The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.

Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic ß-amyloid (Aß)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.

Randomised controlled trials of antihypertensive therapy: does exclusion of orthostatic hypotension alter treatment effect? A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Management of antihypertensive therapy is challenging in patients with symptomatic orthostatic hypotension, a population often excluded from randomised controlled trials of antihypertensive therapy. In this systematic review and meta-analysis, we sought to determine whether the association of antihypertensive therapy and adverse events (e.g. falls, syncope), differed among trials that included or excluded patients with orthostatic hypotension. METHODS: We performed a systematic review and meta-analysis of randomised controlled trials comparing blood pressure lowering medications to placebo, or different blood pressure targets on falls or syncope outcomes and cardiovascular events. A random-effects meta-analysis was used to estimate a pooled treatment-effect overall in subgroups of trials that excluded patients with orthostatic hypotension and trials that did not exclude patients with orthostatic hypotension, and tested P for interaction. The primary outcome was fall events. RESULTS: 46 trials were included, of which 18 trials excluded orthostatic hypotension and 28 trials did not. The incidence of hypotension was significantly lower in trials that excluded participants with orthostatic hypotension (1.3% versus 6.2%, P < 0.001) but not incidences of falls (4.8% versus 8.8%; P = 0.40) or syncope (1.5% versus 1.8%; P = 0.67). Antihypertensive therapy was not associated with an increased risk of falls in trials that excluded (OR 1.00, 95% CI; 0.89-1.13) or included (OR 1.02, 95% CI; 0.88-1.18) participants with orthostatic hypotension (P for interaction = 0.90). CONCLUSIONS: The exclusion of patients with orthostatic hypotension does not appear to affect the relative risk estimates for falls and syncope in antihypertensive trials.

Association of Oral Anticoagulation With Stroke in Atrial Fibrillation or Heart Failure: A Comparative Meta-Analysis.

Background and Purpose: Atrial fibrillation and heart failure with reduced ejection fraction (HFrEF) are common sources of cardioembolism. While oral anticoagulation is strongly recommended for atrial fibrillation, there are marked variations in guideline recommendations for HFrEF due to uncertainty about net clinical benefit. This systematic review and meta-analysis evaluates the comparative association of oral anticoagulation with stroke and other cardiovascular risk in populations with atrial fibrillation or HFrEF in sinus rhythm and identify factors mediating different estimates of net clinical benefit. Methods: PubMed and Embase were searched from database inception to November 20, 2019 for randomized clinical trials comparing oral anticoagulation to control. A random-effects meta-analysis was used to estimate a pooled treatment-effect overall and within atrial fibrillation and HFrEF trials. Differences in treatment effect were assessed by estimating I2 among all trials and testing the between-trial-population P-interaction. The primary outcome measure was all stroke. Secondary outcome measures were ischemic stroke, hemorrhagic stroke, mortality, myocardial infarction, and major hemorrhage. Results: Twenty-one trials were eligible for inclusion, 15 (n=19 332) in atrial fibrillation (mean follow-up: 23.1 months), and 6 (n=9866) in HFrEF (mean follow-up: 23.9 months). There were differences in primary outcomes between trial populations, with all-cause mortality included for 95.2% of HFrEF trial population versus 0.38% for atrial fibrillation. Mortality was higher in controls groups of HFrEF populations (19.0% versus 9.6%) but rates of stroke lower (3.1% versus 7.0%) compared with atrial fibrillation. The association of oral anticoagulation with all stroke was consistent for atrial fibrillation (odds ratio, 0.51 [95% CI, 0.42­0.63]) and HFrEF (odds ratio, 0.61 [95% CI, 0.47­0.79]; I2=12.4%; P interaction=0.31). There were no statistically significant differences in the association of oral anticoagulation with cardiovascular events, mortality or bleeding between populations. Conclusions: The relative association of oral anticoagulation with stroke risk, and other cardiovascular outcomes, is similar for patients with atrial fibrillation and HFrEF. Differences in the primary outcomes employed by trials in HFrEF, compared with atrial fibrillation, may have contributed to differing conclusions of the relative efficacy of oral anticoagulation.

Stroke Severity in Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement: A Systematic Review and Meta-Analysis.

OBJECTIVES: An assessment of the comparative incidence of fatal or disabling stroke may influence choice of intervention for patients with severe aortic stenosis. We explored whether transcatheter aortic valve implantation (TAVI) is associated with a lower incidence of fatal or disabling stroke, compared to surgical aortic valve replacement (SAVR). MATERIALS & METHODS: We classified stroke into two categories; fatal or disabling, or non-disabling, and completed meta-analyses for each. We explored randomised controlled trials to assess the effect publication year, predicted operative risk, and route of TAVI access. RESULTS: There was no difference between treatment groups per 100 person years of follow up for disabling or non-disabling stroke outcomes. In a stratified analysis by year of publication, there was a lower rate of fatal or disabling stroke with TAVI in trials published after 2015, compared to those published in 2015 or before (p-interaction = 0.01 at 30 days). Higher proportions of transfemoral route access (>90%), more common in recent trials, were associated with a lower rate of fatal or disabling stroke (p-interaction = 0.03 at 30 days). Lower average surgical risk scores were associated with lower rates of fatal or disabling stroke (p = 0.02 at 30 days). CONCLUSION: We found that treatment of aortic stenosis with TAVI compared with SAVR was not associated with an overall reduced risk in fatal or disabling stroke. Subgroup analyses suggested a lower risk of fatal or disabling stroke with TAVI in situations which reflect contemporary practice.

The brain parenchyma has a type I interferon response that can limit virus spread.

The brain has a tightly regulated environment that protects neurons and limits inflammation, designated "immune privilege." However, there is not an absolute lack of an immune response. We tested the ability of the brain to initiate an innate immune response to a virus, which was directly injected into the brain parenchyma, and to determine whether this response could limit viral spread. We injected vesicular stomatitis virus (VSV), a transsynaptic tracer, or naturally occurring VSV-derived defective interfering particles (DIPs), into the caudate-putamen (CP) and scored for an innate immune response and inhibition of virus spread. We found that the brain parenchyma has a functional type I interferon (IFN) response that can limit VSV spread at both the inoculation site and among synaptically connected neurons. Furthermore, we characterized the response of microglia to VSV infection and found that infected microglia produced type I IFN and uninfected microglia induced an innate immune response following virus injection.

Association of Blood Pressure Lowering With Incident Dementia or Cognitive Impairment: A Systematic Review and Meta-analysis.

Importance: The benefit of blood pressure lowering for the prevention of dementia or cognitive impairment is unclear. Objective: To determine the association of blood pressure lowering with dementia or cognitive impairment. Data Sources and Study Selection: Search of PubMed, EMBASE, and CENTRAL for randomized clinical trials published from database inception through December 31, 2019, that evaluated the association of blood pressure lowering on cognitive outcomes. The control groups consisted of either placebo, alternative antihypertensive agents, or higher blood pressure targets. Data Extraction and Synthesis: Data were screened and extracted independently by 2 authors. Random-effects meta-analysis models were used to report pooled treatment effects and CIs. Main Outcomes and Measures: The primary outcome was dementia or cognitive impairment. The secondary outcomes were cognitive decline and changes in cognitive test scores. Results: Fourteen randomized clinical trials were eligible for inclusion (96 158 participants), of which 12 reported the incidence of dementia (or composite of dementia and cognitive impairment [3 trials]) on follow-up and were included in the primary meta-analysis, 8 reported cognitive decline, and 8 reported changes in cognitive test scores. The mean (SD) age of trial participants was 69 (5.4) years and 40 617 (42.2%) were women. The mean systolic baseline blood pressure was 154 (14.9) mm Hg and the mean diastolic blood pressure was 83.3 (9.9) mm Hg. The mean duration of follow-up was 49.2 months. Blood pressure lowering with antihypertensive agents compared with control was significantly associated with a reduced risk of dementia or cognitive impairment (12 trials; 92 135 participants) (7.0% vs 7.5% of patients over a mean trial follow-up of 4.1 years; odds ratio [OR], 0.93 [95% CI, 0.88-0.98]; absolute risk reduction, 0.39% [95% CI, 0.09%-0.68%]; I2 = 0.0%) and cognitive decline (8 trials) (20.2% vs 21.1% of participants over a mean trial follow-up of 4.1 years; OR, 0.93 [95% CI, 0.88-0.99]; absolute risk reduction, 0.71% [95% CI, 0.19%-1.2%]; I2 = 36.1%). Blood pressure lowering was not significantly associated with a change in cognitive test scores. Conclusions and Relevance: In this meta-analysis of randomized clinical trials, blood pressure lowering with antihypertensive agents compared with control was significantly associated with a lower risk of incident dementia or cognitive impairment.

Lipid Lowering Therapy, Low-Density Lipoprotein Level and Risk of Intracerebral Hemorrhage - A Meta-Analysis.

BACKGROUND: The association of lipid lowering therapy and intracerebral hemorrhage risk is controversial. METHODS: We performed a cumulative meta-analysis of lipid lowering trials that reported intracerebral hemorrhage. Statin, fibrate, ezetimibe, PCSK9, and CETP trials were included. We explored whether the association of lipid lowering therapy and risk of intracerebral hemorrhage may vary by baseline low-density lipoprotein (LDL) level, mean change in LDL or baseline cardiovascular risk of population. RESULTS: Among 39 trials (287,651 participants), lipid lowering therapy was not associated with a statistically significant increased risk of intracerebral hemorrhage (ICH) in primary and secondary prevention trials combined (odds ratio [OR], 1.12; 95% confidence interval [CI], .98-1.28). Lipid lowering was associated with an increased risk of ICH in secondary prevention trials (OR, 1.18; 95% CI, 1.00-1.38), but not in primary prevention trials (OR, 1.01; 95% CI, .78-1.30), but the test for interaction was not significant (P for interaction = .31). Meta-regression of baseline LDL or difference in LDL reduction between active and control did not explain significant heterogeneity between studies for ICH risk. Of 1000 individuals treated for 1 year for secondary prevention, we estimated 9.17 (95% CI, 5.78-12.66) fewer ischemic strokes and .48 (95% CI, .06-1.02) more ICH, and a net reduction of 8.69 in all stroke per 1000 person-years. CONCLUSIONS: The benefits of lipid lowering therapy in prevention of ischemic stroke greatly exceed the risk of ICH. Concern about ICH should not discourage stroke clinicians from prescribing lipid lowering therapy for secondary prevention of ischemic stroke.

Human Alzheimer's disease gene expression signatures and immune profile in APP mouse models: a discrete transcriptomic view of Aß plaque pathology.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease with pathological hallmarks including the formation of extracellular aggregates of amyloid-beta (Aß) known as plaques and intracellular tau tangles. Coincident with the formation of Aß plaques is recruitment and activation of glial cells to the plaque forming a plaque niche. In addition to histological data showing the formation of the niche, AD genetic studies have added to the growing appreciation of how dysfunctional glia pathways drive neuropathology, with emphasis on microglia pathways. Genomic approaches enable comparisons of human disease profiles between different mouse models informing on their utility to evaluate secondary changes to triggers such as Aß deposition. METHODS: In this study, we utilized two animal models of AD to examine and characterize the AD-associated pathology: the Tg2576 Swedish APP (KM670/671NL) and TgCRND8 Swedish plus Indiana APP (KM670/671NL + V717F) lines. We used laser capture microscopy (LCM) to isolate samples surrounding Thio-S positive plaques from distal non-plaque tissue. These samples were then analyzed using RNA sequencing. RESULTS: We determined age-associated transcriptomic differences between two similar yet distinct APP transgenic mouse models, known to differ in proportional amyloidogenic species and plaque deposition rates. In Tg2576, human AD gene signatures were not observed despite profiling mice out to 15 months of age. TgCRND8 mice however showed progressive and robust induction of lysomal, neuroimmune, and ITIM/ITAM-associated gene signatures overlapping with prior human AD brain transcriptomic studies. Notably, RNAseq analyses highlighted the vast majority of transcriptional changes observed in aging TgCRND8 cortical brain homogenates were in fact specifically enriched within the plaque niche samples. Data uncovered plaque-associated enrichment of microglia-related genes such as ITIM/ITAM-associated genes and pathway markers of phagocytosis. CONCLUSION: This work may help guide improved translational value of APP mouse models of AD, particularly for strategies aimed at targeting neuroimmune and neurodegenerative pathways, by demonstrating that TgCRND8 more closely recapitulates specific human AD-associated transcriptional responses.

Differential contribution of microglia and monocytes in neurodegenerative diseases.

Neuroinflammation is a hallmark of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Microglia, the innate immune cells of the CNS, are the first to react to pathological insults. However, multiple studies have also demonstrated an involvement of peripheral monocytes in several neurodegenerative diseases. Due to the different origins of these two cell types, it is important to distinguish their role and function in the development and progression of these diseases. In this review, we will summarize and discuss the current knowledge of the differential contributions of microglia and monocytes in the common neurodegenerative diseases AD, PD, and ALS, as well as multiple sclerosis, which is now regarded as a combination of inflammatory processes and neurodegeneration. Until recently, it has been challenging to differentiate microglia from monocytes, as there were no specific markers. Therefore, the recent identification of specific molecular signatures of both cell types will help to advance our understanding of their differential contribution in neurodegenerative diseases.

Acute in utero exposure to lipopolysaccharide induces inflammation in the pre- and postnatal brain and alters the glial cytoarchitecture in the developing amygdala.

BACKGROUND: Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders such as autism and schizophrenia, as well as seizure development. The amygdala is a brain region involved in the regulation of emotions, and amygdalar maldevelopment due to infection-induced MIA may lead to amygdala-related disorders. MIA priming of glial cells during development has been linked to abnormalities seen in later life; however, little is known about its effects on amygdalar biochemical and cytoarchitecture integrity. METHODS: Time-mated C57BL6J mice were administered a single intraperitoneal injection of 50 µg/kg lipopolysaccharide (LPS) on embryonic day 12 (E12), and the effects of MIA were examined at prenatal, neonatal, and postnatal developmental stages using immunohistochemistry, real-time quantitative PCR, and stereological quantification of cytoarchitecture changes. RESULTS: Fetal brain expression of pro-inflammatory cytokines (IL-1ß, TNFα, and IL-6) was significantly upregulated at 4 h postinjection (E12) and remained elevated until the day of birth (P0). In offspring from LPS-treated dams, amygdalar expression of pro-inflammatory cytokines was also increased on day 7 (P7) and expression was sustained on day 40 (P40). Toll-like receptor (TLR-2, TLR-4) expression was also upregulated in fetal brains and in the postnatal amygdala in LPS-injected animals. Morphological examination of cells expressing ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) suggested long-term microglial activation and astrogliosis in postnatal amygdalar regions. CONCLUSIONS: Our results showed that LPS-induced MIA at E12 induces a pro-inflammatory cytokine profile in the developing fetal brain that continues up to early adulthood in the amygdala. Inflammation elicited by MIA may activate cells in the fetal brain and lead to alterations in glial (microglia and astrocyte) cells observed in the postnatal amygdala. Moreover, increased pro-inflammatory cytokines and their effects on glial subpopulations may in turn have deleterious consequences for neuronal viability. These MIA-induced changes may predispose offspring to amygdala-related disorders such as heightened anxiety and depression and also neurodevelopmental disorders, such as autism spectrum disorders.

Contribution of amygdala pathology to comorbid emotional disturbances in temporal lobe epilepsy.

The amygdala contributes to the generation and propagation of epileptiform activity in temporal lobe epilepsy (TLE). Ictal symptoms such as fear, dreamy states (déjà vu, memory flashbacks, experiential hallucinations), epigastric auras, or sympathetic outflow with cardiovascular changes are often linked to a seizure focus in the amygdala. However, the amygdala may also play a role in comorbid anxiety, depression, and other psychiatric symptoms experienced in the interictal phase, especially in pharmacoresistant TLE. The few studies available on TLE-related alterations in surgical amygdala specimens indicate loss of both excitatory spiny projection neurons as well as interneurons in nuclei with a cortex-like architecture, which may influence mechanisms of feedforward and feedback inhibition. Studies of the human amygdala indicate global alterations in the density of AMPA/kainate, metabotropic glutamate, γ-aminobutyric acid type A (GABAA ), muscarinic M2 and M3, serotonergic 5-HT1A, and adrenergic α1 receptors. Also, amygdala GABAergic and neuropeptide Y (NPY) systems affected in human TLE are both involved in antiepileptic and anxiolytic effects. Experimental and human positron emission tomography studies indicate changes in amygdala serotonergic, NPY Y1 receptor, neurokinin, and opioid systems in emotional disturbances in TLE. Of particular interest is the reduction in amygdala volume in conjunction with ictal fear, seizure focus in the amygdala, and amygdala and hippocampal sclerosis in TLE patients. In contrast, patients with interictal depression often have an intact or even enlarged amygdala and a negative MRI associated with amygdala hypometabolism, which can be associated with limbic autoimmune encephalitis. These findings suggest a differential role of TLE-related amygdala changes in ictal and interictal emotional disturbances.

Interdependent and independent roles of type I interferons and IL-6 in innate immune, neuroinflammatory and sickness behaviour responses to systemic poly I:C.

Type I interferons (IFN-I) are expressed in the brain during many inflammatory and neurodegenerative conditions and have multiple effects on CNS function. IFN-I is readily induced in the brain by systemic administration of the viral mimetic, poly I:C (synthetic double-stranded RNA). We hypothesised that IFN-I contributes to systemically administered poly I:C-induced sickness behaviour, metabolic and neuroinflammatory changes. IFN-I receptor 1 deficient mice (IFNAR1(-/-)) displayed significantly attenuated poly I:C-induced hypothermia, hypoactivity and weight loss compared to WT C57BL/6 mice. This amelioration of sickness was associated with equivalent IL-1ß and TNF-α responses but much reduced IL-6 responses in plasma, hypothalamus and hippocampus of IFNAR1(-/-) mice. IFN-ß injection induced trivial IL-6 production and limited behavioural change and the poly I:C-induced IFN-ß response did not preceed, and would not appear to mediate, IL-6 induction. Rather, IFNAR1(-/-) mice lack basal IFN-I activity, have lower STAT1 levels and show significantly lower levels of several inflammatory transcripts, including stat1. Basal IFN-I activity appears to play a facilitatory role in the full expression of the IL-6 response and activation of the tryptophan-kynurenine metabolism pathway. The deficient IL-6 response in IFNAR1(-/-) mice partially explains the observed incomplete sickness behaviour response. Reconstitution of circulating IL-6 revealed that the role of IFNAR in burrowing activity is mediated via IL-6, while IFN-I and IL-6 have additive effects on hypoactivity, but the role of IFN-I in anorexia is independent of IL-6. Hence, we have demonstrated both interdependent and independent roles for IFN-I and IL-6 in systemic inflammation-induced changes in brain function.

Expression of neuropeptide Y1 receptors in the amygdala and hippocampus and anxiety-like behavior associated with Ammon's horn sclerosis following intrahippocampal kainate injection in C57BL/6J mice.

Damage to the amygdala is often linked to Ammon's horn sclerosis (AHS) in surgical specimens of patients suffering from temporal lobe epilepsy (TLE). Moreover, amygdalar pathology is thought to contribute to the development of anxiety symptoms frequently found in TLE. The neuropeptide Y (NPY) Y1 receptor is critical in the regulation of anxiety-related behavior and epileptiform activity in TLE. Therefore, intrahippocampal kainate (KA) injection was performed to induce AHS-associated TLE and to investigate behavioral and cytoarchitectural changes that occur in the amygdala related to Y1 receptor expression. Status epilepticus was induced by intrahippocampal KA injection in C57BL/6J mice. Anxiety-like behavior was assessed using the elevated plus maze (EPM). Pathology of hippocampus and amygdala (volume loss and gliosis) was examined in KA-injected and saline-injected controls. Y1 receptor expression was measured using immunohistochemistry and ELISA. Animal injected with KA showed increased anxiety-like behaviors and reduced risk assessment in the EPM test compared with saline-injected controls. In the ipsilateral hippocampus of KA-injected animals, CA1 ablation, granule cell dispersion, and volume reduction were accompanied by astrogliosis indicating the development of AHS. In the amygdala, a significant decrease in the volume of nuclei and numbers of neurons was observed in the ipsilateral lateral, basolateral, and central amygdalar nuclei, which was accompanied by astrogliosis. In addition, a decrease in Y1 receptor-expressing cells in the ipsilateral CA1 and CA3 sectors of the hippocampus, ipsilateral and contralateral granule cell layer of the dentate gyrus, and ipsilateral central nucleus of the amygdala was found, consistent with a reduction in Y1 receptor protein levels. Our results suggest that plastic changes in hippocampal and/or amygdalar Y1 receptor expression may negatively impact anxiety levels. Moreover, intrahippocampal KA injection can induce amygdalar damage suggesting that AHS-associated amygdala damage may contribute to behavioral alterations seen in patients with TLE.

The impact of hospital presentation time on stroke outcomes: A nationally representative Irish cohort study.

OBJECTIVES: There is conflicting evidence regarding the outcomes of acute stroke patients who present to hospital within normal working hours ('in-hours') compared with the 'out-of-hours' period. This study aimed to assess the effect of time of stroke presentation on outcomes within the Irish context, to inform national stroke service delivery. MATERIALS AND METHODS: A secondary analysis of data from the Irish National Audit of Stroke (INAS) from Jan 2016 to Dec 2019 was carried out. Patient and process outcomes were assessed for patients presenting 'in-hours' (8:00-17:00 Monday-Friday) compared with 'out-of-hours' (all other times). RESULTS: Data on arrival time were available for 13,996 patients (male 56.2%; mean age 72.5 years), of which 55.7% presented 'out-of-hours'. In hospital mortality was significantly lower among those admitted 'in-hours' (11.3%, n = 534) compared with 'out-of-hours' (12.8%, n = 749); (adjusted Odds Ratio (OR) 0.82; 95% Confidence Interval CI [95% CI] 0.72-0.89). Poor functional outcome at discharge (Modified Rankin Scale ≥ 3) was also significantly lower in those presenting 'in-hours' (adjusted OR 0.79; 95% CI 0.68-0.91). In patients receiving thrombolysis, mean door to needle time was shorter for 'in-hours' presentation at 55.8 mins (n = 562; SD 35.43 mins), compared with 'out-of-hours' presentation at 80.5 mins (n = 736; SD 38.55 mins, p < .001). CONCLUSION: More than half of stroke patients in Ireland present 'out-of-hours' and these presentations are associated with a higher mortality and a lower odds of functional independence at discharge. It is imperative that stroke pathways consider the 24 hour period to ensure the delivery of effective stroke care, and modification of 'out-of-hours' stroke care is required to improve overall outcomes.

A cross-sectional survey of doctors' views on flexible postgraduate physician training in Ireland.

Recruitment and retention of doctors is a priority for the Irish healthcare service, with many leaving to work in regions with more favourable conditions. Aligning flexible training options with other jurisdictions may be an effective means of improving working conditions. We sought to assess possible improvements to the existing system and to review barriers to flexible training. We carried out a survey using 'Survey Monkey' and disseminated it to 1557 basic specialist (BST) and higher specialist trainee (HST) doctors of the Institute of Medicine, 3500 members of the Irish Medical Organisation (IMO), and across social media. There were 854 respondents; 303 (35.5%) BST, 352 (41.2%) HST, 125 (14.6%) non-training doctors, unknown, n = 74. The response rate was approximately 15-23%. Non-consultant doctors identified a preference for access to flexible training (n = 849, 99.4%), with 82.2 of doctors reporting that they would consider applying (n = 702). Most (92.4%) considered the current provision of 16 whole-time equivalent positions as inadequate (n = 789). Of doctors who would not apply for flexible training, themes identified included a perceived negative impact on their career, not meeting eligibility criteria, prolonged training, and salary implications. Suggestions for improving the system included expanding the number of places available, removing eligibility criteria, job sharing options, and the provision of regional training schemes. Access to flexible training should be a priority for the healthcare service, which may enhance recruitment and retention. A majority of our sample of non-consultant doctors identified a preference for access to flexible training options.

Audit of inpatient acute stroke services in a university teaching hospital, 2020.

BACKGROUND: We aimed to assess stroke care at an Irish university teaching hospital and benchmark against national (Irish National Audit of Stroke 2019) and international (6th SSNAP Annual Report; American Heart Association, 2013) practice to inform a quality improvement strategy. METHODS: All patients with a HIPE discharge diagnosis of Cerebral Infarction or Cerebral Haemorrhage (1 January to 31 December 2019) were identified through both the HIPE database and the institutional Stroke Portal. RESULTS: A total of 419 patients were included (56.6% male, mean age 72). The following were comparable/better than findings from the Irish National Audit of Stroke: median duration of symptoms-3 h 6 min; 10% received thrombolysis; median door to needle time-60 min; 78.5% admitted to the stroke unit; 81.1% had a swallow assessment; in-patient mortality rate-10.5%; rates of institutionalisation-3.8%. The following areas were below the national average: overall door to imaging time-median 104 min; rate of thrombectomy-4%; 11.5% had mood screening; median length of stay- 12 days. DISCUSSION: Using national and international audit data as an institutional benchmark provides a standard with which a service can be compared to highlight areas for improvement. We identified mood screening, swallow screening, thrombectomy rates, length of stay and time to neuroimaging as key areas for development in our centre. We are currently completing a process map to determine cause, effect, and solutions, and we will implement change using PDSA methodology as per SQUIRE 2.0 guidelines. The results of the re-audit cycle for 2020 will be available in 2021 to inform our progress. Ongoing quality improvement is essential for stroke care, which is a leading cause of death and disability in Ireland.

Effect of a Run-In Period on Estimated Treatment Effects in Cardiovascular Randomized Clinical Trials: A Meta-Analytic Review.

Background A run-in period may increase adherence to intervention and reduce loss to follow-up. Whether use of a run-in period affects the magnitude of treatment effects is unknown. Methods and Results We conducted a meta-analysis comparing treatment effects from 11 systematic reviews of cardiovascular prevention trials using a run-in period with matched trials not using a run-in period. We matched run-in with non-run-in trials by population, intervention, control, and outcome. We calculated a ratio of relative risks (RRRs) using a random-effects meta-analysis. Our primary outcome was a composite of cardiovascular events, and the primary analysis was a matched comparison of clinical trials using a run-in period versus without a run-in period. We identified 66 run-in trials and 111 non-run-in trials (n=668 901). On meta-analysis there was no statistically significant difference in the magnitude of treatment effect between run-in trials (relative risk [RR], 0.83 [95% CI, 0.80-0.87]) compared with non-run-in trials (RR, 0.88 [95% CI, 0.84-0.91]; RRR, 0.95 [95% CI, 0.90-1.01]). There was no significant difference in the RRR for secondary outcomes of all-cause mortality (RRR, 0.97 [95% CI, 0.91-1.03]) or medication discontinuation because of adverse events (RRR, 1.05 [95% CI, 0.85-1.21]). Post hoc exploratory univariate meta-regression showed that on average a run-in period is associated with a statistically significant difference in treatment effect (RRR, 0.94 [95% CI, 0.90-0.99]) for cardiovascular composite outcome, but this was not statistically significant on multivariable meta-regression analysis (RRR, 0.95 [95% CI, 0.90-1.0]). Conclusions The use of a run-in period was not associated with a difference in the magnitude of treatment effect among cardiovascular prevention trials.

Increased Salt Intake for Orthostatic Intolerance Syndromes: A Systematic Review and Meta-Analysis.

BACKGROUND: Guidelines recommend increased salt intake as a first-line recommendation in the management of symptomatic orthostatic hypotension and recurrent syncope. There have been no systematic reviews of this intervention. We sought to summarize the evidence for increased salt intake in patients with orthostatic intolerance syndromes. METHODS: We conducted a systematic review and meta-analysis of studies in PubMed, EMBASE, and CINAHL. Interventional studies that increased salt intake in individuals with orthostatic intolerance syndromes were included. Primary outcome measures included incidence of falls and injuries, and rates of syncope and presyncope. Secondary outcome measures included other orthostatic intolerance symptoms, blood pressure, and heart rate. RESULTS: A total of 14 studies were eligible, including participants with orthostatic hypotension, syncope, postural orthostatic tachycardia syndrome, and idiopathic orthostatic tachycardia (n = 391). Mean age was 35.6 (± 15) years. All studies were small and short-term (<60 mins-90 days). No study reported on the effect of increased salt intake on falls or injuries. Meta-analysis demonstrated that during head-up tilt, mean time to presyncope with salt intake increased by 1.57 minutes (95% confidence interval [CI], 1.26-1.88), mean systolic blood pressure increased by 12.27 mm Hg (95% CI, 10.86-13.68), and mean heart rate decreased by -3.97 beats per minute (95% CI, -4.08 to -3.86), compared with control. Increased salt increased supine blood pressure by 1.03 mm Hg (95% CI, 0.81 to 1.25). Increased salt intake resulted in an improvement or resolution of symptoms in 62.3% (95% CI, 51.6 to 72.6) of participants in short-term follow-up studies (mean follow-up of 44.3 days, 6 studies; n=91). Methodological quality of studies were low with high statistical heterogeneity in all meta-analyses. CONCLUSIONS: Our meta-analysis provides low-quality evidence of a short-term improvement in orthostatic intolerance with increased salt intake. There were no clinical trials demonstrating the efficacy and safety of increased salt intake on long-term clinical outcomes. Overall, there is a paucity of clinical trial evidence to support a cornerstone recommendation in the management of orthostatic intolerance syndromes.

Aspirin for primary prevention of stroke in individuals without cardiovascular disease-A meta-analysis.

BACKGROUND: The benefits of aspirin for primary prevention of stroke are uncertain. METHODS: We performed a cumulative meta-analysis of trials investigating aspirin for primary prevention of cardiovascular disease with a focus on stroke. We assessed the effects of aspirin on non-fatal stroke, hemorrhagic stroke, non-fatal myocardial infarction, all-cause mortality, cardiovascular mortality, major gastrointestinal bleeding, and an analysis of net clinical effect, in populations without a history of clinical or subclinical cardiovascular disease. SUMMARY OF REVIEW RESULTS: Among 11 trials (157,054 participants), aspirin was not associated with a statistically significant reduction in non-fatal stroke (odds ratio, 0.94; 95% CI, 0.85 to 1.04) but was associated with an increased risk of hemorrhagic stroke (odds ratio, 1.29; 95% CI, 1.06 to 1.56). Aspirin was not associated with a statistically significant reduction in all-cause mortality (odds ratio, 0.97; 95% CI, 0.92 to 1.03) or cardiovascular mortality (odds ratio, 0.94; 95% CI, 0.85 to 1.03). Aspirin was associated with a reduction in non-fatal myocardial infarction (odds ratio, 0.80; 95% CI, 0.69 to 0.94) and an increased risk of major gastrointestinal bleeding (odds ratio, 1.83; 95% CI, 1.43 to 2.35). Using equal weighting for non-fatal events and major bleeding, we observed no net clinical benefit with aspirin use for primary prevention. CONCLUSION: Our meta-analysis reports no benefit of aspirin for primary stroke prevention.

Microglial Phenotypes and Functions in Multiple Sclerosis.

Microglia are the resident immune cells that constantly survey the central nervous system. They can adapt to their environment and respond to injury or insult by altering their morphology, phenotype, and functions. It has long been debated whether microglial activation is detrimental or beneficial in multiple sclerosis (MS). Recently, the two opposing yet connected roles of microglial activation have been described with the aid of novel microglial markers, RNA profiling, and in vivo models. In this review, microglial phenotypes and functions in the context of MS will be discussed with evidence from both human pathological studies, in vitro and in vivo models. Microglial functional diversity-phagocytosis, antigen presentation, immunomodulation, support, and repair-will also be examined in detail. In addition, this review discusses the emerging evidence for microglia-related targets as biomarkers and therapeutic targets for MS.