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Background: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project., Methods: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted., Results: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH ( P =0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05., Conclusions: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181., Competing Interests: Disclosures Dr Awad is a consultant and Dr Kim oversees data and safety monitoring board for Neurelis, Inc. Dr Awad reports compensation from Medicoegal consulting for expert witness services. S. Kinkade reports employment by UChicago. Drs Kim and Flemming are consultants for Recursion Pharmaceuticals. Dr Huang is the Director for the American Board of Neurological Surgery; reports compensation by Longevity Neuro Solutions; reports employment by School of Medicine, Johns Hopkins University; and reports other intellectual property for Fundamentals of Operative Neurosurgery. Dr Hutson is a stockholder in Navinetics and Resoundant; reports grants from Batterman Family Foundation; reports compensation from Eisai, Inc; and reports a provisional patent for Brain MR Elastography licensed to Mayo Clinic. Dr Lupo has a grant from GE Healthcare. Dr Mabray is employed by Mind Research Network and is a consultant for Smart Soft Healthcare. K. Lane and Dr Hanley report funding from the National Institute of Neurological Disorders and Stroke. N. Ostapkovich reports employment by Johns Hopkins University. Dr Koenig is employed by the National Institutes of Health (NIH). This report does not represent the official view of the NIH or any part of the US Federal Government, and no official support or endorsement of this article by the NIH is intended or should be inferred. The other authors report no conflicts.

New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or "hybrid" trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology., Competing Interests: Dr Benjamin, Jr. reports consultancy for Allergan, Melinta Therapeutics, and Sun Pharma Advanced Research Co. The remaining authors declare no conflicts of interest., (© The Author(s) 2023.)

Background: Timely trial start-up is a key determinant of trial success; however, delays during start-up are common and costly. Moreover, data on start-up metrics in pediatric clinical trials are sparse. To expedite trial start-up, the Trial Innovation Network piloted three novel mechanisms in the trial titled Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multi-site, randomized, double-blind, placebo-controlled trial in the pediatric intensive care setting., Methods: The three novel start-up mechanisms included: 1) competitive activation; 2) use of trial start-up experts, called site navigators; and 3) supplemental funds earned for achieving pre-determined milestones. After sites were activated, they received a web-based survey to report perceptions of the DOSE start-up process. In addition to perceptions, metrics analyzed included milestones met, time to start-up, and subsequent enrollment of subjects., Results: Twenty sites were selected for participation, with 19 sites being fully activated. Across activated sites, the median (quartile 1, quartile 3) time from receipt of regulatory documents to site activation was 82 days (68, 113). Sites reported that of the three novel mechanisms, the most motivating factor for expeditious activation was additional funding available for achieving start-up milestones, followed by site navigator assistance and then competitive site activation., Conclusion: Study start-up is a critical time for the success of clinical trials, and innovative methods to minimize delays during start-up are needed. Milestone-based funds and site navigators were preferred mechanisms by sites participating in the DOSE study and may have contributed to the expeditious start-up timeline achieved., Clinicaltrials: gov #: NCT03938857., Competing Interests: Declaration of Competing Interest AEB receives salary support through the US government National Institute of Child Health and Human Development T32 training grant (1T32HD094671). MLB receives salary support from the National Institutes of Health (5R01HD089928–05, 5U24TR001608–4, HHSN275201800003I, 3U24TR001608-04S1), PCORI (PaCr-2017C2–8177), FDA Arthritis Advisory Committee, and the Childhood Arthritis and Rheumatology Research Alliance. CDH has performed consulting services for Tellus Therapeutics and Amarin Pharma, Inc. unrelated to the content of this article. JMC receives salary support from the National Institutes of Health (U24HL135691). RGG and KGA have provided consulting services for industry unrelated to the content of this article. CPH receives salary support for research from National Institute for Child Health and Human Development (NICHD) (R13HD102136; RL1HD107784; R01HD106588), the National Heart Lung and Blood Institute (NHLBI) (R61/R33HL147833), the US Food and Drug Administration (R01-FD006099, PI Laughon; and U18-FD006298), the U.S. government for his work in pediatric clinical pharmacology (Government Contract HHSN275201800003I, PI: Benjamin under the Best Pharmaceuticals for Children Act), the non-profit Burrhoughs Wellcome Fund, and other sponsors for drug development in adults and children (https://dcri.org/about-us/conflict-of-interest/). KOZ received salary support from NICHD (1K23HD091398; Zimmerman), Duke CTSA (KL2TR001115; Zimmerman), Pediatric Trials Network (NIH/HHSN-275201000003I), and FDA (UG3/UH3 FD 006797)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Given the convergence of the long and challenging development path for medical devices with the need for diagnostic capabilities for mild traumatic brain injury (mTBI/concussion), the effective role of public-private partnership (PPP) can be demonstrated to yield Food and Drug Administration (FDA) clearances and innovative product introductions. An overview of the mTBI problem and landscape was performed. A detailed situation analysis of an example of a PPP yielding an innovative product was further demonstrated. The example of PPP has led to multiple FDA clearances and product introductions in the TBI diagnostic product category where there was an urgent military and public need. Important lessons included defining the primary public and military health objective for new product introduction, the importance of the government-academia-industry PPP triad with a "collaboration towards solutions" Quality-by-Design (QbD) mindset to assure clinical validity with regulatory compliance, the development of device comparators and integration of measurements into a robust, evidence-based statistical and FDA pathway, and the utility of top-down, flexible, practical action while operating within governmental guidelines and patient safety., (© The Author(s) 2022.)

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 <5). However, perceived health problems affecting quality of life were reported in >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.

Status epilepticus (SE) is a potentially life-threatening condition that requires prompt and aggressive treatment. Prolonged status seizures are associated with significant physiological sequelae and neurological deficits. Although systemic events such as hyperthermia and anoxia contribute to neuronal damage, SE in and of itself can induce cell death. In general, the sooner it is brought under control, the more favourable is the prognosis. Benzodiazepines, as a group, are the most frequently used anticonvulsants in the management of status seizures. Midazolam, a water-soluble benzodiazepine, is a potent anticonvulsant that offers many advantages over typical benzodiazepines. Because of its stability in aqueous media, midazolam dissolves in common diluents such as normal saline or dextrose water. Consequently, midazolam both intravenously (i.v.) and intramuscularly (i.m.) is well tolerated locally and is associated with less venoirritation than benzodiazepines or antiepileptics that require organic solvents. The water solubility of midazolam also allows rapid and reliable absorption of the drug from the i.m. injection site. Because it is rapidly metabolised and its metabolites are pharmacologically inactive, midazolam has a short duration of action. Most patients regain full conscious state and can be evaluated soon after the cessation of treatment. Midazolam by continuous i.v. infusion and by the i.m. route has been successfully used in the treatment of SE. Although some respiratory and haemodynamic side-effects have been associated with midazolam, no clinically significant side-effects were observed with its use for the indication of SE. It is suggested that midazolam is a safe and rapidly effective treatment option in the management of SE in the critical care setting.

Background: Antiplatelet agents are widely recognized for their efficacy in reducing the occurrence of vascular events in patients with atherothrombotic disease. Aspirin is currently considered to be the "reference standard" antiplatelet agent and is recommended by the American Heart Association for use in patients with a wide range of manifestations of cardiovascular disease on the basis of its high benefit-to-risk and benefit-to-cost ratios. Recently, clopidogrel (Plavix, Bristol-Myers Squibb Co), another antiplatelet agent, was approved by the Food and Drug Administration for many of the same indications as aspirin., Summary of Review: Because physicians will be faced with deciding whether to switch from the well-established practice of recommending aspirin for use in patients with atherothrombotic disease, both aspirin and clopidogrel are compared with respect to the primary factors that influence such decisions (ie, their relative efficacy, safety, cost, and convenience of use)., Conclusions: Based on the available evidence, aspirin is preferred for the majority of stroke or myocardial infarction patients at risk of recurrent atherothrombotic events. Clopidogrel may, however, provide valuable therapeutic benefit over aspirin in patients with peripheral arterial disease and in stroke or myocardial infarction patients for whom aspirin treatment is contraindicated or for whom aspirin fails to achieve the desired therapeutic effect.

In this article, we have reviewed the pathophysiology and several therapeutic strategies for cerebral ischemia. It seems likely that there will never be simple therapeutic answers to the complex pathophysiology of cerebral ischemia as we now understand it. Ultimate therapies will probably involve combinations of interventions designed to block several ongoing pathophysiologic processes in neuronal death. Progress in this field will likely be slow and difficult.