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The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.

Background: Quantitative susceptibility mapping (QSM) is a measure of iron content, and ≥6% increase in QSM has been correlated with new hemorrhage in previously stable cavernous angiomas. Longitudinal changes in QSM are not known in cavernous angiomas with symptomatic hemorrhage (CASH) with high rates of rebleeding and are the targets of novel pharmacotherapies. In a prospective multisite Trial Readiness project (clinicaltrials.gov NCT03652181), QSM is longitudinally assessed. Methods: Trial eligible subjects with CASH in the prior year and not undergoing lesion resection or radiation, were enrolled. Mean QSM of CASH lesion was acquired at baseline and at 1 and 2 year planned follow-ups. Relative change in mean lesional QSM during each follow-up year was assessed, and any symptomatic hemorrhage (SH), asymptomatic changes (AC; defined as subclinical bleed or growth) in the lesion during the same epoch. Results: Paired QSM assessments were completed to date in 99 CASH lesions (67 year 1, and 32 year 2) and are reported herein. Four SH and 6 ACs occurred during 1 st follow-up year, and 3 SH during 2 nd year. QSM increased in 54 lesion-years, decreased in 44, and remained stable in 1. The % lesional QSM change in year 1 was significantly higher than that observed in year 2 (mean +9.33, SD 37.52 vs. +5.20; SD= 24.86; p=0.05; Spearman correlation ρ -0.36). CAs with clinical SH or AC had a significantly higher % QSM change than lesions without (mean +28.03, SD 17.77 vs. +4.97, SD= 34.75; p=0.0014). All 13 lesions with SH/AC demonstrated a QSM increase ≥6% while 31 of 86 (36%) lesions with no clinical events had a ≥6% QSM increase. Conclusion: QSM change of ≥6% is present in every CASH lesion manifesting a new SH or AC (100% specificity), and is more common than clinical events (3.4X higher sensitivity). The biomarker can hence be used as a more sensitive categorical outcome than SH or AC in clinical trials of novel therapies aimed at bleeding in CASH lesions. Effect of an intervention on % QSM change may also be proposed as a time-averaged difference between 2 arms using a repeated measures analysis implemented as an unadjusted linear mixed model. These results are the basis of application for certification by the U.S F.D.A. of QSM as a monitoring biomarker of drug effect in CASH.

Background and Purpose: Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH. Methods: This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample t test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion. Results: As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score 30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety ( P =0.007), but better depression ( P =0.002) and social satisfaction scores ( P =0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites. Conclusions: These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.

Introduction: The National Institute of Neurological Disorders and Stroke (NINDS) Common Data Element (CDE) project provides standardized data collection formats for neuroscience clinical research. Goals are to increase harmonization, efficiency, and data quality in studies, and facilitate collaboration through data sharing and analysis. Stroke-specific CDEs were developed in 2010. The Stroke Oversight Committee (OC) reviewed Core CDEs in 2015. Subarachnoid hemorrhage and unruptured cerebral aneurysms (SAH)-specific CDEs were developed in 2017. In 2018, the Stroke OC recommended that Stroke CDEs be updated to Version 2.0. Methods: NINDS in August 2018, convened the Stroke V2.0 Working Group (WG) consisting of over 50 international subject matter experts. Each domain-specific subgroup: Biospecimens, Biomarkers, and Laboratory Tests; Hospital Course and Acute Therapies; Imaging; Long Term Therapies; Medical History and Prior Health Status; Outcomes and Endpoints; Stroke Presentation and Vital Signs; and Stroke Types and Subtypes, reviewed Stroke V1.0 and SAH CDEs relevant to their purview. Subgroups met regularly to discuss updates to existing Stroke CDEs, addition of new instruments and case report forms (CRFs), and harmonization with SAH CDEs. Draft V2.0 recommendations were posted for public review from February 26 to April 8, 2020. The WG considered public feedback before V2.0 was finalized. Results: This comprehensive review led to updates across CDEs and additions to therapies, outcomes, and imaging domains including Imaging Acquisition and SAH Surgical/Procedural Interventions CRFs and Fugl-Meyer Assessment and PROMIS-29 outcome measures. Following review of 39 V1.0 Stroke outcome measures, 11 were reclassified. Stroke V2.0 CDE recommendations include revised and new template CRFs, data dictionaries, instrument informational documents and guidance documents. Stroke V2.0 was posted to the NINDS CDE website in summer 2020. Conclusions: Updates to the NINDS CDEs based on scientific advancements and user feedback ensure they remain a useful resource. The Stroke v2.0 CDEs provide a current tool for clinical investigators across research domains. NINDS encourages CDE use to standardize research data collection across studies.

Background: Patients with cerebral cavernous angiomas with symptomatic hemorrhage (CASH) have high risk of disability from recurrent bleeding. Candidate medications to prevent rebleeding in CASH lesions will require multisite clinical trials with standardized data collection. Objective: To report the prevalence and baseline cohort features in CASH patients and establish a research network infrastructure for trials. Methods: This prospective observational cohort study includes adults with radiologically verified CASH lesion within 1-year of consent. Exclusions include prior or planned surgical intervention, spinal location, or prior brain irradiation. Six sites enrolled patients into the screening and clinical assessment portion of the study starting July 2018. Patients also had the option to participate in the follow up biomarker validation at 4 sites. Baseline demographics, clinical and imaging information, and outcomes (mRS, PROMIS-29, NIHSS, and EuroQol-5D) were collected. Biomarker imaging included dynamic contrast enhanced quantitative perfusion (DCEQP) and quantitative susceptibility mapping (QSM) that correlated with symptomatic bleeding. Descriptive statistics were performed and one-sample t-test was used to compare whether mean T-scores for PROMIS-29 domains differed significantly from a reference population. Results: As of May 2020, 849 CASH patients were screened of whom 110 (13%) were eligible and enrolled; 73 also enrolled into the biomarker validation study. Average age at enrollment was 46±16 years at a mean of 4.4 months after symptom onset; 53% were female, 41% were familial, and 43% of CASH lesions were brainstem location. At enrollment, 90% of the cohort had independent functional outcome (mRS ≤ 2 and NIHSS 30% (EuroQol-5D). CASH cases had significantly worse anxiety but better depression and social satisfaction scores compared to a general population (all P Conclusion: We demonstrate feasibility of multisite recruitment of CASH patients and report prevalence of baseline features that will aid in design of clinical trials and inclusion of appropriate outcome measures.

Objective: The National Institute of Neurological Disorders and Stroke (NINDS) initiated the Common Data Element (CDE) project to provide standardized clinical research data collection formats that increase the efficiency and effectiveness of studies and reduce start-up time, as well as improve data quality and facilitate and accelerate data sharing. In 2010, Stroke-specific CDEs were posted on the NINDS CDE website. The Stroke Oversight Committee (OC) reviewed Core CDEs in 2015; and in 2018, recommended that Stroke CDEs undergo a comprehensive review and update to Version 2.0. Background: In August 2018, a Stroke V2.0 Working Group (WG) consisting of over 50 worldwide subject matter experts was convened by NINDS. The WG was asked to review all current Stroke CDEs and subarachnoid hemorrhage and unruptured cerebral aneurysms (SAH) CDEs (developed in 2017) for harmonization and inclusion within Stroke V2.0. Methods: The Stroke V2.0 WG divided into eight domain-specific subgroups: Biospecimens, Biomarkers, and Laboratory Tests; Hospital Course and Acute Therapies; Imaging; Long Term Therapies; Medical History and Prior Health Status; Outcomes and Endpoints; Stroke Presentation and Vital Signs; and Stroke Types and Subtypes. Subgroups met regularly to review, revise and add to the existing Stroke CDEs based on developments in stroke research. Following an internal WG review, a public review of the draft updates will be held. The WG will consider public feedback before V2.0 is finalized. The Stroke OC plans to review the project status at the 2020 International Stroke Conference. Results: The Stroke V2.0 CDE recommendations will include updated and new template case report forms, data dictionaries, instrument informational documents and guideline documents. The updates will reflect the current state of science, streamline CDE recommendations, and incorporate SAH CDEs. Stroke V2.0 CDEs will be available on the NINDS CDE website in 2020. Conclusions: The NINDS CDEs are periodically revised as research progresses. Through the update of the Stroke CDEs to V2.0, the initiative strives to maintain the utility of CDEs as a valuable clinical research resource. NINDS encourages use of CDEs to standardize research data collection across studies.

Importance Hyperglycemia during acute ischemic stroke is common and is associated with worse outcomes. The efficacy of intensive treatment of hyperglycemia in this setting remains unknown. Objectives To determine the efficacy of intensive treatment of hyperglycemia during acute ischemic stroke. Design, Setting, and Participants The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with hyperglycemia (glucose concentration of >110 mg/dL if had diabetes or ≥150 mg/dL if did not have diabetes) and acute ischemic stroke who were enrolled within 12 hours from stroke onset at 63 US sites between April 2012 and August 2018; follow-up ended in November 2018. The trial included 1151 patients who met eligibility criteria. Interventions Patients were randomized to receive continuous intravenous insulin using a computerized decision support tool (target blood glucose concentration of 80-130 mg/dL [4.4-7.2 mmol/L]; intensive treatment group: n = 581) or insulin on a sliding scale that was administered subcutaneously (target blood glucose concentration of 80-179 mg/dL [4.4-9.9 mmol/L]; standard treatment group: n = 570) for up to 72 hours. Main Outcomes and Measures The primary efficacy outcome was the proportion of patients with a favorable outcome based on the 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) that was adjusted for baseline stroke severity. Results Among 1151 patients who were randomized (mean age, 66 years [SD, 13.1 years]; 524 [46%] women, 923 [80%] with diabetes), 1118 (97%) completed the trial. Enrollment was stopped for futility based on prespecified interim analysis criteria. During treatment, the mean blood glucose level was 118 mg/dL (6.6 mmol/L) in the intensive treatment group and 179 mg/dL (9.9 mmol/L) in the standard treatment group. A favorable outcome occurred in 119 of 581 patients (20.5%) in the intensive treatment group and in 123 of 570 patients (21.6%) in the standard treatment group (adjusted relative risk, 0.97 [95% CI, 0.87 to 1.08],P = .55; unadjusted risk difference, −0.83% [95% CI, −5.72% to 4.06%]). Treatment was stopped early for hypoglycemia or other adverse events in 65 of 581 patients (11.2%) in the intensive treatment group and in 18 of 570 patients (3.2%) in the standard treatment group. Severe hypoglycemia occurred only among patients in the intensive treatment group (15/581 [2.6%]; risk difference, 2.58% [95% CI, 1.29% to 3.87%]). Conclusions and Relevance Among patients with acute ischemic stroke and hyperglycemia, treatment with intensive vs standard glucose control for up to 72 hours did not result in a significant difference in favorable functional outcome at 90 days. These findings do not support using intensive glucose control in this setting. Trial Registration ClinicalTrials.gov Identifier:NCT01369069

ObjectiveThe NINDS Common Data Element (CDE) project provides data standards for clinical research in neuroscience. NINDS/NIH and DoD collaborated to develop CDE recommendations for Biomechanical Devices in TBI. CDEs increase efficiency of clinical research studies by reducing study start-up time and cost, increasing data quality, facilitating data sharing and aggregation, and helping educate new clinical investigators.BackgroundIn January 2017, a working group (WG) of subject matter experts from academia, industry and the military convened to develop CDE recommendations for blast, blunt head impact and inertial-loading exposures measured by biomechanical devices. These CDEs are available as a subset of the TBI recommendations under the Disease/Injury Related Events Domain and Biomechanical Devices Sub-Domain on the NINDS CDE website.Design/methodsThe WG divided into 3 subgroups: Head Accelerometry, Impact Video and Blast Exposure to review commonly collected data and analysis methods. The Head Accelerometry subgroup focused on data captured by kinematic sensors in sports/activities. The Impact Video subgroup addressed the use of video information to confirm device measurements. The Blast Exposure subgroup compared data from research sources using blast overpressure sensors. Subgroup recommendations were reviewed internally across the WG before being posted for public review.ResultsThe WG's end products are summaries, CDE metadata and template case report forms. Assigned classifications guide researchers in selecting CDEs: Supplemental-Highly Recommended (essential for specified conditions, study types or designs), Supplemental (commonly collected, but not required), and Exploratory (reasonable to use, but require further validation). Version 1.0 recommendations were made available for use through the NINDS CDE website in late February 2018.ConclusionThese new CDE recommendations will facilitate robust metadata analysis and data-sharing. NINDS encourages use of CDEs for all clinical research in neuroscience. NINDS CDEs are a dynamic resource, which is updated periodically based on the current state of science.

ObjectiveThe purpose of the NINDS CDE project is to educate new clinical investigators, increase efficiency and effectiveness of clinical research studies and treatment, increase data quality, facilitate data sharing, significantly reduce study start-up time, and more effectively aggregate information into significant metadata results. In 2016, as part of the NINDS CDE project to develop data standards for all clinical neuroscience research, NINDS, NIH and the DoD initiated the development of Sport-Related Concussion (SRC) CDEs.BackgroundTBI CDE recommendations were published on the NINDS CDE website in 2010, but lacked a thorough inclusion of SRC. In August 2016, a new SRC-specific working group (WG) began developing and identifying CDEs, template case report forms (CRFs), and guidelines to assist investigators conducting SRC-specific clinical research studies.Design/methodsThe CDE WG, which consisted of 34 worldwide SRC research experts, met regularly via teleconference over several months. The WG was divided into 3 subgroups to examine SRC during defined periods relative to time of injury: Acute (72 hours post-concussion), Sub-Acute (3 days-3 months post-concussion) and Persistent/Chronic (3 months and greater post-concussion).ResultsVersion 1.0 of the SRC CDEs were available on the NINDS CDE website in June 2017. These include Core and Supplemental, Highly Recommended CDEs or instruments for cognitive measures and symptom checklists, as well as, other outcomes and endpoints, and sample CRFs for domains typically included in clinical research studies (e.g., vestibular, oculomotor, balance, anxiety, depression).ConclusionThe NINDS CDEs are reviewed and updated regularly as research advancements or changes to specific recommendations are deemed appropriate. Because the CDEs are an evolving resource, continued feedback is important for improved use and utility. The use of SRC CDE recommendations is highly encouraged for SRC related researchers as they serve as a valuable starting point and facilitate streamlining and sharing data.