP patients with MRI brain, none had meningeal thickening (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.

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.

We would like to commend Rahman et al for their work highlighting the reasons for delays in inpatient consultations.1 The authors found that miscommunication between referring and receiving teams was responsible for 34% of all delays each with an average delay of 1.6 days in length of stay (combining communication and power dynamic categories). Miscommunication is avoidable and modifiable and should become a priority target for quality improvement projects. At University College London Hospital, in Neurology, we have switched from a mobile phone service to an email referral system in November 2018. We quantitatively evaluated both the phone call-log in October 2018 and the new referral email inbox in January 2019 (table 1). With our phone system, 63% of incoming calls were missed and 44% of outgoing calls were …

AIMS: To examine the association between statin use before and after intracranial haemorrhage (ICH) and the risk of poststroke epilepsy (PSE). METHODS: Patients with new‐onset ICH between 2004 and 2012 were identified from the Taiwan National Health Insurance Research Database. The main outcome was the occurrence of epilepsy after stroke. Multivariable Cox regression modelling was used to estimate the association between statin use and the risk of PSE, with poststroke medication exposures being treated as time‐dependent variables. RESULTS: A total of 7435 patients with ICH were enrolled with a median follow‐up of 17.6 months. Within the study cohort, 709 patients developed PSE. Poststroke, but not prestroke, stain use was associated with a reduced risk of PSE (adjusted hazard ratio 0.62, 95% confidence interval 0.42–0.90, P = 0.01). In subanalyses, a trend of a dose–response relationship was observed. A significant PSE risk reduction was correlated with a higher cumulative statin dose. Moreover, the risk of PSE was lower in patients receiving moderate‐to‐high‐intensity statin therapy (adjusted hazard ratio 0.37, 95% confidence interval 0.18–0.75, P = 0.01). Lipophilic and hydrophilic statins were similar with regard to their associations with the reduced risk of PSE. CONCLUSIONS: Statin therapy may reduce the risk of PSE after ICH, especially with moderate‐to‐high therapy intensity. Further research is needed to understand the mechanisms underlying the potential protective effects of statins against PSE in this patient population.

Atrial fibrillation (AF) is the most common arrhythmia worldwide. The prevalence of AF in persons older than 55 years is at least 33.5 million globally and is predicted to more than double in the next half-century. Anticoagulation, heart rate control, and heart rhythm control comprise the 3 main treatment strategies in AF. Anticoagulation is aimed at preventing debilitating stroke, systemic embolism, and associated mortality. Historically, anticoagulation in AF was achieved with a vitamin K antagonist such as warfarin, which is supported by evidence demonstrating reduced incident stroke and all-cause mortality. However, warfarin has unpredictable pharmacokinetics with many drug-drug interactions that require regular monitoring to ensure patients remain in the therapeutic anticoagulant range. Non–vitamin K antagonist oral anticoagulants including dabigatran, rivaroxaban, apixaban, and edoxaban provide a possible solution to these issues with their more predictable pharmacokinetics, rapid onset of action, and greater specificity. Results from large randomized, controlled trials indicate that these agents are at least noninferior to warfarin in prevention of stroke. These trials also demonstrate a consistently lower incidence of intracranial hemorrhage, almost always all life-threatening bleeds, and many forms of major bleeds with the possible exception of gastrointestinal and some other forms of mucosal bleeding, compared with warfarin. Patients with AF are a heterogeneous population with diverse risk of stroke and bleeding, and different subgroups respond differently to anticoagulation. Important clinical questions have arisen regarding optimal anticoagulation drug selection in distinct populations such as those with renal impairment, older age, coronary artery disease, and heart failure as well as those at particularly high risk for bleeding or thromboembolism. In this review, treatment strategies in AF management are discussed in the context of different individual subgroups of patients.

Background: Some previous studies have reported that survivors of childhood cancer are at an increased risk of developing long-term mental health morbidity, whilst others have reported that this is not the case. Therefore, we analysed 5-year survivors of childhood cancer using the British Childhood Cancer Survivor Study (BCCSS) to determine the risks of aspects of long-term mental health dysfunction. Procedure: Within the BCCSS, 10 488 survivors completed a questionnaire that ascertained mental health-related information via 10 questions from the Short Form-36 survey. Internal analyses were conducted using multivariable logistic regression to determine risk factors for mental health dysfunction. External analyses were undertaken using direct standardisation to compare mental health dysfunction in survivors with UK norms. Results: This study has shown that overall, childhood cancer survivors had a significantly higher prevalence of mental health dysfunction for 6/10 questions analysed compared to UK norms. Central nervous system (CNS) and bone sarcoma survivors reported the greatest dysfunction, compared to expected, with significant excess dysfunction in 10 and 6 questions, respectively; the excess ranged from 4.4–22.3% in CNS survivors and 6.9–15.9% in bone sarcoma survivors. Compared to expected, excess mental health dysfunction increased with attained age; this increase was greatest for reporting ‘limitations in social activities due to health', where the excess rose from 4.5% to 12.8% in those aged 16–24 and 45+, respectively. Within the internal analyses, higher levels of educational attainment and socio-economic classification were protective against mental health dysfunction. Conclusions: Based upon the findings of this large population-based study, childhood cancer survivors report significantly higher levels of mental health dysfunction than those in the general population, where deficits were observed particularly among CNS and bone sarcoma survivors. Limitations were also observed to increase with age, and thus it is important to emphasise the need for mental health evaluation and services across the entire lifespan. There is evidence that low educational attainment and being unemployed or having never worked adversely impacts long-term mental health. These findings provide an evidence base for risk stratification and planning interventions.

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.

Heart failure is rapidly increasing in prevalence and will redraw the global landscape for cardiovascular health. Alleviating and repairing cardiac injury associated with myocardial infarction (MI) is key to improving this burden. Homing signals mobilize and recruit stem cells to the ischaemic myocardium where they exert beneficial paracrine effects. The chemoattractant cytokine SDF-1α and its associated receptor CXCR4 are upregulated after MI and appear to be important in this context. Activation of CXCR4 promotes both cardiomyocyte survival and stem cell migration towards the infarcted myocardium. These effects have beneficial effects on infarct size, and left ventricular remodelling and function. However, the timing of endogenous SDF-1α release and CXCR4 upregulation may not be optimal. Furthermore, current ELISA-based assays cannot distinguish between active SDF-1α, and SDF-1α inactivated by dipeptidyl peptidase 4 (DPP4). Current therapeutic approaches aim to recruit the SDF-1α-CXCR4 pathway or prolong SDF-1α life-time by preventing its cleavage by DPP4. This review assesses the evidence supporting these approaches and proposes SDF-1α as an important confounder in recent studies of DPP4 inhibitors.

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.

The potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy.Our primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8-26.9%), when compared with untreated controls (P 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1-25.3%; P 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization.RIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition that is invariably fatal, usually within 3 to 5 years of diagnosis. The etiology of ALS remains unresolved and no effective treatments exist. There is therefore a desperate and unmet need for discovery of disease mechanisms to guide novel therapeutic strategies. The single major risk factor for ALS is aging, yet the molecular consequences of cell type‐specific aging remain understudied in this context. Induced pluripotent stem cells (iPSCs) have transformed the standard approach of examining human disease, generating unlimited numbers of disease‐relevant cells from patients, enabling analysis of disease mechanisms and drug screening. However, reprogramming patient cells to iPSCs reverses key hallmarks of cellular age. Therefore, although iPSC models recapitulate some disease hallmarks, a crucial challenge is to address the disparity between the advanced age of onset of neurodegenerative diseases and the fetal‐equivalent maturational state of iPSC‐derivatives. Increasing recognition of cell type‐specific aging paradigms underscores the importance of heterogeneity in ultimately tipping the balance from a state of compensated dysfunction (clinically pre‐symptomatic) to decompensation and progression (irreversible loss of neurological functions). In order to realize the true promise of iPSC technology in ALS, efforts need to prioritize faithfully recapitulating the clinical pathophysiological state, with proportionate emphasis on capturing the molecular sequelae of both cellular age and non‐cell‐autonomous disease mechanisms within this context.

The abstract has also been presented as an oral presentation at the ESOC conference.Background and aimsObservational studies have suggested increased risk of intracranial haemorrhage (ICrH) in patients receiving selective serotonin reuptake inhibitors (SSRI). We sought to clarify the impact of SSRI on ICrH, accounting for study methodology.MethodA comprehensive search of Medline, Embase and Cochrane from 1960 to December 2017 comparing SSRI with control. ICrH was meta-analysed using a random-effects model and the review was prospectively registered (PROSPERO:CRD42017084513).Results25 observational studies, but no randomised trials, were available for meta-analysis, with a combined total of 4,843,857 patient-years follow-up. Those treated with SSRI were more likely to have depression (pConclusionSSRI are associated with increased risk of first-ever ICrH, but not with recurrence. These findings, based solely on observational data, should be taken with caution due to fundamental differences in patients receiving treatment, highlighting the need for randomised trials.

Dear SirWe read with interest the article published by Gooi & Sommerfeld (2015), suggesting a new era of medical school, “Medical School 2.0”, that can be achieved by developing a student-generated...

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.

Structural learning theory suggests that experiencing motor task variation enables the central nervous system to extract general rules regarding tasks with a similar structure—rules that can subsequently be applied to novel situations. Complex minimally invasive surgery (MIS) requires different port sites, but switching ports alters the limb movements required to produce the same endpoint control of the surgical instrument. The purpose of the present study was to determine if structural learning theory can be applied to MIS to inform training methods. A tablet laptop running bespoke software was placed within a laparoscopic box trainer and connected to a monitor situated at eye level. Participants (right-handed, non-surgeons, mean age = 23.2 years) used a standard laparoscopic grasper to move between locations on the screen. There were two training groups: the M group (n = 10) who trained using multiple port sites, and the S group (n = 10) who trained using a single port site. A novel port site was used as a test of generalization. Performance metrics were a composite of speed and accuracy (SACF) and normalized jerk (NJ; a measure of movement ‘smoothness’). The M group showed a statistically significant performance advantage over the S group at test, as indexed by improved SACF (p

Background Venous thromboembolism (VTE) is the most common preventable cause of death with safe and effective prevention measures available. Inpatients at high risk for VTE often fail to be provided prophylaxis despite clear guidelines and this mismatch between VTE prophylaxis and thromboembolic risk is a major issue for clinicians. We sought to clarify compliance of practice with the NICE quality standard and to assess accuracy of the Commissioning for Quality and Innovation (CQUIN) VTE form. Methods A point prevalence study was performed involving a comprehensive review of 100 consecutive patients at Barnet Hospital. We assessed compliance against the NICE guideline 92 by ensuring appropriate assessment of VTE and bleeding risk, clarifying that those where the VTE risk outweighs the bleeding risk are offered prophylaxis. We also assessed the accuracy of VTE risk assessment form completion using validated bleeding risk (HASBLED) and VTE risk (Wells) scores. We implemented technical improvements in the VTE risk assessment form; medical education through mandatory completion of VTE eLearning modules; and involvement of the MDT through grand round discussions. Following implementation, a reaudit of 50 patients was performed. Results In 100 patients assessed, mean age was 71 years, 55 were male, with mean weight 74.8kg; see Table 1. Based on the drug chart, VTE prophylaxis was appropriately offered in 69% of patients; see Figure 1. The VTE risk assessment form was accurately completed in 57% for VTE risk status, in 69% for bleeding risk, and in 69% for VTE prophylaxis prescribed. After implementations, the reaudit revealed VTE prophylaxis was appropriate in 88%, VTE risk assessment form was accurate in 78% for VTE risk status, 90% for bleeding risk, and 89% for VTE prophylaxis prescribed. The section of the drug chart devoted to VTE risk assessment was poorly utilised; 21% in the initial audit and 18% in the reaudit. Conclusion Whilst single centre and modest in size, this robust, complete audit demonstrated compliance with VTE prophylaxis guidelines was poor, for both risk assessment and appropriate prescribing. Technical improvements to the VTE form, educating trainees and involving the MDT significantly improved compliance with guidelines. Future work is required to overcome accuracy issues of form completion ensuring patients receive optimal care.

We have observed that junior doctors appear reluctant to attempt a diagnosis nowadays and tend to leave the diagnosis box in the clerking form blank, or record a descriptive term, eg ‘collapse ?cause’. This absence could lead to a delay in appropriate treatment or non-specific use of broad

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

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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.