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This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of early versus late surgical start times for on‐pump cardiac surgery on mortality, cardiac outcomes, and quality of life.

Patients with stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) are at risk of recurrent ICH, ischaemic stroke, and other serious vascular events. We aimed to analyse these risks in population-based studies and compare them with the risks in RESTART, which assessed antiplatelet therapy after ICH.We pooled individual patient data from two prospective, population-based inception cohort studies of all patients with an incident firs-in-a-lifetime ICH in Oxfordshire, England (Oxford Vascular Study; April 1, 2002, to Sept 28, 2018) and Lothian, Scotland, UK (Lothian Audit of the Treatment of Cerebral Haemorrhage; June 1, 2010, to May 31, 2013). We quantified the absolute and relative risks of recurrent ICH, ischaemic stroke, or any serious vascular event (non-fatal stroke, non-fatal myocardial infarction, or vascular death), stratified by ICH location (lobar vs non-lobar) and comorbid atrial fibrillation (AF). We compared pooled event rates with those after allocation to avoid antiplatelet therapy in RESTART.Among 674 patients (mean age 74·7 years [SD 12·6], 320 [47%] men) with 1553 person-years of follow-up, 46 recurrent ICHs (event rate 3·2 per 100 patient-years, 95% CI 2·0-5·1) and 25 ischaemic strokes (1·7 per 100 patient-years, 0·8-3·3) were reported. Patients with lobar ICH (n=317) had higher risk of recurrent ICH (5·1 per 100 patient-years, 95% CI 3·6-7·2) than patients with non-lobar ICH (n=355; 1·8 per 100 patient-years, 1·0-3·3; hazard ratio [HR] 3·2, 95% CI 1·6-6·3; p=0·0010), but there was no evidence of a difference in the risk of ischaemic stroke (1·8 per 100 patient-years, 1·0-3·2, vs 1·6 per 100 patient-years, 0·6-4·4; HR 1·1, 95% CI 0·5-2·8). Conversely, there was no evidence of a difference in recurrent ICH rate in patients with AF (n=147; 3·3 per 100 patient-years, 95% CI 1·0-10·7) compared with those without (n=526; 3·2 per 100 patient-years, 2·2-4·7; HR 0·9, 95% CI 0·4-2·1), but the risk of ischaemic stroke was higher with AF (6·3 per 100 patient-years, 3·7-10·9, vs 0·7 per 100 patient-years, 0·1-5·6; HR 8·2, 3·3-20·3; p0·0001), resulting in patients with AF having a higher risk of all serious vascular events than patients without AF (15·5 per 100 patient-years, 10·0-24·1, vs 6·8 per 100 patient-years, 3·6-12·5; HR 1·78, 95% CI 1·16-2·74; p=0·0090). Only for patients with lobar ICH without comorbid AF was the risk of recurrent ICH greater than the risk of ischaemic stroke (5·2 per 100 patient-years, 95% CI 3·6-7·5, vs 0·9 per 100 patient-years, 0·2-4·8; p=0·00034). Comparing data from the pooled population-based studies with that from patients allocated to not receive antiplatelet therapy in RESTART, there was no evidence of a difference in the rate of recurrent ICH (3·5 per 100 patient-years, 95% CI 1·9-6·0, vs 4·4 per 100 patient-years, 2·6-6·1) or ischaemic stroke (3·4 per 100 patient-years, 1·9-5·9, vs 5·3 per 100 patient-years, 3·3-7·2).The risks of recurrent ICH, ischaemic stroke, and all serious vascular events after ICH differ by ICH location and comorbid AF. These data enable risk stratification of patients in clinical practice and ongoing randomised trials.UK Medical Research Council, Stroke Association, British Heart Foundation, Wellcome Trust, and the National Institute for Health Research Oxford Biomedical Research Centre.

ObjectivesTo investigate the effects of adding high-grade quantitative evidence of outcomes of treatments into relevant Wikipedia pages on further information-seeking behaviour by the use of routinely collected data.SettingWikipedia, Cochrane summary pages and the Cochrane Library.DesignRandomised trial.ParticipantsWikipedia pages which were highly relevant to up-to-date Cochrane Schizophrenia systematic reviews that contained a Summary of Findings table.InterventionsEligible Wikipedia pages in the intervention group were seeded with tables of best evidence of the effects of care and hyperlinks to the source Cochrane review. Eligible Wikipedia pages in the control group were left unchanged.Main outcome measuresRoutinely collected data on access to the full text and summary web page (after 12 months).ResultsWe randomised 70 Wikipedia pages (100% follow-up). Six of the 35 Wikipedia pages in the intervention group had the tabular format deleted during the study but all pages continued to report the same data within the text. There was no evidence of effect on either of the coprimary outcomes: full-text access adjusted ratio of geometric means 1.30, 95% CI: 0.71 to 2.38; page views 1.14, 95% CI: 0.6 to 2.13. Results were similar for all other outcomes, with exception of Altmetric score for which there was some evidence of clear effect (1.36, 95% CI: 1.05 to 1.78).ConclusionsThe pursuit of fair balance within Wikipedia healthcare pages is impressive and its reach unsurpassed. For every person who sought and clicked the reference on the ‘intervention’ Wikipedia page to seek more information (the primary outcome), many more are likely to have been informed by the page alone. Enriching Wikipedia content is, potentially, a powerful way to improve health literacy and it is possible to test the effects of seeding pages with evidence. This trial should be replicated, expanded and developed.Trial registration numberIRCT2017070330407N2.

Background and Purpose— The frequency and prognostic implications of incident cerebral microbleeds (CMB), defined as development of one or more new CMB, after intracerebral hemorrhage (ICH) is unclear. Therefore, we performed a systematic review and meta-analysis to investigate the frequency and prognostic implications of incident CMB after ICH. Methods— We searched Ovid Medline and Embase in May 2018 for longitudinal studies of adults who underwent brain magnetic resonance imaging at 2 or more times after ICH. We calculated the pooled proportion of adults with incident CMB and sought associations between incident CMB and clinical outcomes (death, recurrent ICH, or new ischemic stroke). We planned subgroup analyses to investigate clinical variables associated with incident CMB. Results— We identified 2354 publications, of which we included 4 cohort studies involving 349 patients. The pooled proportion of adults with at least one new CMB during a mean 27 months follow-up (SD 20 months) was ≈40% (95% CI, 30%–50%). In one study, as the number of incident CMB increased (0 versus 1–3 new CMB versus ≥4 new CMB) the risk of recurrent symptomatic lobar ICH increased (hazard ratio 3.0; 95% CI, 1.2–7.3). No study reported on outcomes of incident ischemic stroke or death. Conclusions— Incident CMB occurs in ≈40% of adults after ICH. The association of incident CMB with recurrent lobar ICH needs confirmation and their association with death and ischemic stroke investigation.

Background and aims Glial fibrillary acidic protein (GFAP) has shown promise in several studies for its ability to diagnose intracerebral hemorrhage (ICH). We evaluated the diagnostic accuracy of blood GFAP level to differentiate (ICH) from acute ischemic stroke (AIS) and stroke mimics, both overall, and in the first three hours after symptom onset. Methods We searched multiple databases, without language restriction, from inception until December 2017. Hierarchical summary receiver operating characteristic (HSROC) modeling was used to meta-analyze results. We conducted subgroup analyses restricted to blood samples collected within 0–60, 60–120, and 120–180 min time groups after symptom onset, to evaluate diagnostic accuracy in the early pre-hospital phase. Between and within study heterogeneity was explored using meta-regression. Results The search identified 199 potentially relevant citations from which 11 studies involving 1297 participants (350 ICH, 947 AIS, or mimic) were included. The pooled sensitivity, specificity, and area under the HSROC curve were 0.756 (95% CI 0.630–0.849), 0.945 (95% CI 0.858–0.980), and 0.904 (95% CI 0.878–0.931), respectively. Differences in assays used, but not the other covariates, partially explained between-study heterogeneity ( p = 0.034). The summary estimates for the 0–60, 60–120, and 120–180 min subgroups were comparable to the primary analysis and there was no statistically significant difference in diagnostic accuracy between subgroups. Conclusions GFAP is a promising diagnostic biomarker for ICH diagnosis in the early pre-hospital phase. Test accuracy is affected by assay subtype, but there are still unexplained sources of heterogeneity. High quality, international multi-center trials are warranted to develop and validate a point-of-care GFAP assay for the rapid triage and evaluation of acute stroke in the pre-hospital setting.

BACKGROUND: Many individuals who have a diagnosis of schizophrenia experience a range of distressing and debilitating symptoms. These can include positive symptoms (such as delusions, hallucinations, disorganised speech), cognitive symptoms (such as trouble focusing or paying attention or using information to make decisions), and negative symptoms (such as diminished emotional expression, avolition, alogia, and anhedonia). Antipsychotic drugs are often only partially effective, particularly in treating negative symptoms, indicating the need for additional treatment. Mirtazapine is an antidepressant drug that when taken in addition to an antipsychotic may offer some benefit for negative symptoms. OBJECTIVES: To systematically assess the effects of mirtazapine as adjunct treatment for people with schizophrenia. SEARCH METHODS: The Information Specialist of Cochrane Schizophrenia searched the Cochrane Schizophrenia Group’s Study‐Based Register of Trials (including registries of clinical trials) up to May 2018. SELECTION CRITERIA: All randomised‐controlled trials (RCTs) with useable data focusing on mirtazapine adjunct for people with schizophrenia. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention‐to‐treat (ITT) basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a fixed‐effect model for analyses. For included studies we assessed risk of bias and created 'Summary of findings' table using GRADE. MAIN RESULTS: We included nine RCTs with a total of 310 participants. All studies compared mirtazapine adjunct with placebo adjunct and were of short‐term duration. We considered five studies to have a high risk of bias for either incomplete outcome data, selective reporting, or other bias. Our main outcomes of interest were clinically important change in mental state (negative and positive symptoms), leaving the study early for any reason, clinically important change in global state, clinically important change in quality of life, number of days in hospital and incidence of serious adverse events. One trial defined a reduction in the Scale for the Assessment of Negative Symptoms (SANS) overall score from baseline of at least 20% as no important response for negative symptoms. There was no evidence of a clear difference between the two treatments with similar numbers of participants from each group showing no important response to treatment (RR 0.81, 95% CI 0.57 to 1.14, 1 RCT, n = 20, very low‐quality evidence). Clinically important change in positive symptoms was not reported, however, clinically important change in overall mental state was reported by two trials and data for this outcome showed a favourable effect for mirtazapine (RR 0.69, 95% CI 0.51 to 0.92; I(2) = 75%, 2 RCTs, n = 77, very low‐quality evidence). There was no evidence of a clear difference for numbers of participants leaving the study early (RR 1.03, 95% CI 0.64 to 1.66, 9 RCTs, n = 310, moderate‐quality evidence), and no evidence of a clear difference in global state Clinical Global Impressions Scale (CGI) severity scores (MD ‐0.10, 95% CI ‐0.68 to 0.48, 1 RCT, n = 39, very low‐quality evidence). A favourable effect for mirtazapine adjunct was found for the outcome clinically important change in akathisia (RR 0.33, 95% CI 0.20 to 0.52, 2 RCTs, n = 86, low‐quality evidence; I(2) = 61%I). No data were reported for quality life or number of days in hospital. In addition to the main outcomes of interest, there was evidence relating to adverse events that the mirtazapine adjunct groups were associated with an increased risk of weight gain (RR 3.19, 95% CI 1.17 to 8.65, 4 RCTs, n = 127) and sedation/drowsiness (RR 1.64, 95% CI 1.01 to 2.68, 7 RCTs, n = 223). AUTHORS' CONCLUSIONS: The available evidence is primarily of very low quality and indicates that mirtazapine adjunct is not clearly associated with an effect for negative symptoms, but there is some indication of a positive effect on overall mental state and akathisia. No effect was found for global state or leaving the study early and data were not available for quality of life or service use. Due to limitations of the quality and applicability of the evidence it is not possible to make any firm conclusions, the role of mirtazapine adjunct in routine clinical practice remains unclear. This underscores the need for new high‐quality evidence to further evaluate mirtazapine adjunct for schizophrenia.

Cerebral amyloid angiopathy is a common hemorrhagic small vessel disease of the brain, often associated with high risk of spontaneous lobar intracerebral hemorrhage. When the suspicion of cerebral amyloid angiopathy is raised, clinicians are hesitant in prescribing oral anticoagulation in patients in whom it is otherwise indicated, including the case of non-valvular atrial fibrillation. This is one of the thorniest clinical dilemmas in the field currently. In this short Leading Opinion piece by an international panel of clinicians-researchers active in the field, we present our consistent approach and future outlook on oral anticoagulation post intracerebral hemorrhage and in the setting of clinical-radiologic evidence of cerebral amyloid angiopathy. We discuss recent advances and support a more balanced approach with implications for the wider neurological clinical community in regards to successful recruiting this patient population in ongoing and future randomized trials.

Lung cancer is the leading cause of cancer-related deaths in the world. Immune checkpoint inhibitors (ICI) stimulate cytotoxic lymphocyte activity against tumour cells. These agents are available for the treatment of nonsmall cell lung cancer (NSCLC) after failure of platinumbased therapy. One recent study has demonstrated that ICI monotherapy was superior to platinum-based chemotherapy for first-line treatment. Nevertheless, this benefit was only for a minority of the population (30%) whose tumour programmed death receptor ligand-1 (PD-L1) expression was above 50%. Therefore, several strategies are under investigation. One option for patients with PD-L1 expression lower than 50% may be the combination of ICI with platinum-based chemotherapy or with ICIs against different targets. However, all of these combinations are at an early stage of investigation and may be very expensive or toxic, producing several harmful adverse events. info:eu-repo/semantics/publishedVersion

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the effectiveness and safety of immune checkpoint inhibitors (anti PD-1 or anti PD-L1) compared with standard chemotherapy for second- or third-line treatment of metastatic non-small cell lung cancer (NSCLC).