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Novel psychoactive substances, such as designer benzodiazepines (DBZD), are a growing public health concern. There are about 30 different DZBDs reported, which can vary widely in their effect and potential for harmful outcomes, ranging from agitation to confusion to coma. Despite the scope of this widespread phenomena, little information on the management of DBZD dependence is available in the literature.In this case report, we present a patient with DBZD dependence requesting assistance tapering off the DBZD, clonazolam. He began self-medicating with clonazolam seven years prior for panic attacks to the point he was using 40 drops per day and having significant withdrawal during the day. He was prescribed gabapentin for his underlying anxiety while he tapered his clonazolam dose. Once he achieved a 75% reduction in his use of clonazolam, he had trouble managing withdrawal and anxiety symptoms and could not taper further.We discuss the challenges of treating patients with DBZD use disorder in an outpatient setting. Switching a patient from a DZBD to a prescription benzodiazepine for the purposes of a taper can be dangerous as an outpatient due to the inability to monitor at-home DBZD usage and the resulting risk of overdose. DBZDs can also be highly potent and make it difficult to achieve success using current withdrawal guidelines.

Blood-brain barrier (BBB) dysfunction may be involved in the increased sensitivity of Alzheimer’s disease (AD) patients to antipsychotics, including amisulpride. Studies indicate that antipsychotics interact with facilitated glucose transporters (GLUT), including GLUT1, and that GLUT1 BBB expression decreases in AD. We tested the hypotheses that amisulpride (charge: +1) interacts with GLUT1, and that BBB transport of amisulpride is compromised in AD.GLUT1 substrates and inhibitors, and GLUT-interacting antipsychotics were identified by literature review and their physicochemical characteristics summarised. Interactions between amisulpride, and GLUT1 were studied usingin silicoapproaches and the human cerebral endothelial cell line, hCMEC/D3. Brain distribution of [3H]amisulpride was determined usingin situperfusion in wild type (WT) and 5xFamilial AD (5xFAD) mice. With transmission electron microscopy (TEM) we investigated brain capillary degeneration in WT and 5xFAD mice, and human samples. Western blots determined BBB transporter expression in mouse and human.Literature review revealed that, although D-glucose has no charge, charged molecules can interact with GLUT1. GLUT1 substrates are smaller (184.95±6.45g/mol) than inhibitors (325.50±14.40g/mol), and GLUT-interacting antipsychotics (369.38±16.04). Molecular docking showed beta-D-glucose (free energy binding: –15.39kcal/mol) and amisulpride (–29.04kcal/mol) interact with GLUT1. Amisulpride did not affect [14C]D-glucose accumulation in hCMEC/D3. 5xFAD mice showed increased brain [3H]amisulpride uptake, and no cerebrovascular space changes compared to WT. TEM revealed brain capillary degeneration in human AD. There was no significant effect of AD on mouse GLUT1 and P-gp BBB expression, and in human GLUT1 expression. In contrast, caudate P-glycoprotein expression was decreased in human AD capillaries versus controls.This study provides new details about the BBB transport of amisulpride, evidence that amisulpride interacts with GLUT1, and that BBB transporter expression is altered in AD. This suggests that antipsychotics exacerbate the cerebral hypometabolism in AD. Further research into the mechanism of amisulpride transport by GLUT1 is important for improving antipsychotics safety.

Objective To evaluate clinical data regarding the use of amivantamab and mobocertinib for epidermal growth factor receptor (EGFR) exon 20 insertion mutation non–small cell lung cancer (NSCLC) and assess their potential impact on the care of patients. Data Sources A comprehensive literature search of PubMed and Clinicaltrials.gov was conducted using the terms amivantamab, Rybrevant, JNJ-61186372, mobocertinib, Exkivity, TAK-788. Study Selection and Data Extraction Relevant English-language clinical trials were evaluated. Data Synthesis Amivantamab and mobocertinib were Food and Drug Administration (FDA) approved based on phases 1 and 2 studies. Amivantamab demonstrated an overall response rate (ORR) of 40% and median progression-free survival (PFS) of 8.3 months. Patients commonly experienced rash (86%), paronychia (45%), and stomatitis (21%). Mobocertinib demonstrated an ORR of 28% and median PFS of 7.3 months in phase 1/2 study. Patients frequently experienced diarrhea (91%), rash (45%), and paronychia (38%). Cardiac monitoring is recommended with mobocertinib due to risk of QTc prolongation and cardiac failure. Relevance to Patient Care For NSCLC patients who possess an EGFR exon 20 insertion mutation, amivantamab and mobocertinib are indicated as second-line therapy. Ongoing studies are evaluating these therapies as first-line monotherapy and as part of combination regimens in multiple cancer types. Dosage forms, drug interactions, and patient comorbidities should be considered when deciding which of the 2 agents may be most appropriate. Conclusion Amivantamab and mobocertinib target an uncommon NSCLC mutation that has historically marked a poor prognosis because of innate resistance to previously approved EGFR tyrosine kinase inhibitors. Promising results from early phase trials supported accelerated FDA approval.

Background: The benefits of tPA (tissue-type plasminogen activator) in acute ischemic stroke are time-dependent. However, delivery of thrombolytic therapy rapidly after hospital arrival was initially occurring infrequently in hospitals in the United States, discrepant with national guidelines. Methods: We evaluated door-to-needle (DTN) times and clinical outcomes among patients with acute ischemic stroke receiving tPA before and after initiation of 2 successive nationwide quality improvement initiatives: Target: Stroke Phase I (2010–2013) and Target: Stroke Phase II (2014–2018) from 913 Get With The Guidelines-Stroke hospitals in the United States between April 2003 and September 2018. Results: Among 154 221 patients receiving tPA within 3 hours of stroke symptom onset (median age 72 years, 50.1% female), median DTN times decreased from 78 minutes (interquartile range, 60–98) preintervention, to 66 minutes (51–87) during Phase I, and 50 minutes (37–66) during Phase II ( P P P Conclusions: A nationwide quality improvement program for acute ischemic stroke was associated with substantial improvement in the timeliness of thrombolytic therapy start, increased thrombolytic treatment, and improved clinical outcomes.

Intercalation chemistry has dominated electrochemical energy storage for decades, and storage capacity worldwide has now reached the terawatt-hour level. State-of-the-art intercalation cathodes for Li-ion batteries operate within the limits of transition metal cation electrochemistry, but the discovery of anion-redox processes in recent decades suggests rich opportunities for substantially increasing stored energy densities. The diversity of compounds that exhibit anion redox in the solid state has inspired the exploration of new materials for next-generation cathodes. In this Review, we outline the mechanisms proposed to contribute to anion redox and the accompanying kinetic pathways that can occur in layered transition metal oxides. We discuss the crucial role of structural changes at both the atomic and mesoscopic scales with an emphasis on their impact on electrochemical performance. We emphasize the need for an integrated approach to studying the evolution of both the bulk structure and electrode–electrolyte interphase by combining characterization with computation. Building on the fundamental understanding of electrochemical reaction mechanisms, we discuss engineering strategies such as composition design, surface protection and structural control to achieve stable anion redox for next-generation energy storage devices.

PDF file - 46KB, Effects of administration of PTH on a)osteoclast activity and b) tumour growth in bone.

Purpose: Clinical trials in early breast cancer have suggested that benefits of adjuvant bone-targeted treatments are restricted to women with established menopause. We developed models that mimic pre- and postmenopausal status to investigate effects of altered bone turnover on growth of disseminated breast tumor cells. Here, we report a differential antitumor effect of zoledronic acid (ZOL) in these two settings.Experimental design: Twleve-week-old female Balb/c-nude mice with disseminated MDA-MB-231 breast tumor cells in bone underwent sham operation or ovariectomy (OVX), mimicking the pre- and postmenopausal bone microenvironment, respectively. To determine the effects of bone-targeted therapy, sham/OVX animals received saline or 100 μg/kg ZOL weekly. Tumor growth was assessed by in vivo imaging and effects on bone by real-time PCR, micro-CT, histomorphometry, and measurements of bone markers. Disseminated tumor cells were detected by two-photon microscopy.Results: OVX increased bone resorption and induced growth of disseminated tumor cells in bone. Tumors were detected in 83% of animals following OVX (postmenopausal model) compared with 17% following sham operation (premenopausal model). OVX had no effect on tumors outside of bone. OVX-induced tumor growth was completely prevented by ZOL, despite the presence of disseminated tumor cells. ZOL did not affect tumor growth in bone in the sham-operated animals. ZOL increased bone volume in both groups.Conclusions: This is the first demonstration that tumor growth is driven by osteoclast-mediated mechanisms in models that mimic post- but not premenopausal bone, providing a biologic rationale for the differential antitumor effects of ZOL reported in these settings. Clin Cancer Res; 20(11); 2922–32. ©2014 AACR.

PDF file - 50KB, Numbers of MDA-MB-231 cells present in long bones of 12 week old mice 24h after inter-cardiac injection.

PDF file - 166KB, Effects of 4 week estradiol supplementation on bone turnover in mouse tibiae. Histograms showing a) numbers of osteoclasts and b) numbers of osteoblasts per mm of bone. Representative images of control and estradiol tibiae, a) by microCT and b) on H&E satined histological sections.

PDF file - 182KB, Effects of ovariectomy and zoledronic acid treatment on serum bone turnover markers and gene expression in mouse long bones.

PDF file - 1125KB, MDA-MB-231 tumour growth in 6 week and 12 week old Balb/c nude mice 4 weeks following intra-cardiac injection.

IntroductionThirty oral targeted antineoplastic agents are associated with prolongation of the QT interval. However, limited data exists regarding QTc prolongation and associated risk factors in the ambulatory oncology setting.MethodsThis retrospective study was completed to describe QTc prolongation incidence among patients receiving oral targeted tyrosine kinase inhibitors (TKI) and identify potential risk factors in the ambulatory community-based oncology clinic.ResultsOf the 341 patients identified as receiving oral TKI, 49 with a baseline and follow-up ECG were included. The incidence of QTc prolongation (QTc > 470 ms in males, QTc > 480 ms in females, or >20 ms increase in QTc from baseline) was 24%. Three patients developed significant QTc prolongation (QTc >500 ms or >60 ms increase in QTc from baseline). No patients discontinued therapy primarily due to QTc prolongation or experienced symptomatic torsades de pointes. Analysis of risk factors demonstrated that patients with QTc prolongation were more likely to receive concomitant therapy with a loop diuretic (41% vs 11%, respectively, p=0.029).DiscussionThe frequency of QTc prolongation may be higher in the real-world setting than that observed in clinical trials; however, continuation of therapy may be possible. Patients receiving concomitant loop diuretics should be monitored more closely for QTc prolongation and electrolyte abnormalities.

Background: Patient-reported outcome measures (PROMs) describe health status from the perspective of the patient. There is growing interest in the use of PROMs in clinical trials and there have been major efforts to develop PROMs for neurological conditions (e.g., Neuro-QOL, PROMIS). However, the extent to which such measures are used in stroke trials is uncertain. We sought to determine how often contemporary acute stroke trials included PROMs as primary or secondary outcome measures. Methods: We searched MEDLINE for completed RCTs published in one of nine major journals between 2010 and 2020. Eligible studies were phase 2 or 3 trials undertaken to test therapeutic interventions within one month of stroke onset. For each trial we accessed the primary publication as well as the published protocol and supplement when available. We abstracted key trial characteristics including all primary and secondary efficacy outcome measures. We defined PROMs using online databases (qolid.org) with the focus on self-reported measures of quality of life, symptoms, and function collected without interpretation of an external party. Results: 115 trials met eligibility criteria. Only one trial used a PROM for its primary outcome measure (visual analogue pain scale), but 40 trials (35%) listed at least one PROM as a secondary outcome measure in its primary publication. An additional 15 trials (13%) listed at least one PROM in their protocol. Among the 55 trials that defined at least one PROM as a secondary outcome measure, the most commonly used measure was Euro-QOL (n=42, 76%) followed by SIS-16 (n=9, 16%), SF-36 (n=7, 13%), and the stroke-specific QOL scale (n=5, 9%). Other PROMs included various measures of anxiety and depression (n=9, 16%). Only one study used a Neuro-QOL based measure. Of the 41 trials that listed a PROM as a primary or secondary outcome in the primary publication, 39 (95%) provided PROM results, but of these only 7 (18%) found statistically significant treatment differences. Conclusions: While about half of acute stroke trials listed at least one PROM as a secondary outcome, they played a minor role in the presentation of trial results. Inclusion of PROMs in acute stroke trials requires greater attention during both the design and reporting phases of the trial.

Background: Monitoring changes in ischemic stroke severity at the population level is important as changes in risk factors and clinical treatments could influence stroke severity. We describe trends in the distribution of NIHSS across 3 time periods in a population-based epidemiologic stroke study. Methods: In 2005, 2010, and 2015 all adult acute ischemic strokes occurring within the Greater Cincinnati area presenting to 15 hospitals were ascertained using discharge codes (ICD-9 433-436; IDC-10 I63-I68, G45-46). Following physician verification, confirmed ischemic stroke cases underwent chart abstraction including estimation of a retrospective (rNIHSS) score at presentation. Descriptive statistics (rNIHSS median, IQR) were generated by survey year, demographics, and medical history. Using a binary definition of stroke severity (median rNIHSS score &gt 4 versus &lt 4), multivariable logistic regression was used to estimate changes in stroke severity over time, adjusting for potential confounders. Random effects were used to account for multiple admissions occurring in the same subject. Results: The number of ischemic stroke admissions in the 2005, 2010, and 2015 surveys was 1778, 1903, and 1933, respectively (Table). The median (IQR) rNIHSS scores were 3 (2-7), 3 (1-6), and 2 (1-6) across the 3 surveys, respectively; the proportion of admissions with rNIHSS &gt 4 was 48%, 39% and 37%, respectively. After adjusting for demographics, medical history and pre-stroke function, compared to 2005, the odds ratio for more severe stroke was 0.69 (95% CI= 0.60-0.79, p=0.001) in 2010 and 0.63 (95% CI= 0.55-0.73, p=0.001) in 2015. Conclusions: In this population- based study there was a statistically significant change in the severity of ischemic stroke hospitalizations with increases in the proportion of milder strokes over time. Potential reasons for this change need to be explored but could include changes in risk factors, clinical treatments or diagnostic approach.

Introduction: Ischemic stroke (IS) patients are frequently transferred between hospitals. Our objective was to determine whether patient insurance status contributes to variation in access to stroke center care among transferred patients with IS. Methods: We compiled California data on every nonfederal hospital admission from 2010-17 and used ICD-9, ICD-10, and DRG codes to identify IS patients transferred from an initial emergency department to another hospital. Transfers were categorized based on whether or not the patient was ultimately discharged from a stroke center hospital (primary or comprehensive). Patient insurance status was categorized as private, Medicare, Medicaid or self/uninsured. Clusters of closely connected hospitals via transfer frequency were identified using network science community detection methods. Within each cluster, we examined the degree of disparity in stroke center access by quantifying the difference between the insurance groups with the highest and lowest proportion of transfers discharged from a stroke center. Results: We identified 10,049 IS transfers during the study period (private 5,297 [53%]; Medicare 3,328 [33%]; Medicaid 904 [9%]; self/uninsured 520 [5%]). Stroke center access varied by patient insurance (overall 87%, private 89%, Medicare 87%, Medicaid 82%, self 72%). There were 14 clusters of closely connected hospitals via transfers. In the highest performing cluster, 100% of transferred patients in each insurance category were discharged from a stroke center (delta 0). The lowest performing cluster was also the largest (n=2,364 transfers); in this cluster 69% of transfers were discharged from a stroke center, ranging from 32% of self-pay transfers to 81% of privately insured transfers (highest delta among all clusters: 49%). Conclusions: These findings demonstrate that current care patterns differ by insurance status. Further research is needed to determine interventions to address this disparity.

Introduction: An increasing number of patients with acute ischemic stroke (AIS) have recently used non-vitamin K antagonist oral anticoagulants (NOACs). However, there are limited data on safety of endovascular therapy (EVT) in these patients. Methods: We performed a retrospective, observational, cohort study of patients treated with EVT within 6 hours of symptom onset in the American Heart Association’s “Get With The Guideline-Stroke Program” between October 2015 and March 2020 to compare safety and functional outcomes in patients who were or were not taking NOACs in the 7 days prior to stroke. Results: Of 33,355 patients (median age 72 years (60,81); 50.8% female), 3,727 (11.2%) were taking NOACs, and 29,628 (88.8%) were not taking any oral anticoagulants (OAC) prior to stroke. Compared with those not on OAC, patients taking NOACs were older (median age 75 vs. 71 years) and had a higher prevalence of comorbidities including cardiovascular risk factors, although stroke severity was similar between the groups (median NIHSS 18 vs. 17). After adjusting for baseline clinical factors including intravenous alteplase, patients taking NOACs were not at a significantly higher risk of sICH compared with patients not taking anticoagulants (4.9% vs 6.4%; aOR, 0.93 [95% CI, 0.75-1.14]) or in-hospital mortality (14.1% vs 13.1%; aOR, 0.90 [95% CI, 0.78-1.02]). Of the secondary discharge outcomes, 3 of 7 showed significant differences in favor of the NOAC group including ambulating independently (33.7% vs 38.7%; aOR, 1.15 [95% CI, 1.02-1.30]) and freedom from disability (modified Rankin Scale [mRS] 0-1, 13.0% vs 16.2%; aOR, 1.23 [95% CI, 1.04-1.46]) at discharge. In a subset of patients with documented time of last NOACs dose (n=213), sICH rate was 3.1% (6/196) with last dose ≤2 days and 0% (0/17) with >2 days. Conclusions: Among patients with acute ischemic stroke treated with EVT within 6 hours, use of NOACs within the preceding 7 days, compared with no use of anticoagulants, was not associated with a significantly increased risk of adverse events and was associated with better functional outcomes at discharge.

Introduction: Hospitals strongly influence whether acute stroke patients receive stroke rehabilitation at Inpatient Rehabilitation Facilities (IRFs) or Skilled Nursing Facilities (SNFs), but little is known about drivers of variation. Our objective was to quantify the impact of hospital-level factors on discharge decisions. Methods: A cohort of acute stroke patients who were discharged to IRFs or SNFs was generated from Medicare data (2011-2014). A multi-level random effects logistic regression model that included patient- and hospital-level predictors (fixed effects) of discharge to an IRF (vs. SNF) was constructed. From this model, the amount of variation in discharge decisions due to hospitals was estimated from the intraclass correlation coefficient (ICC). Average effect sizes of hospital-level factors were estimated by adjusted odds ratios (aORs). Variations in effect sizes of factors between hospitals was estimated using 80% Interval Odds Ratios (80% IORs) which reflects a range of estimated effect sizes of factors across individual hospitals. Results: The cohort included 1,816 acute care hospitals which discharged 66,548 patients to IRFs and 68,867 patients to SNFs. Acute hospitals accounted for a quarter of the variation in IRF (vs. SNF) discharge (ICC=0.26). Important hospital-level factors associated with IRF discharge included IRF affiliation (aOR=2.53, 95% CI: 2.25-2.84), urban setting (aOR=1.71 95%CI:1.44-2.03) and Southern vs. Mid-west CMS region (aOR=3.12 95% CI: 2.55-3.83). All 80% IORs were wide which indicates substantial variation in the effects of these factors across hospitals which suggests that despite several significant aORs, much of the hospital-level variability remains poorly explained. Conclusion: Hospitals account for a quarter of the variation in use of IRFs (vs. SNFs). Several hospital-level factors were associated with IRF discharge but there was wide variation in the effects of these factors across hospitals.

The growing number of stroke survivors in the US, especially among women, makes understanding sex-specific trends in recurrent strokes crucial. Yet, such data are rare. We estimated 20-year sex-specific trends in recurrence in a population-based stroke study. Methods: We included first-ever ischemic strokes (IS) ascertained between January 1, 2000 and December 31, 2019 from the Brain Attack Surveillance in Corpus Christi (BASIC) Project in South Texas. Time to recurrence was calculated from first-ever IS to recurrence, death, or December 31, 2019, whichever came first. We estimated the cumulative incidence function (CIF) of recurrence by a multivariable Fine-Gray subdistribution hazard model, which accounted for the competing risk of death. An interaction term between calendar year and sex was used to generate 1-year and 5-year sex-specific trends in risks of recurrence between 2000-2019 from the fitted CIF. Results: Among the 5,752 IS (median age 69, 49.9% women), 786 (13.7%) had recurrences over a median of 7.6 years of follow-up and 2,653 (46.1%) died over a median of 3.7 years of follow-up. Women had significantly higher adjusted 1-year and 5-year risks of recurrence than men in 2000 (Figure). One-year and 5-year risk of recurrence declined in both sexes over time but women experienced larger declines such that the risks were similar between both sexes around 2009 but higher among men after that. The largest sex difference in recurrence was in the 5-year risk in 2000 with women having 5.0% (1.5%-8.4%) higher risk. Conclusions: The welcoming trends in recurrent strokes suggest successful secondary stroke prevention, especially in women, where greater declines were noted.

Introduction: Observational studies indicate that stroke rehabilitation at Inpatient Rehabilitation Facilities (IRFs) is superior to Skilled Nursing Facilities (SNFs). Nationally, IRF vs. SNF use varies widely at the hospital level, but the impact on individual patients is unclear. Our objective was to quantify the effect of the admitting hospital on the probability of receiving IRF or SNF care for individual stroke patients. Methods: Medicare claims data (2011-2014) was used to generate a cohort of acute ischemic and hemorrhagic stroke patients who were discharged to IRFs or SNFs. We generated 2 multivariable effects logistic regression models. Model 1 predicted IRF admission (vs. SNF) using only patient-level factors as fixed effects, whereas Model 2 added a hospital random effect. The impact of the admitting hospital on an individual patients’ probability of IRF care was estimated by taking the difference in predicted probabilities (p^) between the 2 models. Hospital effects were categorized as moderate (10-19%) or large (>20%) based on the change in size of p^. The magnitude and direction of the random effect terms in Model 2 was used to categorize individual hospitals as being either neutral, SNF-, or IRF- favoring. Results: The cohort included 1,816 acute care hospitals which discharged 135,415 patients to IRFs (n=66,548) or SNFs (n= 68,867). Half of the hospitals were categorized as neutral (n=870, 47.9%) with the remaining being SNF- favoring (n=485, 26.7%) or IRF- favoring (n=461, 25.4%). For half of all patients, acute care hospital had a moderate influence on the type of rehabilitation that they received. For SNF and IRF-favoring hospitals, there were large (55% and 37% of patients) or moderate (30% and 42% of patients) hospital effects on discharge setting for the majority of patients. Conclusion: For the majority of stroke patients, which acute care hospital they happen to be admitted to meaningfully impacts the type of rehabilitation care they receive

Background: Ischemic stroke is the 5 th leading cause of death in the US. As a measure of stroke severity, initial NIHSS has been used to predict clinical outcome. We sought to identify the optimal cut-points of NIHSS at initial presentation that are associated with higher 30-day mortality. Methods: In 2005, 2010, and 2015 all hospitalized, first acute ischemic stroke events occurring within the Greater Cincinnati area were ascertained. Potential ischemic stroke cases underwent chart abstraction and physician adjudication, including retrospective NIHSS score (range 0 - 42) based on clinical findings at initial presentation. Descriptive statistics for NIHSS were estimated by study year, demographics, and medical history. Data regarding mortality was obtained from the National Death Index. The Contal and O’Quigley method based on a modified log-rank test statistic was used to determine cut-points of the NIHSS score associated with 30-day mortality, and hazard ratios were obtained from Cox models with adjustment for sex, race, and age. Results: In 2005, 2010, and 2015 there were 1704, 1818 and 1852 ischemic stroke events with 30-day mortality rates of 10.5%, 9.6% and 9.0%, respectively. Optimal cut-points of NIHSS 16 were identified. Across all 3 periods, 3431 (84.5%) cases had NIHSS 0-8, 352 (8.7%) had NIHSS 9-16 and 274 (6.8%) >16. Kaplan Meier Survival Curves for the 3 NIHSS groups are shown in the Figure. Strokes with NIHSS >16 at initial presentation were associated with a 15-fold (HR with 95% CI: 13, 19) increase in the risk of death at 30-days compared to those with NIHSS Discussion: NIH Stroke Scale scores are a reliable predictor of mortality, with higher NIHSS scores having higher risk of death. The cut points reported identify subgroups of stroke patients with dramatically different prognoses. Future studies should assess if this excess mortality risk among severe strokes persists after the more widespread implementation of thrombectomy beyond 2015.

Background: We performed a systematic review of acute stroke trials to determine features associated with premature termination of trial enrollment. Methods: MEDLINE was searched for stroke RCTs between 1/1/2013-6/11/2020. Included studies were Phase 2 or 3, had a preplanned sample size ≥100, had time to treatment within 24 hours of onset for TIA, ischemic stroke, or ICH, and were published in a major clinical journal (BMJ, Circulation, Stroke, Neurology, JAMA, JAMA Neurology, Lancet, Lancet Neurology, NEJM). Studies were deemed prematurely terminated if authors reported early termination. Study variables and inclusion criteria are listed in Table 1. Complex trials required specialized training and expertise, high degree of monitoring, or procedural intervention. Univariate Chi-square tests/Fisher’s exact test were used to determine characteristics associated with early termination, and multivariable lasso logistic regression was used to select the most important predictors. Results: Of 1,219 studies assessed, 69 trials met eligibility criteria for inclusion (Table 1); 34 (49%) were prematurely terminated. In univariate analysis, variables associated with premature termination were complexity of treatment, industry involvement, exclusion of older patients, and presence of a futility stopping rule. In lasso regression, complex treatment trials (OR 3.77, 95% CI 1.30-10.97, versus moderate or simple trials combined), presence of a futility rule (OR 3.56, 95% CI 1.02-12.40 versus no rule), and geographic region (North America OR 1.97, 95% CI 0.57-6.81 versus all other regions combined) were selected as important factors. Conclusion: Half of acute stroke trials were terminated prematurely. Broadening inclusion/exclusion criteria and simplifying the complexity of trials may decrease the likelihood of unplanned premature termination, whereas planned futility analyses may appropriately terminate trials early, saving money and resources.

Introduction: Emergent endovascular thrombectomy (EVT) is effective in improving outcomes in patients with stroke caused by large vessel occlusion. However, there are limited data on the use of EVT in patients taking an oral vitamin K antagonist (VKA), constraining guideline development around EVT use in this vulnerable population. Methods: To address this knowledge gap, we performed a retrospective, observational, cohort study based on a population-based sample of stroke admissions in the US (the AHAs “Get With The Guidelines-Stroke" Program) between October 2015 and March 2020. We aimed to determine whether use of VKA was associated with the risk of symptomatic intracranial hemorrhage (sICH) and functional outcomes in patients undergoing EVT within 6 hours of time last known well after adjusting for pre-specified confounders. Results: Of 32,715 patients (median age 72 years; 50.7% female), 3,087 were taking a VKA and 29,628 were not on an OAC prior to stroke. Patients taking VKAs were older (median age 78 vs. 71 years) but stroke severity was similar between the groups (median NIHSS 18 vs. 17). Of patients taking a VKA, 211 (6.8%) suffered a sICH whereas 1,904 (6.4%) patients not on OAC developed a sICH. VKA was not associated with sICH (adjusted odds ratio 1.20, 95% CI: 0.96-1.49). VKA use was associated with a higher risk of life-threatening systemic hemorrhage (1.2% vs. 1.02%; aOR 1.93 (1.17-3.19)) but not with mortality/discharge to hospice (27.1% vs. 20.6%; aOR 1.02 (0.90-1.14)). Patients taking a VKA prior to EVT were more likely to be able to be ambulatory at discharge (aOR 1.24 [1.11-1.39]) and to have an mRS of 0-2 (aOR 1.23 [1.07-1.42]). Conclusions: Among patients with acute ischemic stroke on VKA, EVT appears to be well tolerated without prohibitive risks of sICH. Our results provide support for the deployment of this critical, disability-reducing therapy in this population of patients with a large vessel occlusion presenting within 6 hours of time last known well.

Background Emergency medical services (EMS) compliance with recommended prehospital care for patients with acute stroke is inconsistent; however, sources of variability in compliance are not well understood. The current analysis utilizes a linkage between a statewide stroke registry and EMS information system data to explore patient and EMS agency‐level contributions to variability in prehospital care. Methods and Results This is a retrospective analysis of a cohort of confirmed stroke cases transported by EMS to hospitals participating in a statewide stroke registry. Using EMS information system data, the authors quantified EMS compliance with 6 performance measures derived from national guidelines for prehospital stroke care: prehospital stroke scale performance, glucose check, stroke recognition, on‐scene time ≤15 minutes, time last known well documentation, and hospital prenotification. Multilevel multivariable logistic regression analysis was then used to examine associations between patient‐level demographic and clinical characteristics and EMS compliance while accounting for and quantifying the variation attributable to agency of transport and recipient hospital. Over an 18‐month period, EMS and stroke registry records were linked for 5707 EMS‐transported stroke cases. Compliance ranged from 24% of cases for last known well documentation to 82% for documentation of a glucose check. The other measures were documented in approximately half of cases. Older age, higher National Institutes of Health Stroke Scale, and earlier presentation were associated with more compliant prehospital care. EMS agencies accounted for more than half of the variation in EMS prehospital stroke scale documentation and last known well documentation and 27% of variation in glucose check but Conclusions EMS stroke care remains highly variable across different performance measures and EMS agencies. EMS agency and electronic medical record type are important sources of variability in compliance with key prehospital performance metrics for stroke.

Small/er soccer nations rely strongly on developing youth athletes into experts in adulthood due to financial, logistical, and\ud coach education constraints. One factor that contributes to this expertise is activities engaged in during childhood.\ud Researchers have described these activities by focusing on larger, well-developed countries that often have larger participation rates and higher competition levels than their smaller counterparts. Therefore, to provide more specific information to support talent development in smaller soccer nations, a survey of the youth development system of a small\ud soccer nation was conducted, alongside recording the developmental activities of skilled and less-skilled soccer players\ud within this system. Key stakeholders (e.g., technical director) completed a youth development system survey. Skilled soccer players (n = 12) who were representing their country at U17 level and less-skilled players (n = 13) that had never\ud played for their country completed a Participation History Questionnaire. Skilled players engaged in significantly higher\ud amounts of individual practice in both childhood and early adolescence compared to less-skilled players. Survey data indicated that the greater amounts of individual practice for the skilled players stemmed from a lack of finances, playing facilities, and a formal coach education program. Results from this study may inform future practices and processes in the\ud youth development systems of small/er soccer nations and their national associations.

This study reports on outcomes for 169 caregivers enrolled in the Michigan Stroke Transitions Trial (MISTT), an RCT of social work case management for stroke patients returning home. A mixed-model approach examined the mean change from 7- to 90-days post-discharge with group-by-time interactions for differences between treatment groups. Caregivers reported few life changes or depressive symptoms from caregiving. There was no significant change over time or treatment effects. Negative aspects of stroke caregiving may take longer to develop. Focused caregiver assessment at discharge and a better understanding of how caregiving develops over time may improve the type and timing of support.

Instrument-assisted soft tissue mobilization (IASTM) is a common intervention among clinicians. Despite its popularity, little is known about the forces applied by the clinician using the instruments during treatment. The purpose of this investigation was to examine the forces applied by trained clinicians using IASTM instruments during a simulated treatment. Eleven IASTM–trained (Graston Technique, Técnica Gavilán, or RockBlades) clinicians (physical therapists = 2, chiropractors = 2, athletic trainers = 7) participated in the study. Each clinician performed 75 two-handed strokes distributed evenly across 5 IASTM instruments on a skin simulant attached to a force plate. Instrument-assisted soft tissue mobilization stroke application was analyzed for peak normal forces and mean normal forces by stroke. We observed an average peak normal force of 8.9 N and mean normal force of 6.0 N across all clinicians and instruments. Clinicians and researchers may use the descriptive values as reference for the application of IASTM in practice and research.

Background and ObjectivesWomen have been underrepresented in cardiovascular disease clinical trials but there is less certainty over the level of disparity specifically in stroke. We examined the participation of women in trials according to stroke prevalence in the population.MethodsPublished randomized controlled trials with ≥100 participants enrolled between 1990 and 2020 were identified from ClinicalTrials.gov. To quantify sex disparities in enrollment, we calculated the participation to prevalence ratio (PPR), defined as the percentage of women participating in a trial vs the prevalence of women in the disease population.ResultsThere were 281 stroke trials eligible for analyses with a total of 588,887 participants, of whom 37.4% were women. Overall, women were represented at a lower proportion relative to their prevalence in the underlying population (mean PPR 0.84; 95% confidence interval [CI] 0.81–0.87). The greatest differences were observed in trials of intracerebral hemorrhage (PPR 0.73; 95% CI 0.71–0.74), trials with a mean age of participants p for trend = 0.201).DiscussionWomen are disproportionately underrepresented in stroke trials relative to the burden of disease in the population. Clear guidance and effective implementation strategies are required to improve the inclusion of women and thus broader knowledge of the impact of interventions in clinical trials.

Objective: To examine changes in leisure participation following stroke/transient ischaemic attack (TIA) and explore its relationship to modifiable and non-modifiable participant characteristics. Design: An observational study design with self-report questionnaires collected at two time points (baseline and 6-months). Setting: The study was conducted across 21 hospital sites in England, Wales, and Northern Ireland. Participants: Participants were aged 18+ and had experienced a first or recurrent stroke or TIA and had a post-stroke/TIA modified Rankin score (mRS) of ≤3. Procedure: Research practitioners at each site approached potential participants. Individuals who agreed to participate completed a baseline questionnaire whilst an inpatient or at a first post-stroke/TIA clinic appointment. A follow-up questionnaire was posted to participants with a freepost return envelope. Two questionnaires were developed that collected demographic information, pre-stroke/TIA mRS, social circumstances (e.g., employment situation) and incorporated the shortened Nottingham Leisure Questionnaire (sNLQ). Results: The study recruited eligible participants (N = 3295); 2000 participants returned questionnaires at follow-up. Data showed three participant variables were significant predictors of engagement in leisure activities post-stroke/TIA: age, sex, and deprivation decile. There was an overall decline in the number and variety of leisure activities, with an average loss of 2.2 activities following stroke/TIA. Only one activity, “exercise/fitness” saw an increase in engagement from baseline to follow-up; watching TV remained stable, whilst participation in all other activities reduced between 10% and 40% with an average activity engagement reduction of 22%. Conclusions: Some groups experienced a greater reduction in activities than others—notably older participants, female participants, and those living in a low socioeconomic area. Registration: researchregistry4607. Strengths and limitations of this study: 1. This is the largest-ever study to survey life and leisure activity engagement following stroke/TIA. 2. Survey responses were self-reported retrospectively and, therefore, may have been misreported, or misremembered. 3. Despite the large cohort, there were few participants, and so respondents, from ethnic minority groups.

Objective: The aim of this article is to assess available data regarding use of nivolumab/relatlimab for adult and pediatric patients 12 years of age and older with unresectable or metastatic melanoma. Data Sources: A search of PubMed conducted from August 2019 to August 2022 with the search terms Opdualag, nivolumab AND relatlimab, and BMS-986016 resulted in 14 publications. Study Selection and Data Extraction: Relevant clinical trials written in English language were analyzed. Data Synthesis: Nivolumab/relatlimab was approved by the Food and Drug Administration following results of a phase 1/2 trial and phase 2/3 RELATIVITY-047 trial. Nivolumab/relatlimab demonstrated a median progression free survival (PFS) of 10.1 months in the first-line setting without new safety signals. The PFS benefits appear greatest in those with programmed cell death-ligand 1 (PD-L1) Relevance to Patient Care and Clinical Practice: For patients 12 years of age and older with unresectable or metastatic melanoma, nivolumab/relatlimab offers a new first-line treatment option. Evaluation of PD-L1 expression along with concomitant use of medications with potential interactions should be evaluated when deciding if nivolumab/relatlimab is the most appropriate treatment option. Conclusions: Nivolumab/relatlimab adds an additional first-line treatment option demonstrating promising improved PFS for patients with unresectable or metastatic melanoma, particularly those with PD-L1