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In multi-regional clinical trials, planning the sample size for participating regions is essential for the evaluation of the treatment effect consistency across regions. Based on the MRCT design and sample size allocation to regions, consistency probability is usually used to predict the consistent trend between regions and the overall population, while preserving a certain proportion of the overall treatment effect. Specific enrollment characteristics in a region of interest should also be considered during the time of the sample size planning. To facilitate efficient and harmonized regional sample size planning, we have developed RegionSizeR, a comprehensive and user-friendly interactive web-based R shiny application that can be obtained from https://github.com/rsr-ss/RegionSizeR . This simulation-based app can serve as an initial point for discussions on sample size allocation plans, following preservation of treatment effect method in ICH E17. The app accommodates various types of endpoints and designs, including continuous, binary, and time-to-event endpoints, for superiority, non-inferiority, and MCP-Mod designs. To ensure the validity of this app, independent testing is conducted allowing a discrepancy of no more than 1% across all results considering various scenarios., (© 2024. The Author(s).)

Background: Sarcopenia is a geriatric disease characterized by loss of muscle mass and strength. Although combined exercise and nutrition intervention are known to be effective for sarcopenia, clinical trials involving outpatients with sarcopenia in primary care are scarce. We describe a protocol for a trial to examine the effects of a 12-week combined exercise and nutrition intervention in Korean older adults with possible sarcopenia in community-based primary care., Methods: This multicenter, randomized, controlled trial will include 94 community-dwelling older outpatients aged 65-85 years with possible sarcopenia (47 participants in the intervention and control groups each). Resistance exercises, which incorporate concentric and eccentric exercises, will consist of an introductory phase (3 weeks: twice-weekly supervised exercise sessions and once-weekly home exercises; contraction exercises), an expanded phase (3 weeks: twice-weekly supervised exercise sessions and once-weekly home exercises; eccentric exercises), and a maintenance phase (6 weeks: once-weekly supervised exercise sessions and twice-weekly home exercises; power/eccentric exercises). Nutritional supplementation will be provided according to the nutritional status of the participants using a Mini-Nutritional Assessment. Participants will be assessed at baseline, 12 and 24 weeks, and the primary outcome will be the 5-times chair stand test results., Discussion: To the best of our knowledge, this will be the first clinical trial to evaluate the efficacy of a combined exercise and nutritional supplementation intervention in older outpatients with possible sarcopenia in community-based primary care clinics. These findings will provide new insights to clinicians regarding the long-term usability for doctors and outpatients with possible sarcopenia in community-based primary care., Trial Registration: This trial was prospectively registered at ClinicalTrials.gov on September 16, 2023 (registration number: NCT06049914)., (© 2024. The Author(s).)

Background: The discrepancy between experimental research and clinical trial outcomes is a persistent challenge in preclinical studies, particularly in stroke research. A possible factor contributing to this issue is the lack of standardization across experimental stroke models, leading to poor reproducibility in multicenter studies. This study addresses this gap by aiming to enhance reproducibility and the efficacy of multicenter studies through the harmonization of protocols and training of involved personnel., Methods: We established a set of standard operating procedures for various stroke models and the Neuroscore. These standard operating procedures were implemented across multiple research centers, followed by specialized, in-person training for all participants. We measured the variability in infarct volume both before and after the implementation of these standardized protocols and training sessions., Results: The standardization process led to a significant reduction in variability of infarct volume across different stroke models (40%-50% reduction), demonstrating the effectiveness of our harmonized protocols and training. Additionally, the implementation of the Neuroscore system across centers showed low variability and consistent results up to 28 days poststroke, underscoring its utility in chronic phase evaluations., Conclusions: The harmonization of protocols and surgeon training significantly reduced variability in experimental outcomes across different centers. This improvement can increase the comparability of data between research groups and enhance the statistical power of multicenter studies. Our findings also establish the Neuroscore as a reliable tool for long-term assessment in stroke research, paving the way for more consistent and impactful multicenter preclinical studies., Competing Interests: None.

Despite a growing body of literature in the area of recruitment modeling for multicenter studies, in practice, statistical models to predict enrollments are rarely used and when they are, they often rely on unrealistic assumptions. The time-dependent Poisson-Gamma model (tPG) is a recently developed flexible methodology which allows analysts to predict recruitments in an ongoing multicenter trial, and its performance has been validated on data from a cohort study. In this article, we illustrate and further validate the tPG model on recruitment data from randomized controlled trials. Additionally, in the appendix, we provide a practical and easy to follow guide to its implementation via the tPG R package. To validate the model, we show the predictive performance of the proposed methodology in forecasting the recruitment process of two HIV vaccine trials conducted by the HIV Vaccine Trials Network in multiple Sub-Saharan countries., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aims: Regulatory guidelines recommend that sponsors develop a risk-based approach to monitoring clinical trials. However, there is a lack of evidence to guide the effective implementation of monitoring activities encompassed in this approach. The aim of this study was to assess the efficiency and impact of the risk-based monitoring approach used for a multicentre randomised controlled trial comparing treatments in paediatric patients undergoing cardiac bypass surgery., Methods: This is a secondary analysis of data from a randomised controlled trial that implemented targeted source data verification as part of the risk-based monitoring approach. Monitoring duration and source to database error rates were calculated across the monitored trial dataset. The monitored and unmonitored trial dataset, and simulated trial datasets with differing degrees of source data verification and cohort sizes were compared for their effect on trial outcomes., Results: In total, 106,749 critical data points across 1,282 participants were verified from source data either remotely or on-site during the trial. The total time spent monitoring was 365 hours, with a median (interquartile range) of 10 (7, 16) minutes per participant. An overall source to database error rate of 3.1% was found, and this did not differ between treatment groups. A low rate of error was found for all outcomes undergoing 100% source data verification, with the exception of two secondary outcomes with error rates >10%. Minimal variation in trial outcomes were found between the unmonitored and monitored datasets. Reduced degrees of source data verification and reduced cohort sizes assessed using simulated trial datasets had minimal impact on trial outcomes., Conclusions: Targeted source data verification of data critical to trial outcomes, which carried with it a substantial time investment, did not have an impact on study outcomes in this trial. This evaluation of the cost-effectiveness of targeted source data verification contributes to the evidence-base regarding the context where reduced emphasis should be placed on source data verification as the foremost monitoring activity.

Background: Knowing the predictive factors of the variation in a center-level continuous outcome of interest is valuable in the design and analysis of parallel-arm cluster randomized trials. The symbolic two-step method for sample size planning that we present incorporates this knowledge while simultaneously accounting for patient-level characteristics. Our approach is illustrated through application to cluster randomized trials in cancer care delivery research. The required number of centers (clusters) depends on the between- and within-center variance; the within-center variance is a function of estimates obtained by regressing the log within-center variance on predictive factors. Obtaining accurate estimates of the components needed to characterize the within-center variation is challenging., Methods: Using our previously derived sample size formula, our objective in the current research is to directly account for the imprecision in these estimates, using a Bayesian approach, to safeguard against designing an underpowered study when using the symbolic two-step method. Using estimates of the required components, including the number of centers that contribute to those estimates, we make formal allowance for the imprecision in these estimates on which a sample size will be based., Results: The mean of the distribution for power is consistently smaller than the single point estimate that the sample size formula yields. The reduction in power is more pronounced in the presence of increased uncertainty about the estimates with the reduction becoming more attenuated with increased numbers of centers that contribute to the estimates., Conclusions: Accounting for imprecision in the estimates of the components required for sample size estimation using the symbolic two-step method in the design of a cluster randomized trial yields conservative estimates of power., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: To improve the site selection process for clinical trials, we expanded a site survey to include standardized assessments of site commitment time, team experience, feasibility of tight timelines, and local medical community equipoise as factors that might better predict performance. We also collected contact information about institutional research services ahead of site onboarding., Aim: As a first step, we wanted to confirm that an expanded survey could be feasible and generalizable-that asking site teams for more details upfront was acceptable and that the survey could be completed in a reasonable amount of time, despite the assessment length., Methods: A standardized, two-part Site Assessment Survey Instrument (SASI), examining qualitative components and with multiple contact list sections, was developed using a publicly accessible dashboard and later transferred to a REDCap platform. After multiple rounds of internal testing, the SASI was deployed 11 times for multicenter trials. Follow-up questionnaires were sent to site teams to confirm that an expanded survey instrument is acceptable to the research community and could be completed during a brief work shift., Results: Respondents thought the SASI collected useful and relevant information about their sites (100%). Sites were "comfortable" (90%) supplying detailed information early in the site selection process and 57% completed the SASI in one to two hours., Conclusions: Coordinating centers and sites found the SASI tool to be acceptable and helpful when collecting data in consideration of multicenter trial site selection., Competing Interests: Declaration of competing interest Bradley Barney's relationship with Johns Hopkins University includes: consulting or advisory and receives financial support. Salina Waddy and Ken Wiley work for the National Institutes of Health., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/aims: COVID-19 necessitated a shift to virtual data collection for many research projects, providing the opportunity for novel approaches to carrying out multi-site clinical trials. Virtual multiteam systems (VMTS) are a type of team structure in which multiple geographically dispersed teams collaborate using technology-mediated communication. The article presents a case study of our use of VMTS, in response to COVID-19, to carry out a multisite randomized hybrid effectiveness-implementation trial of a caregiver-implemented intervention., Methods: We describe how we modified our team structure from predominantly site-specific, co-located teams to predominantly cross-site, virtual teams. We then present examples of how we have conducted the two primary data collection activities virtually. To demonstrate the feasibility of this approach, we present participant demographic information, the percent of cross-site data collection activities, and fidelity data., Results: In the first 20 months of data collection, we have enrolled 108 EI providers and 132 families, with 17% and 9% attrition respectively. The family sample is highly diverse in terms of race/ethnicity, parent education, and household income. The majority of provider training activities and roughly 50% of family assessment activities have been conducted cross-site. Fidelity is high, with no differences across site., Conclusions: Our data illustrate the feasibility of using virtual teams, training, and assessment in a multisite clinical trial in the Part C system. We discuss the strengths and challenges of this approach, as well as lessons learned to facilitate the planning of future multisite randomized clinical trials which may benefit from this approach., Clinical Trials: NCT05114538., Competing Interests: Declaration of competing interest This work was supported in part by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) by Grant Numbers 1 R01MH122725–01, 1 R01 MH122726–01, 1 R01 MH122727–01, and 1 R01 MH122728–01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Quality study monitoring is fundamental to patient safety and data integrity. Regulators and industry consortia have increasingly advocated for risk-based monitoring (RBM) and central statistical monitoring (CSM) for more effective and efficient monitoring. Assessing which statistical methods underpin these approaches can best identify unusual data patterns in multi-center clinical trials that may be driven by potential systematic errors is important., Methods: We assessed various CSM techniques, including cross-tests, fixed-effects, mixed-effects, and finite mixture models, across scenarios with different sample sizes, contamination rates, and overdispersion via simulation. Our evaluation utilized threshold-independent metrics such as the area under the curve (AUC) and average precision (AP), offering a fuller picture of CSM performance., Results: All CSM methods showed consistent characteristics across center sizes or overdispersion. The adaptive finite mixture model outperformed others in AUC and AP, especially at 30% contamination, upholding high specificity unless converging to a single-component model due to low contamination or deviation. The mixed-effects model performed well at lower contamination rates. However, it became conservative in specificity and exhibited declined performance for binary outcomes under high deviation. Cross-tests and fixed-effects methods underperformed, especially when deviation increased., Conclusion: Our evaluation explored the merits and drawbacks of multiple CSM methods, and found that relying on sensitivity and specificity alone is likely insufficient to fully measure predictive performance. The finite mixture method demonstrated more consistent performance across scenarios by mitigating the influence of outliers. In practice, considering the study-specific costs of false positives/negatives with available resources for monitoring is important., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

In recent years, multi-regional clinical trials (MRCTs) have increased in popularity in the pharmaceutical industry due to their ability to accelerate the global drug development process. To address potential challenges with MRCTs, the International Council for Harmonisation released the E17 guidance document which suggests the use of statistical methods that utilize information borrowing across regions if regional sample sizes are small. We develop an approach that allows for information borrowing via Bayesian model averaging in the context of a joint analysis of survival and longitudinal data from MRCTs. In this novel application of joint models to MRCTs, we use Laplace's method to integrate over subject-specific random effects and to approximate posterior distributions for region-specific treatment effects on the time-to-event outcome. Through simulation studies, we demonstrate that the joint modeling approach can result in an increased rejection rate when testing the global treatment effect compared with methods that analyze survival data alone. We then apply the proposed approach to data from a cardiovascular outcomes MRCT., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. [br]For permissions, please e-mail: journals.permissions@oup.com.)

The article presents the special role of the outpatient unit (urban polyclinics) in the system of urban medical organizations, which has significant development potential in the field of clinical research. This activity became possible due to the systematic work on equipping outpatient clinics with the most modern diagnostic equipment, the availability of specialists trained in the organization and conduct of clinical trials according to the international rules of good clinical practice. A special value lies in the fact that the polyclinic network has an extensive database that includes millions of patients and provides the opportunity to perform the highest level of medical expertise and research.

Multiregional clinical trials (MRCTs) have become increasingly common during the development of new drugs to obtain simultaneous drug approvals worldwide. When planning MRCTs, a major statistical challenge is determination of the regional sample size. In general, the regional sample size must be determined as the sample size such that the regional consistency probability, defined as the probability of meeting the regional consistency criterion, is greater than a prespecified value. The Japanese Ministry of Health, Labour and Welfare proposed two criteria for regional consistency. Moreover, many researchers have proposed corresponding closed-form formulas for calculating regional consistency probabilities when the primary outcome is continuous. Although some researchers have argued that those formulas are also applicable to cases with binary outcomes, it remains questionable whether such an argument can be true. Based on simulation results, we demonstrate that the existing formulas are inappropriate for binary cases, even when the regional sample size is sufficiently large. To address this issue, we develop alternative formulas and use simulation to show that they provide accurate regional consistency probabilities. Furthermore, we present an application of our proposed formulas for an MRCT of advanced or metastatic clear-cell renal cell carcinoma., (© 2023 John Wiley & Sons Ltd.)

To acquire larger samples for answering complex questions in neuroscience, researchers have increasingly turned to multi-site neuroimaging studies. However, these studies are hindered by differences in images acquired across multiple sites. These effects have been shown to bias comparison between sites, mask biologically meaningful associations, and even introduce spurious associations. To address this, the field has focused on harmonizing data by removing site-related effects in the mean and variance of measurements. Contemporaneously with the increase in popularity of multi-center imaging, the use of machine learning (ML) in neuroimaging has also become commonplace. These approaches have been shown to provide improved sensitivity, specificity, and power due to their modeling the joint relationship across measurements in the brain. In this work, we demonstrate that methods for removing site effects in mean and variance may not be sufficient for ML. This stems from the fact that such methods fail to address how correlations between measurements can vary across sites. Data from the Alzheimer's Disease Neuroimaging Initiative is used to show that considerable differences in covariance exist across sites and that popular harmonization techniques do not address this issue. We then propose a novel harmonization method called Correcting Covariance Batch Effects (CovBat) that removes site effects in mean, variance, and covariance. We apply CovBat and show that within-site correlation matrices are successfully harmonized. Furthermore, we find that ML methods are unable to distinguish scanner manufacturer after our proposed harmonization is applied, and that the CovBat-harmonized data retain accurate prediction of disease group., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Multisite magnetic resonance imaging (MRI) is increasingly used in clinical research and development. Measurement biases-caused by site differences in scanner/image-acquisition protocols-negatively influence the reliability and reproducibility of image-analysis methods. Harmonization can reduce bias and improve the reproducibility of multisite datasets. Herein, a traveling-subject (TS) dataset including 56 T1-weighted MRI scans of 20 healthy participants in three different MRI procedures-20, 19, and 17 subjects in Procedures 1, 2, and 3, respectively-was considered to compare the reproducibility of TS-GLM, ComBat, and TS-ComBat harmonization methods. The minimum participant count required for harmonization was determined, and the Cohen's d between different MRI procedures was evaluated as a measurement-bias indicator. The measurement-bias reduction realized with different methods was evaluated by comparing test-retest scans for 20 healthy participants. Moreover, the minimum subject count for harmonization was determined by comparing test-retest datasets. The results revealed that TS-GLM and TS-ComBat reduced measurement bias by up to 85 and 81.3%, respectively. Meanwhile, ComBat showed a reduction of only 59.0%. At least 6 TSs were required to harmonize data obtained from different MRI scanners, complying with the imaging protocol predetermined for multisite investigations and operated with similar scan parameters. The results indicate that TS-based harmonization outperforms ComBat for measurement-bias reduction and is optimal for MRI data in well-prepared multisite investigations. One drawback is the small sample size used, potentially limiting the applicability of ComBat. Investigation on the number of subjects needed for a large-scale study is an interesting future problem., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Recent literature supports the efficacy and efficiency of telemedicine in improving various health outcomes despite the wide variability in results. Understanding site-specific issues in the implementation of telemedicine trials for broader replication and generalizability of results is needed. Lessons can be learned from existing trials, and a blueprint can guide researchers to conduct these challenging studies using telemedicine more efficiently and effectively. This viewpoint presents relevant challenges and solutions for conducting multisite telemedicine trials using 7 ongoing and completed studies funded by the Patient-Centered Outcomes Research Institute portfolio of large multisite trials to highlight the challenges in implementing telemedicine trials. Critical issues of ensuring leadership and buy-in, appropriate funding, and diverse and representative trials are identified and described, as well as challenges related to clinical, informatics, regulatory, legal, quality, and billing. The lessons learned from these studies were used to create a blueprint of key aspects to consider for the design and implementation of multisite telemedicine trials., (©Patricia Commiskey, April W Armstrong, Tumaini R Coker, Earl Ray Dorsey, John C Fortney, Kenneth J Gaines, Brittany M Gibbons, Huong Q Nguyen, Daisy R Singla, Eva Szigethy, Elizabeth A Krupinski. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 20.09.2021.)

Functional localizers are invaluable as they can help define regions of interest, provide cross-study comparisons, and most importantly, allow for the aggregation and meta-analyses of data across studies and laboratories. To achieve these goals within the non-human primate (NHP) imaging community, there is a pressing need for the use of standardized and validated localizers that can be readily implemented across different groups. The goal of this paper is to provide an overview of the value of localizer protocols to imaging research and we describe a number of commonly used or novel localizers within NHPs, and keys to implement them across studies. As has been shown with the aggregation of resting-state imaging data in the original PRIME-DE submissions, we believe that the field is ready to apply the same initiative for task-based functional localizers in NHP imaging. By coming together to collect large datasets across research group, implementing the same functional localizers, and sharing the localizers and data via PRIME-DE, it is now possible to fully test their robustness, selectivity and specificity. To do this, we reviewed a number of common localizers and we created a repository of well-established localizer that are easily accessible and implemented through the PRIME-RE platform., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Stroke is a leading cause of the adult disability epidemic in the United States, with a major contribution from poststroke cognitive impairment and dementia (PSCID), the rates of which are disproportionally high among the health disparity populations. Despite the PSCID's overwhelming impact on public health, a knowledge gap exists with regard to the complex interaction between the acute stroke event and highly prevalent preexisting brain pathology related to cerebrovascular and Alzheimer disease or related dementia. Understanding the factors that modulate PSCID risk in relation to index stroke event is critically important for developing personalized prognostication of PSCID, targeted interventions to prevent it, and for informing future clinical trial design. The DISCOVERY study (Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery), a collaborative network of thirty clinical performance clinical sites with access to acute stroke populations and the expertise and capacity for systematic assessment of PSCID will address this critical challenge. DISCOVERY is a prospective, multicenter, observational, nested-cohort study of 8000 nondemented ischemic and hemorrhagic stroke patients enrolled at the time of index stroke and followed for a minimum of 2 years, with serial cognitive evaluations and assessments of functional outcome, with subsets undergoing research magnetic resonance imaging and positron emission tomography and comprehensive genetic/genomic and fluid biomarker testing. The overall scientific objective of this study is to elucidate mechanisms of brain resilience and susceptibility to PSCID in diverse US populations based on complex interplay between life-course exposure to multiple vascular risk factors, preexisting burden of microvascular and neurodegenerative pathology, the effect of strategic acute stroke lesions, and the mediating effect of genomic and epigenomic variation.

Background and Purpose: In this post-hoc analysis using acute dual study dataset, the impacts of cerebral microbleeds (MBs) after mild stroke on clinical outcome were investigated., Methods: The number of MBs on admission was categorized as 1) no MBs, 2) MBs 1-4, 3) MBs 5-9, and 4) MBs ≥ 10. The efficacy outcome was defined as neurological deterioration and stroke recurrence within 14 days. Safety outcomes included ICH and/or SAH as well as extracranial hemorrhages., Results: Of the 1102 patients, 780 (71%) had no MBs on admission, while 230 (21%) had MBs 1-4, 48 (4%) had MBs 5-9, and 44 (4%) had MBs ≥ 10. The number of MBs was not associated with the neurological deterioration and/or stroke recurrence (p = 0.934), ICH and/or SAH (p = 0.743), and extracranial hemorrhage (p = 0.205). Favorable outcome was seem in 84% in the No MBs group, 83% in the MBs 1-4, 94% in the MBs 5-9, and 85% in the MBs ≥ 10 (p = 0.304). Combined cilostazol and aspirin therapy did not alter any rates of efficacy and safety outcomes among the no MBs, MBs 1-4, MBs 5-9, and MBs ≥ 10 groups compared to aspirin alone (all p > 0.05). By multivariate regression analysis, a history of ICH and diastolic blood pressure were the independent parameters to all of the MBs criteria (presence, MBs ≥ 5, and MBs ≥ 10)., Conclusions: MBs did not alter the clinical outcome at 3 months of onset. Elevated diastolic blood pressure and a history of ICH were the essential parameters related to the MBs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor., Methods: The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population., Conclusion: The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Surrogate endpoints are being used more frequently in randomized controlled trials, even though they do not consistently corelate with patient outcomes. We systemically evaluated the use of surrogate endpoints in multiple myeloma randomized controlled trials over the past 15 years. We searched three databases (Pubmed, Embase, Cochrane) for multiple myeloma randomized controlled trials from January 1, 2005 to December 30, 2019. The primary outcome of our study was the proportion of randomized controlled trials that used overall survival as their primary endpoint. Secondary outcomes included the use of surrogate endpoints, and trends over time, and whether they differed based on study sponsorship. We included 151 randomized controlled trials in our analysis. The primary endpoint was overall survival (OS) in 17 (11.3%) of studies, progression free survival (PFS) or event-defined endpoints in 91 studies (60.3%) and response-based endpoints in 44 studies (29.1%). Quality of life was a primary endpoint in only three studies (2%). The use of OS as a primary endpoint decreased from 28.5% of trials from 2005 to 2009 to 5.5% from 2015 to 2019. There has been a decrease in the clinically meaningful endpoint of OS over the past 15 years in multiple myeloma randomized controlled trials. Use of quality of life as a primary endpoint remains exceedingly low. It remains paramount to recognize that the use of surrogate endpoints is imperfect, and care based upon them requires constant physician and patient re-analysis., (© 2021 Wiley Periodicals LLC.)

Background: Dravet syndrome (DS) is a severe, drug-resistant, developmental epileptic encephalopathy. Despite multiple anti-epileptic drug regimens, the syndrome remains poorly controlled and nearly half of patients still experience at least four tonic-clonic seizure per month. Recently, several clinical trials demonstrated that fenfluramine may provide a significant reduction in convulsive seizure frequency in the treatment of Dravet syndrome., Methods: A computerized literature search of Web of Science, MEDLINE (Ovid and PubMed), Cochrane Library, EMBASE, and Google Scholar was performed from inception until December 31, 2019. We included randomized placebo-controlled trials for the treatment of Dravet syndrome. We calculated the risk ratio (RR) of ≥50% and 100% reduction seizure frequency from baseline, along with the treatment-related withdrawals and serious adverse events, using the fixed-effect model. Quality assessment of included studies was performed with the Cochrane Collaboration's tool., Key Results: Two trials with a total of 206 patients were included. The pooled RR of 5.49 (95% CI 3.13-9.65) showed that a significantly greater proportion in the fenfluramine group achieved ≥50% reduction in monthly convulsive seizure frequency (MCSF). As for the complete seizure free rate, the pooled RR of 5.75 (95% CI 1.03-32.07) also demonstrated the favorable efficacy of fenfluramine, even though the difference was not statistically significant (p = 0.046). However, a significantly greater proportion of patients in the fenfluramine group experienced no more than one seizure during the treatment period (RR 13.82, 95% CI 2.68-71.27, p = 0.002). There were no significant differences in withdrawals and serious adverse events between the two treatment groups. No valvular heart disease or pulmonary arterial hypertension was observed in participants. The most common adverse events reported by included trials were diarrhea, fatigue, lethargy, nasopharyngitis, pyrexia, seizure, decreased appetite, and weight loss., Conclusions: Fenfluramine is an effective antiepileptic drug for pediatric patients with Dravet syndrome, demonstrating clinically meaningful reduction in convulsive frequency, and generally could be well tolerated., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Medulloblastoma (MB) is the most common malignant brain tumour in children. Despite significant progress in its management, a proportion of children relapse; tumour recurrence still carries a poor prognosis. While surgery is a mainstay of the management of primary MB, its role in recurrent MB is unclear. The objective of this literature review is to explore current practice and potential benefits of surgery in recurrent MB., Material and Methods: We reviewed all articles published in PubMed and Scholar from 1990 to 2018 with the following terms: "medulloblastoma" AND "recurrence" AND "neurosurgical procedures". Among 69 articles, 12 were directly relevant., Results: A total of 581 cases of recurrent MB were identified from published series. Median time from diagnosis to relapse was 20.4months. The majority of relapses involved disseminated craniospinal disease and only one-fifth relapses was located in the posterior fossa. The outcome was consistently poor, with a median survival of 12.4% and a median survival time after relapse of 18.5months. In the HIP-SIOP-PNET4 study, surgery at relapse was performed in 25% of cases and was associated with improved prognosis in solitary posterior fossa recurrence., Conclusion: Recurrent medulloblastoma is often fatal in children who have previously received radiotherapy. The role of surgery in improving survival is unclear, but there is some evidence that resection of a focal single posterior fossa recurrence can bring survival benefit. The value of biopsy lies in the optimisation and selection of appropriate targeted therapy and in excluding a second malignancy., (Crown Copyright © 2019. Published by Elsevier Masson SAS. All rights reserved.)

Background: Mild cognitive impairment (MCI) is a neurocognitive state between normal cognitive aging and dementia, with evidence of neuropsychological changes but insufficient functional decline to warrant a diagnosis of dementia. Individuals with MCI are at increased risk for progression to dementia; and an appreciable proportion display neuropsychiatric symptoms (NPS), also a known risk factor for dementia. Cerebrovascular disease (CVD) is thought to be an underdiagnosed contributor to MCI/dementia. The Ginkgo biloba extract, EGb 761 ® , is increasingly being used for the symptomatic treatment of cognitive disorders with/without CVD, due to its known neuroprotective effects and cerebrovascular benefits., Aims: To present consensus opinion from the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) regarding the role of EGb 761 ® in MCI., Materials & Methods: The ASCEND Group reconvened in September 2019 to present and critically assess the current evidence on the general management of MCI, including the efficacy and safety of EGb 761 ® as a treatment option., Results: EGb 761 ® has demonstrated symptomatic improvement in at least four randomized trials, in terms of cognitive performance, memory, recall and recognition, attention and concentration, anxiety, and NPS. There is also evidence that EGb 761 ® may help delay progression from MCI to dementia in some individuals., Discussion: EGb 761 ® is currently recommended in multiple guidelines for the symptomatic treatment of MCI. Due to its beneficial effects on cerebrovascular blood flow, it is reasonable to expect that EGb 761 ® may benefit MCI patients with underlying CVD., Conclusion: As an expert group, we suggest it is clinically appropriate to incorporate EGb 761 ® as part of the multidomain intervention for MCI., (© 2020 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Introduction: In current medical practice of curative treatment for non-metastatic oesophageal cancer, surgery on principle is carried out by oesophagectomy after neoadjuvant treatment. However, oesophagectomy is often associated with postoperative morbidity and mortality. Taking into account that modern neoadjuvant therapy is effective and many of patients show no vital tumour cells in the operative specimens, we aim to perform a scoping review as part of the development phase for a prospectively planned multicentre randomised controlled trial investigating 'surgery as needed vs surgery on principle in patients with postneoadjuvant complete response of oesophageal cancer' (Prospective trial registration number DRKS00022801). This scoping approach will allow us to finally define and/or adapt the research question including the design and methodology of the randomised controlled trial taking into account the findings for example, research gaps and/or pitfalls in the currently available study pool addressing this or very similar questions., Methods and Analysis: To identify relevant research, we will conduct searches in the electronic databases Medline, Web of Science Core Collection, Cochrane Library and Science Direct. We will also check references of relevant studies and perform a cited reference research (forward citation tracking). Titles and abstracts of the records identified by the searches will be screened and full texts of all potentially relevant articles will be obtained. We will consider randomised trials and non-randomised controlled studies. Data extraction tables will be set up, including study and patients' characteristics, aim of study and reported outcomes. We will summarise the data using tables and figures (eg, bubble plots) to present the research landscape and to describe potential clusters and/or gaps to support the planning of a randomised trial in this patient population., Ethics and Dissemination: Ethical approval is not required for this scoping review. Study findings will be shared by publication in a peer-reviewed journal and by presentation to key stakeholders on scientific meetings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Inherited cystic kidney disease is a spectrum of disorders in which clusters of renal cysts develop as the result of genetic mutation. The exact methods and pipelines for defining genetic mutations of inherited cystic kidney disease are not clear at this point. This 3-year, prospective, multicenter, cohort study was designed to set up a cohort of Korean patients with inherited cystic kidney disease, establish a customized genetic analysis pipeline for each disease subtype, and identify modifying genes associated with the severity of the disease phenotype., Methods/design: From May 2020 to May 2022, we aim to recruit 800 patients and their family members to identify pathogenic mutations. Patients with more than 3 renal cysts in both kidneys are eligible to be enrolled. Cases of simple renal cysts and acquired cystic kidney disease that involve cyst formation as the result of renal failure will be excluded from this study. Demographic, laboratory, and imaging data as well as family pedigree will be collected at baseline. Renal function and changes in total kidney volume will be monitored during the follow-up period. Genetic identification of each case of inherited cystic kidney disease will be performed using a targeted gene panel of cystogenesis-related genes, whole exome sequencing (WES) and/or family segregation studies. Genotype-phenotype correlation analysis will be performed to elucidate the genetic effect on the severity of the disease phenotype., Discussion: This is the first nationwide cohort study on patients with inherited cystic kidney disease in Korea. We will build a multicenter cohort to describe the clinical characteristics of Korean patients with inherited cystic kidney disease, elucidate the genotype of each disease, and demonstrate the genetic effects on the severity of the disease phenotype., Trial Registration: This cohort study was retrospectively registered at the Clinical Research Information Service ( KCT0005580 ) operated by the Korean Center for Disease Control and Prevention on November 5th, 2020.

Importance: The safety and efficacy of intensive systolic blood pressure reduction in patients with intracerebral hemorrhage who present with systolic blood pressure greater than 220 mm Hg appears to be unknown., Objective: To evaluate the differential outcomes of intensive (goal, 110-139 mm Hg) vs standard (goal, 140-179 mm Hg) systolic blood pressure reduction in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more vs less than 220 mm Hg., Design, Setting, and Participants: This post hoc analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage-II trial was performed in November 2019 on data from the multicenter randomized clinical trial, which was conducted between May 2011 to September 2015. Patients with intracerebral hemorrhage and initial systolic blood pressure of 180 mm Hg or more, randomized within 4.5 hours after symptom onset, were included., Interventions: Intravenous nicardipine infusion titrated to goals., Main Outcomes and Measures: Neurological deterioration and hematoma expansion within 24 hours and death or severe disability at 90 days, plus kidney adverse events and serious adverse events until day 7 or hospital discharge., Results: A total of 8532 patients were screened, and 999 individuals (mean [SD] age, 62.0 [13.1] years; 620 men [62.0%]) underwent randomization and had an initial SBP value. Among 228 participants with initial systolic blood pressures of 220 mm Hg or more, the rate of neurological deterioration within 24 hours was higher in those who underwent intensive (vs standard) systolic blood pressure reduction (15.5% vs 6.8%; relative risk, 2.28 [95% CI, 1.03-5.07]; P = .04). The rate of death and severe disability (39.0% vs 38.4%; relative risk, 1.02 [95% CI, 0.73-1.78]; P = .92) was not significantly different between the 2 groups. There was a significantly higher rate of kidney adverse events in participants randomized to intensive systolic blood pressure reduction (13.6% vs 4.2%; relative risk, 3.22 [95% CI, 1.21-8.56]; P = .01), but no difference was observed in the rate of kidney serious adverse events., Conclusions and Relevance: The higher rate of neurological deterioration within 24 hours associated with intensive treatment in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more, without any benefit in reducing hematoma expansion at 24 hours or death or severe disability at 90 days, warrants caution against generalization of recommendations for intensive systolic blood pressure reduction.

Background and purpose - Physically and mentally fit patients with a displaced femoral neck fracture (FNF) are mostly treated with total hip arthroplasty (THA). Dislocation is a severe and frequent complication in this group, and dual mobility cups (DMC) were developed to reduce the risk of dislocation after THA. The DUALITY trial investigates whether the use of DMC in FNF patients treated with a THA reduces the risk of dislocation.Patients and methods - The trial is a national, multicenter, register-based, randomized controlled trial (rRCT). Patients ≥ 65 years with a non-pathological, displaced FNF (Type Garden 3-4/AO 31-B2 or B3) who are suitable for a THA according to local guidelines are assessed for eligibility using the web-based registration platform of the Swedish Fracture Register (SFR). 1,600 patients will be randomized 1:1 to either insertion of a DMC (intervention group) or a standard cup (control group). The study is pragmatic in that the choice of implant brands, surgical approach, and peri- and postoperative protocols follow the local routines of each participating unit. All outcome variables will be retrieved after linkage of the study cohort obtained from the SFR with the Swedish Hip Arthroplasty Register and the National Patient Register.Outcomes - The primary outcome is the occurrence of any dislocation of the index joint treated with closed or open reduction within 1 year after surgery, expressed as a relative risk when comparing groups, and a risk reduction of at least 45% is considered clinically relevant. Secondary outcomes are the relative risk of any reoperation of the index joint, periprosthetic joint infection, and mortality within 90 days and 1 year. Patient-reported outcomes and health economics are evaluated.Start of trial and estimated duration - The DUALITY trial started recruiting patients in January 2020 and will continue for approximately 5 years.Trial registration - The trial is registered at clinicaltrials.gov (NCT03909815; December 12, 2019).

Background: Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation and chronic inflammation. Predicting exacerbations of COPD, which contribute to disease progression, is important to guide preventative treatment and improve outcomes. Blood eosinophils are a biomarker for patient responsiveness to inhaled corticosteroids (ICS); however, their effectiveness as a predictive biomarker for COPD exacerbations is unclear., Methods: This post hoc analysis pooled data from 11 Boehringer Ingelheim-sponsored Phase III and IV randomised COPD studies with similar methodologies. Exacerbation data were collected from these studies, excluding patients from the ICS withdrawal arm of the WISDOM® study. Patients were grouped according to their baseline blood eosinophil count, baseline ICS use and number of exacerbations in the year prior to each study., Results: Exacerbation rate data and baseline eosinophil count were available for 22,125 patients; 45.6% presented with a baseline blood eosinophil count of ≤ 150 cells/μL, 34.3% with 150-300 cells/μL and 20.1% with > 300 cells/μL. The lowest exacerbation rates were observed in patients with ≤ 150 cells/μL, with small increases in exacerbation rate observed with increasing eosinophil count. When stratified by exacerbation history, the annual rate of exacerbations for patients with 0 exacerbations in the previous year increased in line with increasing eosinophil counts (0.38 for ≤ 150 cells/μL, 0.39 for 150-300 cells/μL and 0.44 for > 300 cells/μL respectively). A similar trend was identified for patients with one exacerbation in the previous year, 0.62, 0.66 and 0.67 respectively. For patients with ≥ 2 exacerbations, exacerbation rates fluctuated between 1.02 (≤ 150 cells/μL) to 1.10 (150-300 cells/μL) and 1.07 (> 300 cells/μL). Higher exacerbation rates were noted in patients treated with ICS at baseline (range 0.75 to 0.82 with increasing eosinophil count) compared with patients not on ICS (range 0.45 to 0.49)., Conclusion: We found no clinically important relationship between baseline blood eosinophil count and exacerbation rate. Hence, the current analysis does not support the use of blood eosinophils to predict exacerbation risk; however, previous exacerbation history was found to be a more reliable predictor of future exacerbations., Trial Registration: ClinicalTrials.gov Identifiers: NCT00168844 , NCT00168831 , NCT00387088 , NCT00782210 , NCT00782509 , NCT00793624 , NCT00796653 , NCT01431274 , NCT01431287 , NCT02296138 and NCT00975195 .

Background: Therapeutic hypothermia (TH) offers cerebral protection following ischemic stroke and may improve outcomes in conjunction with decompressive hemicraniectomy (DHC). We aimed to assess the effectiveness of TH in patients with malignant ischemic stroke and DHC., Methods: We performed a meta-analysis in patients with malignant ischemic stroke undergoing DHC comparing TH versus normothermia in studies published up to August 2019. Included studies had ≥10 adults with acute ischemic stroke. Primary outcome was functional independence, and secondary outcomes included complications. Effect size was pooled and described by relative risk (RR) ratios and 95% confidence intervals (CIs)., Results: Five studies (n = 269 patients; n = 130 TH, n = 139 controls) were included, 4 of which were prospective (n = 2 randomized controlled trials). Median achieved body temperature of TH was 33.6°C (range 33°C-35°C). Median modified Rankin Scale at the study completion was similar between TH and controls (RR 1.08, 95% CI 0.56-2.07, P = 0.8). Three studies reported individual patient modified Rankin Scale outcomes demonstrated a shift toward worse outcomes with TH (unadjusted common odds ratio 1.74; 95% CI 1.05-2.88, P = 0.01). Overall complications were similar between groups (RR 1.20, 95% CI 0.70-2.05, random effects P = 0.5). A suggestion of higher mortality was seen in TH (RR 1.50, 95% CI 0.97-2.32, P = 0.07)., Conclusions: Clinical and functional outcomes were not overall different between patients undergoing systemic TH and controls following DHC despite the shift toward worse outcomes with TH observed in some studies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Current guidelines recommend anticoagulation therapy during primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI). However, whether anticoagulation should be continued after pPCI has not been well investigated., Methods/design: The RIGHT trial is a prospective, multicenter, randomized, double-blind, placebo-controlled trial in STEMI patients treated with pPCI evaluating the prolongation of anticoagulation after the procedure. Patients are randomized in a 1:1 fashion to receive either prolonged anticoagulant or matching placebo (no anticoagulation) for at least 48 hours after the procedure. When randomized to anticoagulation prolongation, the patient is assigned to intravenous unfractionated heparin (UFH) or subcutaneous enoxaparin or intravenous bivalirudin (same drug and same regimen at each center). The primary efficacy endpoint is the composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, stent thrombosis (definite) or urgent revascularization (any vessel) at 30 days. The primary safety endpoint is major bleeding (BARC 3-5) at 30 days. Based on a superiority design and assuming a 35% relative risk reduction (from 7% to 4.5%), 2856 patients will be enrolled, accounting for a 5% drop-out rate (α = 0.05 and power = 80%)., Conclusion: The RIGHT trial tests the hypothesis that post-procedural anticoagulation is superior to no anticoagulation in reducing ischemic events in STEMI patients undergoing pPCI., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Investigators who manage multicenter clinical trials need to pay careful attention to patterns of subject accrual, and the prediction of activation time for pending centers is potentially crucial for subject accrual prediction. We propose a Bayesian hierarchical model to predict subject accrual for multicenter clinical trials in which center activation times vary. We define center activation time as the time at which a center can begin enrolling patients in the trial. The difference in activation times between centers is assumed to follow an exponential distribution, and the model of subject accrual integrates prior information for the study with actual enrollment progress. We apply our proposed Bayesian multicenter accrual model to two multicenter clinical studies. The first is the PAIN-CONTRoLS study, a multicenter clinical trial with a goal of activating 40 centers and enrolling 400 patients within 104 weeks. The second is the HOBIT trial, a multicenter clinical trial with a goal of activating 14 centers and enrolling 200 subjects within 36 months. In summary, the Bayesian multicenter accrual model provides a prediction of subject accrual while accounting for both center- and individual patient-level variation., (© 2020 John Wiley & Sons Ltd.)

Background and Purpose: Patient-centered care prioritizes patient beliefs and values towards wellbeing. We aimed to map functional status (modified Rankin Scale [mRS] scores) and health-related quality of life on the European Quality of Life 5-dimensional questionnaire (EQ-5D) to derive utility-weighted (UW) stroke outcome measures and test their statistical properties and construct validity., Methods: UW-mRS scores were derived using linear regression, with mRS as a discrete ordinal explanatory response variable in 8 large international acute stroke trials. Linear regression models were used to validate UW-mRS scores by assessing differences in mean UW-mRS scores between the treatment groups of each trial. To explore the variability in EQ-5D between individual mRS categories, we generated receiver operator characteristic curves for EQ-5D to differentiate between sequential mRS categories and misclassification matrix to classify individual patients into a matched mRS category based on the closest UW-mRS value to their observed individual EQ-5D value., Results: Among 22 946 acute stroke patients, derived UW-mRS across mRS scores 0 to 6 were 0.96, 0.83, 0.72, 0.54, 0.22, -0.18, and 0, respectively. Both UW-mRS and ordinal mRS scores captured divergent treatment effects across all 8 acute stroke trials. The sample sizes required to detect the treatment effects using UW-mRS scores as a continuous variable were almost half that required in trials for a binary cut point on the mRS. Area under receiver operator characteristic curves based on EQ-5D utility values varied from 0.66 to 0.81. Misclassification matrix showed moderate agreement between actual and matched mRS scores (kappa, 0.68 [95% CI, 0.67-0.68])., Conclusions: Medical strategies that target avoiding dependency may provide maximum benefit in terms of poststroke health-related quality of life. Despite variable differences with mRS scores, the UW-mRS provides efficiency gains as a smaller sample size is required to detect a treatment effect in acute stroke trials through use of continuous scores. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00226096, NCT00716079, NCT01422616, NCT02162017, NCT00120003, NCT02123875. URL: http://ctri.nic.in; Unique identifier: CTRI/2013/04/003557. URL: https://www.isrctn.com; Unique identifier: ISRCTN89712435.

Shared decision making (SDM) facilitates delivery of medical therapies that are in alignment with patients' goals and values. Medicare national coverage decision for several interventions now includes SDM mandates, but few have been evaluated in nationwide studies. Based upon a detailed needs assessment with diverse stakeholders, we developed pamphlet and video patient decision aids (PtDAs) for implantable cardioverter/defibrillator (ICD) implantation, ICD replacement, and cardiac resynchronization therapy with defibrillation to help patients contemplate, forecast, and deliberate their options. These PtDAs are the foundation of the Multicenter Trial of a Shared Decision Support Intervention for Patients Offered Implantable Cardioverter-Defibrillators (DECIDE-ICD), a multicenter, randomized trial sponsored by the National Heart, Lung, and Blood Institute aimed at understanding the effectiveness and implementation of an SDM support intervention for patients considering ICDs. Finalization of a Medicare coverage decision mandating the inclusion of SDM for new ICD implantation occurred shortly after trial initiation, raising novel practical and statistical considerations for evaluating study end points. METHODS/DESIGN: A stepped-wedge randomized controlled trial was designed, guided by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) planning and evaluation framework using an effectiveness-implementation hybrid type II design. Six electrophysiology programs from across the United States will participate. The primary effectiveness outcome is decision quality (defined by knowledge and values-treatment concordance). Patients with heart failure who are clinically eligible for an ICD are eligible for the study. Target enrollment is 900 participants. DISCUSSION: Study findings will provide a foundation for implementing decision support interventions, including PtDAs, with patients who have chronic progressive illness and are facing decisions involving invasive, preference-sensitive therapy options., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The National FondaMental Centers of Expertise (FACE) for Schizophrenia (SZ) have been created to shorten the gap between research and clinical practice., Objectives: To synthetize in a review the 10-year findings issued from the FACE-SZ cohort analyses., Methods: More than 1000 patients were evaluated in 10 expert centers since 2010 with a 2-day long comprehensive standardized battery including neuropsychological testes and physical health assessment and followed-up for 3 years., Results: 1. The phase 0 cross-sectional analyses have confirmed well-known data: over-prescription of first-generation antipsychotics, antipsychotic polytherapy and long-term benzodiazepine and under-prescription of clozapine, 13% of drug-induced parkinsonism, 18% of akathisia, a mean duration of untreated psychosis of 18 months, one third of poorly-adherent patients, 24% of metabolic syndrome and 52% of current tobacco smokers with poor care for physical illnesses; a yearly mean financial cost of 15,000 euro/patient. 2. FACE-SZ also yielded additional data in insufficiently explored area: a half of major depression issues (among them one third of undiagnosed major depression and 44% of treated patients with unremitted depression), major depression having a strong impact on Quality of Life independently of negative symptoms, 22% of moderated to severe untreated physical pain. 3. FACE-SZ has explored emerging fields of research, including development of 4 stages- model of schizophrenia, chronic low-grade peripheral inflammation, latent Toxoplasma infection, hypovitaminosis D, and a model for relapse prediction at 2 years., Discussion: The associated factors and implications for public health programs were discussed. Based on the FACE-SZ findings and literature, the FACE-SZ group has yielded recommendations to improve daily care for schizophrenia and for future research., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Poor recruitment in clinical trials is well-documented. In large, multi-centre trials, communication between the coordinating centre and trial sites is essential. A commonly used communication tool is the hosting of an investigator/collaborator meeting, which offers an opportunity for sites to re-train and receive trial updates, learn from each other, share best practice and troubleshoot issues. Anecdotally, there is a perception that recruitment rates may increase after holding such a meeting. The aim of this before-and-after study was to examine any changes in recruitment after an investigator meeting., Methods: We conducted a retrospective study of nine trials at the Nottingham Clinical Trials Unit (NCTU) that were open to recruitment between 2014 and 2018. In the 8 weeks prior to the date of the investigator meeting, 82 sites (across nine trials) were open to recruitment; 60 of which attended the meeting, 22 who did not. Using meeting attendance data available in Trial Master Files (TMF) and recruitment data from randomisation datasets, we examined recruitment rates in the 8 weeks prior to and following the date of the investigator meeting., Results: For the 82 sites included, 284 participants were recruited in the 8 weeks prior to the meeting, with a further 300 participants recruited in the 8 weeks post meeting. This gives a mean change in weekly recruitment of 0.073 (- 0.129, 0.275) per site, demonstrating no statistically significant increase in recruitment after the investigator meeting. For the 60 attending sites, recruitment increased from 254 participants prior to the meeting to 271 post meeting, giving a 0.100 (- 0.160, 0.360) mean change in weekly recruitment per site, providing no evidence that recruitment rates increase following an investigator meeting., Conclusion: There is no statistical evidence to conclude that holding an investigator meeting increases recruitment in the 8 weeks following the meeting. Thus, if the meeting has been held in the belief that it will have a positive impact upon recruitment, trialists may wish to consider other evidence-based strategies known to increase recruitment rates. However, since there are a variety of reasons why an investigator meeting may be held, trialists should continue to consider this as a communication strategy with sites.

Background Metastatic Squamous cell Penile Carcinoma (mSCPC) is an orphan disease with a virally induced oncogenesis. PD-L1 expression rate is around 60% with a strong correlation between PD-L1 in the primary tumour and metastases. The first line systemic treatment relies on platinum-based chemotherapies with a median progression free survival and overall survival around 7.5 and 16 months, respectively. Immunotherapies targeting PD-1/PD-L1 axis are effective in other squamous cell or HPV related cancers. Methods PULSE is a prospective multicenter open label single arm phase II study. Thirty-two patients will be enrolled after a radiological assessment showing a non-progressive disease after 3 to 6 cycles of a first line platinum-based polychemotherapy. Patients will receive Avelumab injections 10mg/ kg every two weeks until progression or unacceptable toxicity. The primary endpoint will be the progression free survival (PFS) according to RECIST v1.1 criteria. Secondary endpoints will include PFS according to iRECIST criteria, overall survival, quality of life, safety. Ancillary explorations will include assessing blood and tissue biomarkers for association with clinical benefit. Discussion After the first line, the prognosis remains poor with no consensus on a second line systemic treatment in locally advanced or mSCPC. PULSE trial is the first study that assess an anti PD-L1 immunotherapy in maintenance among patients with locally advanced or mSCPC. NCT NUMBER : NCT03774901., (Copyright © 2020 Société Française du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Background: The standard treatment in first line of advanced or metastatic urothelial bladder cancer (MBC) is the association of Gemcitabine and Cisplatin (GC). Avelumab, an anti-PD-L1 agent, has recently demonstrated efficacy. The objective is to evaluate the combination of these 3 agents., Methods: This phase II randomized open-label study, evaluated if GC-avelumab increases response rate and duration of response of patients in 1 st line treatment for MBC compared to GC. Severe toxicities should not overlap and be acceptable. The two co-primary end points are the objective response rate and the incidence of severe toxicity after six cycles of treatment. The study will recruit 90 participants, randomized in two arms (1:2), GC (gemcitabine 1 000 mg/m 2 /j, J1,J8, Cisplatine 70 mg/m 2 , J1 = J21), and GC-avelumab (10 mg/Kg/3 semaines). Randomization will be stratified on Karnofsky status (≥ 80 % vs. < 80 %) and visceral vs non visceral metastases. The duration of the inclusion period is 24 months, with a duration of participation of each patient of 18 months and a total study duration of 42 months., Discussion: If both efficacy and safety of the association of GC+avelumab are in the range of acceptable through this specific study design, this will support a subsequent randomized phase III study comparing both arms with an overall survival end-point. In addition, the evaluation of predictive parameters to be confirmed (e.g. the impact of tumor PD-L1 expression) or other immunological parameters, may support a selection of the population. NCT number : NCT03324282., (Copyright © 2020 Société Française du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Objectives: The ongoing COVID-19 pandemic comprises a total of more than 2,350,000 cases and 160,000 deaths. The interest in anti-coronavirus drug development has been limited so far and effective methods to prevent or treat coronavirus infections in humans are still lacking. Urgent action is needed to fight this fatal coronavirus infection by reducing the number of infected people along with the infection contagiousness and severity. Since the beginning of the COVID-19 outbreak several weeks ago, we observe in GHU PARIS Psychiatrie & Neurosciences (Sainte-Anne hospital, Paris, France) a lower prevalence of symptomatic and severe forms of COVID-19 infections in psychiatric patients (∼4%) compared to health care professionals (∼14%). Similar observations have been noted in other psychiatric units in France and abroad. Our hypothesis is that psychiatric patients could be protected from severe forms of COVID-19 by their psychotropic treatments. Chlorpromazine (CPZ) is a phenothiazine derivative widely used in clinical routine in the treatment of acute and chronic psychoses. This first antipsychotic medication has been discovered in 1952 by Jean Delay and Pierre Deniker at Sainte-Anne hospital. In addition, to its antipsychotic effects, several in vitro studies have also demonstrated a CPZ antiviral activity via the inhibition of clathrin-mediated endocytosis. Recently, independent studies revealed that CPZ is an anti-MERS-CoV and an anti-SARS-CoV-1 drug. In comparison to other antiviral drugs, the main advantages of CPZ lie in its biodistribution: (i) preclinical and clinical studies have reported a high CPZ concentration in the lungs (20-200 times higher than in plasma), which is critical because of the respiratory tropism of SARS-CoV-2; (ii) CPZ is highly concentrated in saliva (30-100 times higher than in plasma) and could therefore reduce the contagiousness of COVID-19; (iii) CPZ can cross the blood-brain barrier and could therefore prevent the neurological forms of COVID-19., Methods: Our hypothesis is that CPZ could decrease the unfavorable evolution of COVID-19 infection in oxygen-requiring patients without the need for intensive care, but also reduce the contagiousness of SARS-CoV-2. At this end, we designed a pilot, phase III, multicenter, single blind, randomized controlled clinical trial. Efficacy of CPZ will be assessed according to clinical, biological and radiological criteria. The main objective is to demonstrate a shorter time to response (TTR) to treatment in the CPZ+standard-of-care (CPZ+SOC) group, compared to the SOC group. Response to treatment is defined by a reduction of at least one level of severity on the WHO-Ordinal Scale for Clinical Improvement (WHO-OSCI). The secondary objectives are to demonstrate in the CPZ+SOC group, compared to the SOC group: (A) superior clinical improvement; (B) a greater decrease in the biological markers of viral attack by SARS-CoV-2 (PCR, viral load); (C) a greater decrease in inflammatory markers (e.g. CRP and lymphopenia); (D) a greater decrease in parenchymal involvement (chest CT) on the seventh day post-randomization; (E) to define the optimal dosage of CPZ and its tolerance; (F) to evaluate the biological parameters of response to treatment, in particular the involvement of inflammatory cytokines. Patient recruitment along with the main and secondary objectives are in line with WHO 2020 COVID-19 guidelines., Conclusion: This repositioning of CPZ as an anti-SARS-CoV-2 drug offers an alternative and rapid strategy to alleviate the virus propagation and the infection severity and lethality. This CPZ repositioning strategy also avoids numerous developmental and experimental steps and can save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easy to manage side effects. Indeed, CPZ is an FDA-approved drug with an excellent tolerance profile, prescribed for around 70 years in psychiatry but also in clinical routine in nausea and vomiting of pregnancy, in advanced cancer and also to treat headaches in various neurological conditions. The broad spectrum of CPZ treatment - including antipsychotic, anxiolytic, antiemetic, antiviral, immunomodulatory effects along with inhibition of clathrin-mediated endocytosis and modulation of blood-brain barrier - is in line with the historical French commercial name for CPZ, i.e. LARGACTIL, chosen as a reference to its "LARGe ACTion" properties. The discovery of those CPZ properties, as for many other molecules in psychiatry, is both the result of serendipity and careful clinical observations. Using this approach, the field of mental illness could provide innovative therapeutic approaches to fight SARS-CoV-2., (Copyright © 2020 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)