PBRM1 directs PBAF to pericentromeres and protects centromere integrity.

The specialised structure of the centromere is critical for effective chromosome segregation, but its repetitive nature makes it vulnerable to rearrangements. Centromere fragility can drive tumorigenesis, but protective mechanisms preventing fragility are still not fully understood. The PBAF chromatin remodelling complex is frequently misregulated in cancer, but its role in cancer is incompletely characterized.

The REpeated ASSEssment of SurvivorS in intracerebral haemorrhage: protocol for a multicentre, prospective observational study.

Background: The REpeated ASSEssment of SurvivorS (REASSESS) study will conduct long-term cognitive, functional and neuropsychiatric performance assessments to determine whether evacuation of spontaneous intracerebral haemorrhage (ICH) reduces the risk of later cognitive decline in the ageing brain.

Methods And Analysis: This study will compare rates of cognitive decline under two treatment strategies for ICH. The first strategy is the use of minimally invasive surgery (MIS) with similar techniques as performed in (1) the Minimally Invasive Surgery plus rt-PA in the Treatment of Intracerebral haemorrhage Evacuation phase III (MISTIE III) trial, (2) the Early MiNimally-invasive Removal of IntraCerebral Haemorrhage (ENRICH) trial and (3) a single-centre cohort of consecutively treated patients with MIS.

Creating a plasma coordination center to support COVID-19 outpatient trials across a national network of hospital blood banks.

Introduction: In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.

Methods: A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.

Selecting trial centers using a standardized, automated site assessment survey instrument (SASI).

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.

Outpatient COVID-19 convalescent plasma recipient antibody thresholds correlated to reduced hospitalizations within a randomized trial.

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup.

Development, implementation, and dissemination of operational innovations across the trial innovation network.

Improving the quality and conduct of multi-center clinical trials is essential to the generation of generalizable knowledge about the safety and efficacy of healthcare treatments. Despite significant effort and expense, many clinical trials are unsuccessful. The National Center for Advancing Translational Science launched the Trial Innovation Network to address critical roadblocks in multi-center trials by leveraging existing infrastructure and developing operational innovations.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part I: Event Rates and Clinical Outcome.

Background: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project (https://www.clinicaltrials.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part II: Biomarkers and Trial Modeling.

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.

Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage.

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults.

Leveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials.

Importance: Multicenter clinical trials play a critical role in the translational processes that enable new treatments to reach all people and improve public health. However, conducting multicenter randomized clinical trials (mRCT) presents challenges. The Trial Innovation Network (TIN), established in 2016 to partner with the Clinical and Translational Science Award (CTSA) Consortium of academic medical institutions in the implementation of mRCTs, consists of 3 Trial Innovation Centers (TICs) and 1 Recruitment Innovation Center (RIC).

Early antibody treatment, inflammation, and risk of post-COVID conditions.

Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC.

Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: a prospective cohort study.

Background: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection.

Methods: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19.

Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned.

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.

Transfusion reactions associated with COVID-19 convalescent plasma in outpatient clinical trials.

Background: COVID-19 convalescent plasma (CCP) is an important therapeutic option for outpatients at high risk of hospitalization from SARS-CoV-2 infection. We assessed the safety of outpatient CCP transfusions administered during clinical trials.

Study Design And Methods: We analyzed data pertaining to transfusion-related reactions from two randomized controlled trials in the U.

Approaches for enhancing the informativeness and quality of clinical trials: Innovations and principles for implementing multicenter trials from the Trial Innovation Network.

One challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities.

Cavernous Angioma Symptomatic Hemorrhage (CASH) Trial Readiness II: Imaging Biomarkers and Trial Modeling.

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast enhanced quantitative perfusion (DCEQP) MRI sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cavernous angiomas. We assessed their prospective changes in cavernous angiomas with symptomatic hemorrhage (CASH) in a multisite trial readiness project ( clinicaltrials.gov NCT03652181 ).

Outpatient COVID-19 convalescent plasma recipient antibody thresholds correlated to reduced hospitalizations within a randomized trial.

Background: The COVID-19 convalescent plasma (CCP) viral specific antibody levels that translate into recipient post-transfusion antibody levels sufficient to prevent disease progression is not defined.

Methods: This secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup.

Early Treatment, Inflammation and Post-COVID Conditions.

Background: Post-COVID conditions (PCC) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about early treatment, inflammation, and PCC.

Reduced time to imaging, length of stay, and hospital charges following implementation of a novel postoperative pathway for craniotomy.

Objective: The authors created a postoperative postanesthesia care unit (PACU) pathway to bypass routine intensive care unit (ICU) admissions of patients undergoing routine craniotomies, to improve ICU resource utilization and reduce overall hospital costs and lengths of stay while maintaining quality of care and patient satisfaction. In the present study, the authors evaluated this novel PACU-to-floor clinical pathway for a subset of patients undergoing craniotomy with a case time under 5 hours and blood loss under 500 ml.

Methods: A single-institution retrospective cohort study was performed to compare 202 patients enrolled in the PACU-to-floor pathway and 193 historical controls who would have met pathway inclusion criteria.

Mechanisms to expedite pediatric clinical trial site activation: The DOSE trial experience.

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.

Incorporating Mental Health Into Lifestyle Medicine.

The evidence-based interconnection between mental health with lifestyle medicine practice is discussed. The extent to which physical health, and mental and behavioral health overlap are significant, and their interaction is seen in many ways. These bidirectional influences form a continuous thread through all lifestyle medicine pillars.

PBAF loss leads to DNA damage-induced inflammatory signaling through defective G2/M checkpoint maintenance.

The PBRM1 subunit of the PBAF (SWI/SNF) chromatin remodeling complex is mutated in ∼40% of clear cell renal cancers. PBRM1 loss has been implicated in responses to immunotherapy in renal cancer, but the mechanism is unclear. DNA damage-induced inflammatory signaling is an important factor determining immunotherapy response.

Using gamification to enhance clinical trial start-up activities.

Background: The Trial Innovation Network (TIN) is a collaborative initiative within the National Center for Advancing Translational Science (NCATS) Clinical and Translational Science Awards (CTSA) Program. To improve and innovate the conduct of clinical trials, it is exploring the uses of gamification to better engage the trial workforce and improve the efficiencies of trial activities. The gamification structures described in this article are part of a TIN website gamification toolkit, available online to the clinical trial scientific community.

Transfusing Convalescent Plasma as Post-Exposure Prophylaxis Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Double-Blinded, Phase 2 Randomized, Controlled Trial.

Background: The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection.

Methods: This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma.