Recommendations for empowering early career researchers to improve research culture and practice.

Early career researchers (ECRs) are important stakeholders leading efforts to catalyze systemic change in research culture and practice. Here, we summarize the outputs from a virtual unconventional conference (unconference), which brought together 54 invited experts from 20 countries with extensive experience in ECR initiatives designed to improve the culture and practice of science. Together, we drafted 2 sets of recommendations for (1) ECRs directly involved in initiatives or activities to change research culture and practice; and (2) stakeholders who wish to support ECRs in these efforts. Importantly, these points apply to ECRs working to promote change on a systemic level, not only those improving aspects of their own work. In both sets of recommendations, we underline the importance of incentivizing and providing time and resources for systems-level science improvement activities, including ECRs in organizational decision-making processes, and working to dismantle structural barriers to participation for marginalized groups. We further highlight obstacles that ECRs face when working to promote reform, as well as proposed solutions and examples of current best practices. The abstract and recommendations for stakeholders are available in Dutch, German, Greek (abstract only), Italian, Japanese, Polish, Portuguese, Spanish, and Serbian.

Predicting 30-day mortality in intensive care unit patients with ischaemic stroke or intracerebral haemorrhage.

BACKGROUND: Stroke patients admitted to an intensive care unit (ICU) follow a particular survival pattern with a high short-term mortality, but if they survive the first 30 days, a relatively favourable subsequent survival is observed. OBJECTIVES: The development and validation of two prognostic models predicting 30-day mortality for ICU patients with ischaemic stroke and for ICU patients with intracerebral haemorrhage (ICH), analysed separately, based on parameters readily available within 24 h after ICU admission, and with comparison with the existing Acute Physiology and Chronic Health Evaluation IV (APACHE-IV) model. DESIGN: Observational cohort study. SETTING: All 85 ICUs participating in the Dutch National Intensive Care Evaluation database. PATIENTS: All adult patients with ischaemic stroke or ICH admitted to these ICUs between 2010 and 2019. MAIN OUTCOME MEASURES: Models were developed using logistic regressions and compared with the existing APACHE-IV model. Predictive performance was assessed using ROC curves, calibration plots and Brier scores. RESULTS: We enrolled 14 303 patients with stroke admitted to ICU: 8422 with ischaemic stroke and 5881 with ICH. Thirty-day mortality was 27% in patients with ischaemic stroke and 41% in patients with ICH. Important factors predicting 30-day mortality in both ischaemic stroke and ICH were age, lowest Glasgow Coma Scale (GCS) score in the first 24 h, acute physiological disturbance (measured using the Acute Physiology Score) and the application of mechanical ventilation. Both prognostic models showed high discrimination with an AUC 0.85 [95% confidence interval (CI), 0.84 to 0.87] for patients with ischaemic stroke and 0.85 (0.83 to 0.86) in ICH. Calibration plots and Brier scores indicated an overall good fit and good predictive performance. The APACHE-IV model predicting 30-day mortality showed similar performance with an AUC of 0.86 (95% CI, 0.85 to 0.87) in ischaemic stroke and 0.87 (0.86 to 0.89) in ICH. CONCLUSION: We developed and validated two prognostic models for patients with ischaemic stroke and ICH separately with a high discrimination and good calibration to predict 30-day mortality within 24 h after ICU admission. TRIAL REGISTRATION: Trial registration: Dutch Trial Registry ( https://www.trialregister.nl/ ); identifier: NTR7438.

Iatrogenic Cerebral Amyloid Angiopathy Post Neurosurgery: Frequency, Clinical Profile, Radiological Features, and Outcome.

BACKGROUND: Prion-like transmission of amyloid-ß through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA). We investigated new and previously described patients to assess the clinical profile, radiological features, and outcome of this presumed iatrogenic CAA-subtype (iCAA). METHODS: Patients were collected from our prospective lobar hemorrhage and CAA database (n=251) with patients presenting to our hospital between 2008 and 2022. In addition, we identified patients with iCAA from 2 other Dutch CAA-expertise hospitals and performed a systematic literature-search for previously described patients. We classified patients according to the previously proposed diagnostic criteria for iCAA, assessed clinical and radiological disease features, and calculated intracerebral hemorrhage (ICH)-recurrence rates. We evaluated the spatial colocalization of cadaveric dura placement and CAA-associated magnetic resonance imaging markers. RESULTS: We included 49 patients (74% men, mean age 43 years [range, 27-84]); 15 from our database (6% [95% CI, 3%-10%]; 45% of patients <55 years), 3 from the 2 other CAA-expertise hospitals, and 31 from the literature. We classified 43% (n=21; 1 newly identified patient) as probable and 57% (n=28) as possible iCAA. Patients presented with lobar ICH (57%), transient focal neurological episodes (12%), or seizures (8%). ICH-recurrence rate in the new patients (16/100 person-years [95% CI, 7-32], median follow-up 18 months) was lower than in the previously described patients (77/100 person-years [95% CI, 59-99], median follow-up 18 months). One patient had a 10 year interlude without ICH-recurrence. We identified no clear spatial relationship between dura placement and CAA-associated magnetic resonance imaging markers. During follow-up (median, 18 months), 20% of the patients developed transient focal neurological episodes and 20% cognitively declined. CONCLUSIONS: iCAA seems common in patients presenting with nonhereditary CAA under the age of 55. Clinical and radiological features are comparable with sCAA. After diagnosis, multiple ICH-recurrences but also long symptom-free intervals can occur. Harmonized registries are necessary to identify and understand this potentially underrecognized CAA-subtype.

The Post-Venous Thromboembolism Functional Status Scale: From Call to Action to Application in Research, Extension to COVID-19 Patients, and Its Use in Clinical Practice.

A broad spectrum of long-term sequelae may be present in venous thromboembolism (VTE) survivors, affecting their quality of life and functioning. To monitor recovery and improve the prognosis of patients with persistent functional limitations, the development of a new outcome measure that could better capture the consequences of VTE was an unmet need. Starting as a call to action, the Post-VTE Functional Status (PVFS) scale was developed to meet this need. The PVFS scale is an easy-to-use clinical tool to measure and quantify functional outcomes after VTE by focusing on key aspects of daily life. As the scale was considered useful in coronavirus disease 2019 (COVID-19) patients as well, the Post-COVID-19 Functional Status (PCFS) scale was introduced early in the pandemic after slight adaptation. The scale has been well incorporated into both the VTE and COVID-19 research communities, contributing to the shift of focus toward patient-relevant functional outcomes. Psychometric properties have been evaluated, mainly for the PCFS scale but recently also for the PVFS scale, including validation studies of translations, showing adequate validity and reliability. In addition to serving as outcome measure in studies, guidelines and position papers recommend using the PVFS and PCFS scale in clinical practice. As broad use of the PVFS and PCFS scale in clinical practice is valuable to capture what matters most to patients, widespread implementation is a crucial next step. In this review, we discuss the development of the PVFS scale and introduction in VTE and COVID-19 care, the incorporation of the scale in research, and its application in clinical practice.

Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events: The Berlin "Cream&Sugar" Study.

BACKGROUND: Elevated triglyceride and glucose levels are associated with an increased cardiovascular disease risk including ischemic stroke. It is not known whether the response to a combined oral triglyceride and glucose challenge after ischemic stroke improves identification of patients with increased risk for recurrent vascular events. METHODS: The prospective, observational Berlin "Cream&Sugar" study was conducted at 3 different university hospital sites of the Charité-Universitätsmedizin Berlin, Germany, between January 24, 2009 and July 31, 2017. Patients with first-ever ischemic stroke were recruited 3 to 7 days after stroke. An oral triglyceride tolerance test (OTTT) and consecutive blood tests before (t0) as well as 3 (t1), 4 (t2), and 5 hours (t3) after OTTT were performed in fasting patients. An oral glucose tolerance test was performed in all nondiabetic patients 3 hours after the start of OTTT. Outcomes of the study were recurrent fatal or nonfatal stroke as well as a composite vascular end point including stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death assessed 1 year after stroke. Cox regression models were used to estimate hazard ratios and corresponding 95% CIs between patients with high versus low levels of triglyceride and glucose levels. RESULTS: Overall 755 patients were included; 523 patients completed OTTT and 1-year follow-up. Patients were largely minor strokes patients with a median National Institutes of Health Stroke Scale score of 1 (0-3). Comparing highest versus lowest quartiles of triglyceride levels, neither fasting (adjusted hazard ratiot0, 1.24 [95% CI, 0.45-3.42]) nor postprandial triglyceride levels (adjusted hazard ratiot3, 0.44 [95% CI, 0.16-1.25]) were associated with recurrent stroke. With regard to recurrent vascular events, results were similar for fasting triglycerides (adjusted hazard ratiot0, 1.09 [95% CI, 0.49-2.43]), however, higher postprandial triglyceride levels were significantly associated with a lower risk for recurrent vascular events (adjusted hazard ratiot3, 0.42 [95% CI, 0.18-0.95]). No associations were observed between fasting and post-oral glucose tolerance test blood glucose levels and recurrent vascular risk. All findings were irrespective of the diabetic status of patients. CONCLUSIONS: In this cohort of patients with first-ever' minor ischemic stroke, fasting triglyceride or glucose levels were not associated with recurrent stroke at one year after stroke. However, higher postprandial triglyceride levels were associated with a lower risk of recurrent vascular events which requires further validation in future studies. Overall, our results do not support the routine use of a combined OTTT/oral glucose tolerance test to improve risk prediction for recurrent stroke.

Exact replication: Foundation of science or game of chance?

The need for replication of initial results has been rediscovered only recently in many fields of research. In preclinical biomedical research, it is common practice to conduct exact replications with the same sample sizes as those used in the initial experiments. Such replication attempts, however, have lower probability of replication than is generally appreciated. Indeed, in the common scenario of an effect just reaching statistical significance, the statistical power of the replication experiment assuming the same effect size is approximately 50%-in essence, a coin toss. Accordingly, we use the provocative analogy of "replicating" a neuroprotective drug animal study with a coin flip to highlight the need for larger sample sizes in replication experiments. Additionally, we provide detailed background for the probability of obtaining a significant p value in a replication experiment and discuss the variability of p values as well as pitfalls of simple binary significance testing in both initial preclinical experiments and replication studies with small sample sizes. We conclude that power analysis for determining the sample size for a replication study is obligatory within the currently dominant hypothesis testing framework. Moreover, publications should include effect size point estimates and corresponding measures of precision, e.g., confidence intervals, to allow readers to assess the magnitude and direction of reported effects and to potentially combine the results of initial and replication study later through Bayesian or meta-analytic approaches.

[Structured Collection of Data on Support Offers for Lung Cancer and Stroke Patients in Berlin]. / Strukturierte Erfassung von Unterstützungsangeboten für Lungenkrebs- und Schlaganfallbetroffene in Berlin.

OBJECTIVES: The aim of this study was to investigate available offers of support for stroke and lung cancer patients and their caregivers in the Berlin region besides direct medical or therapeutic care and to identify barriers in the use of available support from the perspective of care experts. METHODS: A structured search of different sources, including an internet search, print information as well as interviews with experts and a group discussion, was conducted on support services available to lung cancer and stroke patients and their caregivers in Berlin for managing their altered health and life situation. Target groups of identified offers were verified and further information was gathered by a questionnaire. Further, barriers for utilization of support services were analyzed from conducted interviews and the group discussion with health care experts. RESULTS: A total of 150 support services were identified for lung cancer and stroke patients and their caregivers in Berlin. There were many different forms of such offers, including, but not limited to, providing information and counseling, helping with the organization and coordination of the new life situation as well as giving psychosocial support. Missing information or information that was not adjusted to the patients' education level about care entitlements, lack of knowledge about as well as spatial distance to facilities were stated as barriers for utilization. CONCLUSIONS: A variety of support services is available in Berlin for lung cancer and stroke patients and their caregivers regarding different needs that might arise from their altered health and living situation. Providing information on existing offers more broadly to the target group and improving local availability may optimize utilization of such services by patients.

Construct validity of the Post-COVID-19 Functional Status Scale in adult subjects with COVID-19.

BACKGROUND: An increasing number of subjects are recovering from COVID-19, raising the need for tools to adequately assess the course of the disease and its impact on functional status. We aimed to assess the construct validity of the Post-COVID-19 Functional Status (PCFS) Scale among adult subjects with confirmed and presumed COVID-19. METHODS: Adult subjects with confirmed and presumed COVID-19, who were members of an online panel and two Facebook groups for subjects with COVID-19 with persistent symptoms, completed an online survey after the onset of infection-related symptoms. The number and intensity of symptoms were evaluated with the Utrecht Symptom Diary, health-related quality of life (HrQoL) with the 5-level EQ-5D questionnaire, impairment in work and activities with the Work Productivity and Activity Impairment questionnaire and functional status with the PCFS Scale. RESULTS: 1939 subjects were included in the analyses (85% women, 95% non-hospitalized during infection) about 3 months after the onset of infection-related symptoms. Subjects classified as experiencing 'slight', 'moderate' and 'severe' functional limitations presented a gradual increase in the number/intensity of symptoms, reduction of HrQoL and impairment in work and usual activities. No differences were found regarding the number and intensity of symptoms, HrQoL and impairment in work and usual activities between subjects classified as experiencing 'negligible' and 'no' functional limitations. We found weak-to-strong statistical associations between functional status and all domains of HrQoL (r: 0.233-0.661). Notably, the strongest association found was with the 'usual activities' domain of the 5-level EQ-5D questionnaire. CONCLUSION: We demonstrated the construct validity of the PCFS Scale in highly-symptomatic adult subjects with confirmed and presumed COVID-19, 3 months after the onset of symptoms.

Dying in the Neurointensive Care Unit After Withdrawal of Life-Sustaining Therapy: Associations of Advance Directives and Health-Care Proxies With Timing and Treatment Intensity.

BACKGROUND AND PURPOSE: Critically ill patients require a careful approach for prognosis and decision-making. The German health legislation aims to strengthen the role of advance directives (ADs) and health-care proxies (HCPs). Their impact within a dedicated neurocritical care setting is unknown. This study aimed to assess the practice of withdrawal or withholding of life-sustaining therapy (WOLST) in a German neurointensive care unit (NICU) focusing on whether AD or HCP is associated with timing and treatment intensity. METHODS: Data on patients who died after WOLST at a dedicated NICU of a German university hospital, from 2010 to 2013, were retrospectively analyzed. RESULTS: Of 400 deceased patients, 310 (77.5%) died after initiation of WOLST. Among them, 68 (21.9%) were identified to have AD or HCP or both (AD + HCP). WOLST patients with AD, HCP, or AD + HCP were older than those without (median age: 77 vs 72 years, P < .001) but did not show any other distinct baseline features. There was no difference in the specific neurocritical care measures between the groups. Poisson regression analysis showed no significant difference in the probability of time-dependent WOLST initiation between those with and without AD/HCP, after adjusting for age and sex (adjusted incidence rate ratio, 1.10; 95% confidence interval, 0.94-1.28; P = .244). CONCLUSIONS: In this single-center study of mainly cerebrovascular NICU patients, AD or HCP was neither associated with an earlier WOLST nor associated with a difference in treatment intensity before WOLST. Further prospective studies should assess the emerging concept of advance care planning in neurocritical care.

Can routine register data be used to identify vulnerable lung cancer patients of suboptimal care in a German comprehensive cancer centre?

OBJECTIVES: Several patient factors have been described to influence access to optimal cancer care like socioeconomic factors or place of residence. In this study, we investigate whether data routinely collected in a clinical cancer registry can be used to identify populations of lung cancer patients with increased risk of not receiving optimal cancer care. METHODS: We analysed data of 837 lung cancer patients extracted from the clinical cancer registry of a German university hospital. We compared patient populations by two indicators of optimal care, namely implementation of tumour board meeting recommendations as well as the timeliness of care. RESULTS: There was a high rate of implementation of tumour board meeting recommendations of 94.4%. Reasons for non-implementation were mainly a patient's own wish or a worsening of the health situation. Of all patient parameters, only tumour stage was associated with the two optimal care indicators. CONCLUSION: Using routine data from a clinical cancer registry, we were not able to identify patient populations at risk of not getting optimal care and the implementation of guideline-conform care appeared to be very high in this setting. However, limitations were the ambiguity of optimal care indicators and availability of parameters predictive for patients' vulnerability.

Association Between Dispatch of Mobile Stroke Units and Functional Outcomes Among Patients With Acute Ischemic Stroke in Berlin.

Importance: Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been shown to reduce time to treatment. Objective: To determine whether dispatch of MSUs is associated with better clinical outcomes for patients with acute ischemic stroke. Design, Setting, and Participants: This prospective, nonrandomized, controlled intervention study was conducted in Berlin, Germany, from February 1, 2017, to October 30, 2019. If an emergency call prompted suspicion of stroke, both a conventional ambulance and an MSU, when available, were dispatched. Functional outcomes of patients with final diagnosis of acute cerebral ischemia who were eligible for thrombolysis or thrombectomy were compared based on the initial dispatch (both MSU and conventional ambulance or conventional ambulance only). Exposure: Simultaneous dispatch of an MSU (computed tomographic scanning with or without angiography, point-of-care laboratory testing, and thrombolysis capabilities on board) and a conventional ambulance (n = 749) vs conventional ambulance alone (n = 794). Main Outcomes and Measures: The primary outcome was the distribution of modified Rankin Scale (mRS) scores (a disability score ranging from 0, no neurological deficits, to 6, death) at 3 months. The coprimary outcome was a 3-tier disability scale at 3 months (none to moderate disability; severe disability; death) with tier assignment based on mRS scores if available or place of residence if mRS scores were not available. Common odds ratios (ORs) were used to quantify the association between exposure and outcome; values less than 1.00 indicated a favorable shift in the mRS distribution and lower odds of higher levels of disability. Results: Of the 1543 patients (mean age, 74 years; 723 women [47%]) included in the adjusted primary analysis, 1337 (87%) had available mRS scores (primary outcome) and 1506 patients (98%) had available the 3-tier disability scale assessment (coprimary outcome). Patients with an MSU dispatched had lower median mRS scores at month 3 (1; interquartile range [IQR], 0-3) than did patients without an MSU dispatched (2; IQR, 0-3; common OR for worse mRS, 0.71; 95% CI, 0.58-0.86; P < .001). Similarly, patients with an MSU dispatched had lower 3-month coprimary disability scores: 586 patients (80.3%) had none to moderate disability; 92 (12.6%) had severe disability; and 52 (7.1%) had died vs patients without an MSU dispatched: 605 (78.0%) had none to moderate disability; 103 (13.3%) had severe disability; and 68 (8.8%) had died (common OR for worse functional outcome, 0.73, 95% CI, 0.54-0.99; P = .04). Conclusions and Relevance: In this prospective, nonrandomized, controlled intervention study of patients with acute ischemic stroke in Berlin, Germany, the dispatch of mobile stroke units, compared with conventional ambulances alone, was significantly associated with lower global disability at 3 months. Clinical trials in other regions are warranted.

Association Between High-Sensitivity Cardiac Troponin and Risk of Stroke in 96 702 Individuals: A Meta-Analysis.

Background and Purpose- Our study aim was to estimate risk of incident stroke based on levels of hs-cTn (high-sensitivity cardiac troponin), a specific biomarker indicating myocardial injury, in the general population, patients with atrial fibrillation, and patients with previous stroke. Methods- Embase, PubMed, and Web of Science were searched until March 14, 2019 to identify relevant articles. Randomized controlled trials and cohort studies assessing the risk of incident stroke based on hs-cTn were eligible. Pooled adjusted hazard ratios including 95% CI were calculated using a random-effects model due to study heterogeneity per population, coding of hs-cTn (categorical/continuous data), per hs-cTn subunit (T or I), for low risk of bias, and for all-cause and ischemic stroke separately. Results- We included 17 articles with 96 702 participants. In studies conducted in the general population (n=12; 77 780 participants), the pooled adjusted hazard ratio for incident stroke was 1.25 (CI, 1.10-1.40) for high versus low hs-cTn (as defined by included studies) during an average follow-up of 1 to 20 years (median 10). When categorical data were used, this was increased to 1.58 (CI, 1.26-1.90). The results were robust when accounting for stroke classification (all-cause stroke/ischemic stroke), hs-cTn subunit, risk of bias, and coding of hs-cTn. In patients with atrial fibrillation (4 studies; 18 725 participants), the pooled adjusted hazard ratio for incident stroke was 1.95 (CI, 1.29-2.62) for high versus low hs-cTn. Due to lack of data (one study, 197 participants), no meta-analysis could be performed in patients with previous stroke. Conclusions- This meta-analysis suggests that hs-cTn can be regarded as a risk marker for incident stroke, with different effect size in different subgroups. More research about the association between hs-cTn and incident stroke in high-risk populations is needed, especially in patients with history of ischemic stroke.

High-Sensitivity Cardiac Troponin T and Cognitive Function in Patients With Ischemic Stroke.

Background and Purpose- Our study aim was to assess whether high-sensitivity cardiac troponin T (hs-cTnT), a specific biomarker for myocardial injury, is associated with cognitive function in patients after mild-to-moderate first-ever ischemic stroke. Methods- We used data from PROSCIS-B (Prospective Cohort With Incident Stroke Berlin). Cognitive function was assessed by Mini-Mental-State-Examination at baseline, and Telephone Interview for Cognitive Status-modified after 1 to 3 years of follow-up. Patients were categorized according to hs-cTnT quartiles. We performed generalized linear regression to calculate risk ratios of cognitive impairment (Mini-Mental-State-Examination <27; Telephone Interview for Cognitive Status-modified <32). Association of hs-cTnT with cognitive function over time was estimated using a linear mixed model. Results- We included 555 patients (mean age, 67 years, 62% male, median National Institutes of Health Stroke Scale 2 [interquartile range, 1-5], hs-cTnT above upper reference limit 40%, baseline cognitive impairment 28%). Baseline Mini-Mental-State-Examination score and rate of cognitive impairment were lower in patients in the highest versus lowest hs-cTnT quartile (median Mini-Mental-State-Examination 27 versus 29, and 15.3% versus 43.0%, adjusted risk ratio, 1.76 [95% CI, 1.07-2.90], respectively). If anything, cognition seemed to improve in all groups, yet Telephone Interview for Cognitive Status-modified scores were consistently lower in patients within the highest versus lowest hs-cTnT quartile (adjusted ß, -1.33 [95% CI, -2.65 to -0.02]), without difference in the rate of change over time. Conclusions- In patients with mild-to-moderate first-ever ischemic stroke without dementia, higher hs-cTnT was associated with higher prevalence of cognitive impairment at baseline and lower Telephone Interview for Cognitive Status-modified during 3-year follow-up. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856.

Long-Term Mortality Among ICU Patients With Stroke Compared With Other Critically Ill Patients.

OBJECTIVES: Assessment of all-cause mortality of intracerebral hemorrhage and ischemic stroke patients admitted to the ICU and comparison to the mortality of other critically ill ICU patients classified into six other diagnostic subgroups and the general Dutch population. DESIGN: Observational cohort study. SETTING: All ICUs participating in the Dutch National Intensive Care Evaluation database. PATIENTS: All adult patients admitted to these ICUs between 2010 and 2015; patients were followed until February 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of all 370,386 included ICU patients, 7,046 (1.9%) were stroke patients, 4,072 with ischemic stroke, and 2,974 with intracerebral hemorrhage. Short-term mortality in ICU-admitted stroke patients was high with 30 days mortality of 31% in ischemic stroke and 42% in intracerebral hemorrhage. In the longer term, the survival curve gradient among ischemic stroke and intracerebral hemorrhage patients stabilized. The gradual alteration of mortality risk after ICU admission was assessed using left-truncation with increasing minimum survival period. ICU-admitted stroke patients who survive the first 30 days after suffering from a stroke had a favorable subsequent survival compared with other diseases necessitating ICU admission such as patients admitted due to sepsis or severe community-acquired pneumonia. After having survived the first 3 months after ICU admission, multivariable Cox regression analyses showed that case-mix adjusted hazard ratios during the follow-up period of up to 3 years were lower in ischemic stroke compared with sepsis (adjusted hazard ratio, 1.21; 95% CI, 1.06-1.36) and severe community-acquired pneumonia (adjusted hazard ratio, 1.57; 95% CI, 1.39-1.77) and in intracerebral hemorrhage patients compared with these groups (adjusted hazard ratio, 1.14; 95% CI, 0.98-1.33 and adjusted hazard ratio, 1.49; 95% CI, 1.28-1.73). CONCLUSIONS: Stroke patients who need intensive care treatment have a high short-term mortality risk, but this alters favorably with increasing duration of survival time after ICU admission in patients with both ischemic stroke and intracerebral hemorrhage, especially compared with other populations of critically ill patients such as sepsis or severe community-acquired pneumonia patients.

Impact of COPD and anemia on motor and cognitive performance in the general older population: results from the English longitudinal study of ageing.

BACKGROUND: Cognitive and motor-performance decline with age and the process is accelerated by decline in general health. In this study, we aimed to estimate the effects of COPD and HB levels on cognitive and motor performance in the general older population and assess potential interaction. METHODS: The English Longitudinal Study of Aging is a population-based cohort study including measurements of lung-function and HB levels together with cognitive and motor performance testing. Data were collected from 5709 participants including three measurement time over eight years. COPD was defined using lung-function-parameters and clinical symptoms. HB was assessed continuously and low HB was defined using clinical anemia cutoffs. Linear mixed-effects regression models were used to quantify the associations of COPD and HB with outcome measures, both individually and in combination. RESULTS: Participants with both low HB and COPD demonstrated worse motor performance compared to individuals with only one exposure, resulting in up to 1 s (95%CI, 0.04-1.8) longer time needed to complete the five times sit to stand task than what would be expected based on purely additive effects. Additionally in individuals with COPD, the time to complete the motor-performance task per unit decrease in continuous HB levels was longer than in participants without COPD after full adjustment for confounding (up to 1.38 s/unit HB level, 95% CI: 0.65-2.11). CONCLUSION: In persons with COPD low HB levels may contribute to low motor-performance in a supra additive fashion. Further studies should re-evaluate whether earlier treatment of lower HB in these individuals might be beneficial.

Increasing efficiency of preclinical research by group sequential designs.

Despite the potential benefits of sequential designs, studies evaluating treatments or experimental manipulations in preclinical experimental biomedicine almost exclusively use classical block designs. Our aim with this article is to bring the existing methodology of group sequential designs to the attention of researchers in the preclinical field and to clearly illustrate its potential utility. Group sequential designs can offer higher efficiency than traditional methods and are increasingly used in clinical trials. Using simulation of data, we demonstrate that group sequential designs have the potential to improve the efficiency of experimental studies, even when sample sizes are very small, as is currently prevalent in preclinical experimental biomedicine. When simulating data with a large effect size of d = 1 and a sample size of n = 18 per group, sequential frequentist analysis consumes in the long run only around 80% of the planned number of experimental units. In larger trials (n = 36 per group), additional stopping rules for futility lead to the saving of resources of up to 30% compared to block designs. We argue that these savings should be invested to increase sample sizes and hence power, since the currently underpowered experiments in preclinical biomedicine are a major threat to the value and predictiveness in this research domain.

Intrinsic Coagulation Pathway, History of Headache, and Risk of Ischemic Stroke.

Background and Purpose- Hypercoagulable states in migraine patients may play a role in the pathophysiology underlying the association between migraine and ischemic stroke. This study aims to provide more insight into the potential association of headache, ischemic stroke, and the intrinsic coagulation pathway. Methods- We included patients from the RATIO study (Risk of Arterial Thrombosis in Relation to Oral Contraceptives), a Dutch population-based case-control study including young women (age <50) with ischemic stroke and healthy controls. We defined a headache group based on a questionnaire on headache history. Intrinsic coagulation proteins were measured through both antigen levels (FXII, FXI, prekallikrein, HK [high molecular weight kininogen]) and protein activation, determined by measuring activated protein complex with C1esterase-inhibitor (FXIIa-C1-INH, FXIa-C1-INH, Kallikrein-C1-INH) or antitrypsin-inhibitor (FXIa-AT-INH). We calculated adjusted odds ratios and performed an interaction analysis assessing the increase in stroke risk associated with high levels of intrinsic coagulation and history of headache. Results- We included 113 ischemic stroke cases and 598 healthy controls. In total, 134 (19%) patients had a history of headache, of whom 38 were cases and 96 controls. The combination of headache and high intrinsic coagulation protein levels (all but FXII antigen level and both FXIa-inhibitors) was associated with an increase in ischemic stroke risk higher than was expected based on their individual effects (adjusted odds ratio FXI antigen level alone: 1.7, 95% CI, 1.0-2.9; adjusted odds ratio headache alone: 2.0, 95% CI, 1.1-3.7; combination: 5.2, 95% CI, 2.3-11.6) Conclusions- Headache and high intrinsic coagulation protein levels may biologically interact, increasing risk for ischemic stroke.

Serum Anti-NMDA (N-Methyl-D-Aspartate)-Receptor Antibodies and Long-Term Clinical Outcome After Stroke (PROSCIS-B).

Background and Purpose- NMDAR1-abs (anti-N-Methyl-D-Aspartate receptor GluN1 antibodies), predominantly known in the context of autoimmune encephalitis, have been observed in serum of healthy individuals. A previous study found smaller stroke magnetic resonance imaging lesion growth in seropositive patients, suggesting a neuroprotective effect of these antibodies. The impact of NMDAR1-abs seropositivity on long-term functional outcome and recurrent vascular events and death after first-ever stroke remains unclear. Methods- Data from the Prospective Cohort with Incident Stroke-Berlin were used. NMDAR1-abs (ie, IgM, IgA, and IgG) were measured in serum within 7 days after first stroke. Outcomes of interest included modified Rankin Scale at one year and the time-to-event of a combined end point (recurrent stroke, myocardial infarction, and all-cause mortality) within 3 years. We calculated odds ratios from adjusted partial proportional odds models and subsequently compared outcome of patients with low titers (1:10; 1:32; and 1:100), and high titers (1:320; 1:1000) to seronegative patients. Furthermore, we estimated hazard ratios for a secondary vascular event or death in NMDAR1-abs seropositive compared to seronegative patients in models adjusted for confounders. Results- The analyses included 583 patients with antibody measurements (39% female, median National Institutes of Health Stroke Scale:2, IQR:1-4), and NMDAR1-abs were observed in 76 (13%) patients. NMDAR1-abs seroprevalence was not associated with functional outcome (odds ratio=1.27; 95% CI, 0.77-2.09); sub-group analyses, however, showed worse outcome in patients with high titers (odds ratio=3.47; 95% CI, 1.54-7.80). Seropositive patients had an increased risk for a secondary vascular event or death (hazard ratios =1.83, 95% CI, 1.10-3.05). Conclusions- In our study, NMDAR1-abs seropositivity was not associated with functional outcome at one year after stroke, however, high titers (≥1:320) were associated with poor functional outcome. Furthermore, NMDAR1-abs seropositivity was associated with increased cardiovascular risk within 3 years after first stroke, independently from other risk factors. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01363856.

Where Have All the Rodents Gone? The Effects of Attrition in Experimental Research on Cancer and Stroke.

Given small sample sizes, loss of animals in preclinical experiments can dramatically alter results. However, effects of attrition on distortion of results are unknown. We used a simulation study to analyze the effects of random and biased attrition. As expected, random loss of samples decreased statistical power, but biased removal, including that of outliers, dramatically increased probability of false positive results. Next, we performed a meta-analysis of animal reporting and attrition in stroke and cancer. Most papers did not adequately report attrition, and extrapolating from the results of the simulation data, we suggest that their effect sizes were likely overestimated.

Hypercoagulability and the risk of recurrence in young women with myocardial infarction or ischaemic stroke: a cohort study.

BACKGROUND: We aimed to investigate the role of hypercoagulability on the risk of lifetime cardiovascular recurrences after myocardial infarction or ischaemic stroke. METHODS: Young women (< 50 years) with either myocardial infarction (n = 197) or ischaemic stroke (n = 107) were followed between 1995 and 2012 in the RATIO follow-up study. To determine whether hypercoagulability affects the risk or recurrence, a coagulation score based on acquired and inherited markers was compiled and used in a quartile analysis. Hazard ratios (HRs) obtained from Cox proportional models and adjusted for several cardiovascular risk factors were used to compare quartiles of the coagulation score for the risk of recurrence. RESULTS: During a median follow-up of 19 years, 59 cardiovascular recurrences occurred. In patients with myocardial infarction no association was found between a high prothrombotic score and recurrences (highest quartile vs lowest quartile HR 0.7, 95% CI, 0.3-1.8). Conversely, ischaemic stroke patients with a high prothrombotic score showed a doubling in risk of long-term cardiovascular recurrences (HR 1.9, 95% CI 0.6-6.3) compared with ischaemic stroke patients and low levels of the score, with a dose response relationship. CONCLUSIONS: An increased coagulation tendency might be associated with long-term cardiovascular risk in women with ischaemic stroke, but not in women with myocardial infarction.