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Meniscal tears are a common musculoskeletal pathology in the United States, affecting 61 in every 100,000 people. Surgical repair is indicated for certain tear patterns to reduce the risk of joint degeneration, normalize contact forces in the knee, and help restore normal knee kinematics. However, radial meniscus tear repairs fail to completely heal 38% of the time due to tear characteristics, biology, surgical technique, and inadequate rehabilitation. Recent efforts have incorporated biological augmentation to enhance the healing potential of the meniscus. The BioBrace is a biocomposite scaffold designed to mechanically reinforce tissue and biologically enhance healing. The purpose of this article is to describe an all-inside, meniscal radial tear repair augmented with BioBrace.

Atrial fibrillation predisposes to left atrial thrombus formation and carries a sixfold increased risk for stroke. Antithrombotic therapies are the mainstay for stroke prevention. The National Institute of Neurological Disorders and Stroke-sponsored Stroke Prevention in Atrial Fibrillation (SPAF) studies assessed the value of warfarin, aspirin, and their combination for preventing stroke in six multicenter trials involving 3950 participants. This review presents the major results and implications, which offer unique perspectives on antithrombotic therapies for stroke prevention in atrial fibrillation. Warfarin and aspirin reduce stroke. Anticoagulation substantially benefits high-risk patients with atrial fibrillation, while many younger patients with atrial fibrillation have a low stroke rate when given aspirin. Pathogenetic and transesophageal echocardiographic correlations shed light on mechanisms by which antithrombotic agents prevent stroke. Warfarin inhibits formation of atrial appendage thrombi and markedly reduces cardioembolic strokes, while aspirin primarily prevents smaller, noncardioembolic strokes. The SPAF III stroke risk stratification scheme has been validated for identifying patients with high versus moderate versus low risk for stroke. Women with atrial fibrillation benefit from anticoagulation significantly more than men do. Many elderly patients with recurrent paroxysmal atrial fibrillation have high rates of stroke. Antithrombotic prophylaxis should be individualized on the basis of the estimated risk for stroke during aspirin therapy and the risk for bleeding during anticoagulation. Overall, nearly one third of patients with atrial fibrillation are low risk and should be treated with aspirin, and about one third are high risk and should receive warfarin if it can be given safely. For patients at moderate risk for stroke, patient preferences and access to reliable anticoagulation monitoring are particularly relevant. [ABSTRACT FROM AUTHOR]

Abstract Background The Sustainably Managing Environmental Health Risk in Ecuador project was launched in 2004 as a partnership linking a large Canadian university with leading Cuban and Mexican institutes to strengthen the capacities of four Ecuadorian universities for leading community-based learning and research in areas as diverse as pesticide poisoning, dengue control, water and sanitation, and disaster preparedness. Methods In implementing curriculum and complementary innovations through application of an ecosystem approach to health, our interdisciplinary international team focused on the question: “Can strengthening of institutional capacities to support a community of practice of researchers, practitioners, policy-makers and communities produce positive health outcomes and improved capacities to sustainably translate knowledge?” To assess progress in achieving desired outcomes, we review results associated with the logic framework analysis used to guide the project, focusing on how a community of practice network has strengthened implementation, including follow-up tracking of program trainees and presentation of two specific case studies. Results By 2009, train-the-trainer project initiation involved 27 participatory action research Master’s theses in 15 communities where 1200 community learners participated in the implementation of associated interventions. This led to establishment of innovative Ecuadorian-led master’s and doctoral programs, and a Population Health Observatory on Collective Health, Environment and Society for the Andean region based at the Universidad Andina Simon Bolivar. Building on this network, numerous initiatives were begun, such as an internationally funded research project to strengthen dengue control in the coastal community of Machala, and establishment of a local community eco-health centre focusing on determinants of health near Cuenca. Discussion Strengthening capabilities for producing and applying knowledge through direct engagement with affected populations and decision-makers provides a fertile basis for consolidating capacities to act on a larger scale. This can facilitate the capturing of benefits from the “top down” (in consolidating institutional commitments) and the “bottom up” (to achieve local results). Conclusions Alliances of academic and non-academic partners from the South and North provide a promising orientation for learning together about ways of addressing negative trends of development. Assessing the impacts and sustainability of such processes, however, requires longer term monitoring of results and related challenges.

STUDY OBJECTIVE: Anterior ST-segment elevation myocardial infarction (STEMI) can be difficult to differentiate from early repolarization on the ECG. We hypothesize that, in addition to ST-segment elevation, T-wave amplitude to R-wave amplitude ratio (T-wave amplitude(avg)/R-wave amplitude(avg)), and R-wave amplitude in leads V2 to V4, computerized corrected QT interval (QTc) and upward concavity would help to differentiate the 2. We seek to determine which ECG measurements best distinguish STEMI versus early repolarization. METHODS: This was a retrospective study of patients with anterior STEMI (2003 to 2009) and early repolarization (2003 to 2005) at 2 urban hospitals, one of which (Minneapolis Heart Institute) receives 500 STEMI patients per year. We compared the ECGs of nonobvious ('subtle') anterior STEMI with emergency department noncardiac chest pain patients with early repolarization. ST-segment elevation at the J point and 60 ms after the J point, T-wave amplitude, R-wave amplitude, QTc, upward concavity, J-wave notching, and T waves in V1 and V6 were measured. Multivariate logistic regression modeling was used to identify ECG measurements independently predictive of STEMI versus early repolarization in a derivation group and was subsequently validated in a separate group. RESULTS: Of 355 anterior STEMIs identified, 143 were nonobvious, or subtle, compared with 171 early repolarization ECGs. ST-segment elevation was greater, R-wave amplitude lower, and T-wave amplitude(avg)/R-wave amplitude(avg) higher in leads V2 to V4 with STEMI versus early repolarization. Computerized QTc was also significantly longer with STEMI versus early repolarization. T-wave amplitude did not differ significantly between the groups, such that the T-wave amplitude(avg)/R-wave amplitude(avg) difference was entirely due to the difference in R-wave amplitude. An ECG criterion based on 3 measurements (R-wave amplitude in lead V4, ST-segment elevation 60 ms after J-point in lead V3, and QTc) was derived and validated for differentiating STEMI versus early repolarization, such that if the value of the equation ([1.196 x ST-segment elevation 60 ms after the J point in lead V3 in mm]+[0.059 x QTc in ms]-[0.326 x R-wave amplitude in lead V4 in mm]) is greater than 23.4 predicted STEMI and if less than or equal to 23.4, it predicted early repolarization in both groups, with overall sensitivity, specificity, and accuracy of 86% (95% confidence interval [CI] 79, 91), 91% (95% CI 85, 95), and 88% (95% CI 84, 92), respectively, with positive likelihood ratio 9.2 (95% CI 8.5 to 10) and negative likelihood ratio 0.1 (95% CI 0.08 to 0.3). Upward concavity, upright T wave in V1 or T wave, in V1 greater than T wave in V6, and J-wave notching did not provide important information. CONCLUSION: R-wave amplitude is lower, ST-segment elevation greater, and QTc longer for subtle anterior STEMI versus early repolarization. In combination with other clinical data, this derived and validated ECG equation could be an important adjunct in the diagnosis of anterior STEMI. [ABSTRACT FROM AUTHOR]

Introduction: Socially excluded populations, defined by homelessness, substance use disorder, sex work or criminal justice system contact, experience profound health inequity compared with the general population. Cumulative exposure to adverse childhood experiences (ACEs), including neglect, abuse and household dysfunction before age 18, has been found to be independently associated with both an increased risk of social exclusion and adverse health and mortality outcomes in adulthood.Despite this, the impact of ACEs on health and mortality within socially excluded populations is poorly understood., Methods and Analysis: We will search MEDLINE, Cumulative Index of Nursing and Allied Health Literature, Educational Resources Information Center, PsycINFO, Applied Social Science Index and Abstracts and Criminal Justice Database for peer-reviewed studies measuring ACEs and their impact on health and mortality in socially excluded populations.Three review questions will guide our data extraction and analysis. First, what is the prevalence of ACEs among people experiencing social exclusion in included studies? Second, what is the relationship between ACEs and health and mortality outcomes among people experiencing social exclusion? Does resilience modify the strength of association between ACEs and health outcomes among people experiencing social exclusion?We will meta-analyse the relationship between ACE exposure and health outcomes classified into six a prior categories: (1) substance use disorders; (2) sexual and reproductive health; (3) communicable diseases; (4) mental illness; (5) non-communicable diseases and (6) violence victimisation, perpetration and injury. If there are insufficient studies for meta-analysis, we will conduct a narrative synthesis. Study quality will be assessed using the MethodologicAl STandards for Epidemiological Research scale., Ethics and Dissemination: Our findings will be disseminated in a peer-reviewed journal, in presentations at academic conferences and in a brief report for policy makers and service providers. We do not require ethics approval as this review will use data that have been previously published., Prospero Registration Number: CRD42022357565., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The use of administrative health data for research, monitoring, and quality improvement has proliferated in recent decades, leading to improvements in health across many disease areas and across the life course. However, not all populations are equally visible in administrative health data, and those that are less visible may be excluded from the benefits of associated research. Socially excluded populations - including the homeless, people with substance dependence, people involved in sex work, migrants or asylum seekers, and people with a history of incarceration - are typically characterised by health inequity. Yet people who experience social exclusion are often invisible within routinely collected administrative health data because information on their markers of social exclusion are not routinely recorded by healthcare providers. These circumstances make it difficult to understand the often complex health needs of socially excluded populations, evaluate and improve the quality of health services that they interact with, provide more accessible and appropriate health services, and develop effective and integrated responses to reduce health inequity. In this commentary we discuss how linking data from multiple sectors with administrative health data, often called cross-sectoral data linkage , is a key method for systematically identifying socially excluded populations in administrative health data and addressing other issues related to data quality and representativeness. We discuss how cross-sectoral data linkage can improve the representation of socially excluded populations in research, monitoring, and quality improvement initiatives, which can in turn inform coordinated responses across multiple sectors of service delivery. Finally, we articulate key challenges and potential solutions for advancing the use of cross-sectoral data linkage to improve the health of socially excluded populations, using international examples., Competing Interests: Conflicts of interest: None declared.

Rationale: An antibody-drug conjugate (ADC) is a targeted therapy consisting of a cytotoxic payload that is linked to an antibody which targets a protein enriched on malignant cells. Multiple ADCs are currently used clinically as anti-cancer agents significantly improving patient survival. Herein, we evaluated the rationale of targeting the cell surface oncoreceptor CUB domain-containing protein 1 (CDCP1) using ADCs and assessed the efficacy of CDCP1-directed ADCs against a range of malignant tumors. Methods: CDCP1 mRNA expression was evaluated using large transcriptomic datasets of normal/tumor samples for 23 types of cancer and 15 other normal organs, and CDCP1 protein expression was examined in 34 normal tissues, >300 samples from six types of cancer, and in 49 cancer cell lines. A recombinant human/mouse chimeric anti-CDCP1 antibody (ch10D7) was labelled with 89 Zirconium or monomethyl auristatin E (MMAE) and tested in multiple pre-clinical cancer models including 36 cancer cell lines and three mouse xenograft models. Results: Analysis of CDCP1 expression indicates elevated CDCP1 expression in the majority of the cancers and restricted expression in normal human tissues. Antibody ch10D7 demonstrates a high affinity and specificity for CDCP1 inducing cell signalling via Src accompanied by rapid internalization of ch10D7/CDCP1 complexes in cancer cells . 89 Zirconium-labelled ch10D7 accumulates in CDCP1 expressing cells enabling detection of pancreatic cancer xenografts in mice by PET imaging. Cytotoxicity of MMAE-labelled ch10D7 against kidney, colorectal, lung, ovarian, pancreatic and prostate cancer cells in vitro , correlates with the level of CDCP1 on the plasma membrane. ch10D7-MMAE displays robust anti-tumor effects against mouse xenograft models of pancreatic, colorectal and ovarian cancer. Conclusion: CDCP1 directed imaging agents will be useful for selecting cancer patients for personalized treatment with cytotoxin-loaded CDCP1 targeting agents including antibody-drug conjugates., Competing Interests: Competing Interests: Thomas Kryza, Simon Puttick, Yaowu He and John D. Hooper are inventors on a patent covering the use of antibody 10D7 used in this study. No potential conflicts of interest were disclosed by the other authors., (© The author(s).)

Background: Limited data exists on the performance of the healthcare system in opioid use disorder (OUD). We evaluated the face validity and potential risks of a set of health system performance measures for OUD collaboratively with clinicians, policymakers and people with lived experience of opioid use (PWLE) in the interest of establishing an endorsed set of measures for public reporting., Methods: Through a two-stage Delphi-panel approach, a panel of clinical and policy experts validated and considered 102 previously constructed OUD performance measures for endorsement using information on measurement construction, sensitivity analyses, quality of evidence, predictive validity, and feedback from local PWLE. We collected quantitative and qualitative survey responses from 49 clinicians and policymakers, and 11 PWLE. We conducted inductive and deductive thematic analysis to present qualitative responses., Results: A total of 37 measures of 102 were strongly endorsed (9/13 cascade of care, 2/27 clinical guideline compliance, 17/44 healthcare integration, and 9/18 healthcare utilization measures). Thematic analysis of responses revealed several themes regarding measurement validity, unintended consequences, and key contextual considerations. Overall, measures related to the cascade of care (excluding opioid agonist treatment dose tapering) received strong endorsements. PWLE highlighted barriers to accessing treatment, undignified aspects of treatment, and lack of a full continuum of care as their concerns., Conclusion: We defined 37 endorsed health system performance measures for OUD and presented a range of perspectives on their validity and use. These measures provide critical considerations for health system improvement in the care of people with OUD., Competing Interests: BN received a Health Canada Substance Use and Addictions Program award (1819-HQ-000,036) to his institution. All other authors have no conflicts to declare., (© 2022 The Authors.)

Background: Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown., Aims: To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies., Methods: At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression., Results: Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52-1.7)., Conclusions: Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide. Registration: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Background: The effect of interventions on functional impairment is an important outcome in stroke prevention trials and should be considered as an adjunct to counting discrete events. In the NAVIGATE-ESUS trial, 7213 patients with recent embolic strokes of undetermined source were randomized to rivaroxaban (15 mg once daily) or aspirin (100 mg daily). After 11 months there was no effect on the prevention of recurrent stroke., Aims: To determine the effect of rivaroxaban compared to aspirin on functional and cognitive outcomes., Methods: Function and cognition were measured at baseline, 1 year, and study end using the Standard Assessment of Global Everyday Activities (SAGEA), a 15-item scale assessing cognitive, instrumental, and basic activities of daily living as well as mobility, and the Montreal Cognitive Assessment (MoCA). Changes in scores were calculated by subtracting either study end or 1-year scores from baseline, and differences in distributions were compared using the Mann-Whitney U test. SAGEA and MoCA scores were also correlated with recurrent stroke., Results: Follow-up SAGEA scores were available in 6378 (88%) participants. There was no difference in change in function for those allocated to rivaroxaban compared to aspirin (Mann-Whitney U test, p = 0.8), with both distributions having a median (25p,75p) change of 0 (-2,1). Overall, more of those who experienced a recurrent stroke (n=247; mostly minor ischemic), reported functional difficulty at study end versus entry, compared with those who did not (51% versus 30%, chi-square test, p< 0.001), and this was consistent across global regions. There was no difference in the change in cognition by treatment group, nor were recurrent strokes associated with a change in cognition., Conclusions: Rivaroxaban, compared to aspirin, was not associated with changes in functional or cognitive status in patients with recent ESUS. The SAGEA scale detected changes in functional status associated with recurrent strokes in an international stroke population., Competing Interests: Declaration of Competing Interest J.B. received fees for an Advisory Board and as an Adjudication Committee Member from Bayer, outside the submitted work. M.S. reports personal fees from BMS and Daichii Sankyo, outside the submitted work. M.C. received a travel grant from Boehringer Ingelheim and Bayer for conference attendance. W.W. is supported by a Scottish Senior Clinical Fellowship [CSO SCAF/17/01] and received grants from the Alzheimer's Society [UK], Chief Scientist's Office, UK MRC, and the UK Stroke Association. S.Y. is supported by the Heart & Stroke Foundation/Marion W. Burke Chair in Cardiovascular Disease and has received research grants, honoraria and travel expenses for lectures from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb AstraZeneca and Sanofi, outside the submitted work. R.H. reports grants and personal fees from Bayer AG, outside the submitted w, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Objectives: Function is an important outcome after stroke; traditional assessments may not capture functional deficits important to patients. We examined the validity of the Standard Assessment of Global Everyday Activities (SAGEA), a patient-reported outcome that assesses activities important to patients and for use in international clinical trials., Methods: The NAVIGATE-ESUS trial evaluated rivaroxaban compared to aspirin in preventing recurrent stroke in 7213 participants. The Modified Rankin Scale (mRS), the National Institutes of Health Stroke Scale (NIHSS), and the SAGEA were collected at entry. Chi square tests were used to compare proportions and Spearman rank correlations were used to compare between measures. SAGEA was compared to the Modified Frailty Index (MFI) and the occurrence of infarct to examine criterion validity RESULTS: Participants were 67 years, 2/3 were male, and at baseline 30% had no disability and 58% had slight disability according to mRS scores. SAGEA was weakly correlated with the mRS (r=0.37), the NIHSS (r=0.29) and the MFI (r=0.30). Of the 2154 with an mRS score of 0, 61% reported difficulty on the SAGEA. The largest discrepancies between SAGEA and other measures were because of cognitive functional deficits detected by the SAGEA that were not identified on other assessments. A larger number of MRI identified infarcts (acute and covert) were associated with a higher SAGEA score (p=0.007)., Conclusions: The SAGEA is a simple, globally applicable measure of cognitive and functional abilities that identifies issues that other commonly used assessments of disability and function do not capture., Competing Interests: Declaration of Competing Interest J.B. received fees for an Advisory Board and as an Adjudication Committee Member from Bayer, outside the submitted work. M.S. reports personal fees from BMS and Daichii Sankyo, outside the submitted work. M.C. received a travel grant from Boehringer Ingelheim and Bayer for conference attendance. W.W. is supported by a Scottish Senior Clinical Fellowship [CSO SCAF/17/01] and received grants from the Alzheimer's Society [UK], Chief Scientist's Office, UK MRC, and the UK Stroke Association. S.Y. is supported by the Heart & Stroke Foundation/Marion W. Burke Chair in Cardiovascular Disease and has received research grants, honoraria and travel expenses for lectures from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb AstraZeneca and Sanofi, outside the submitted work. R.H. reports grants and personal fees from Bayer AG, outside the submitted work., (Copyright © 2022. Published by Elsevier Inc.)

Background and Purpose: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial., Methods: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics., Results: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26-115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack ( P <0.001), modified Rankin Scale score >0 ( P <0.001), and current tobacco use ( P =0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS., Conclusions: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02313909.

Importance: It is uncertain whether anticoagulation is superior to aspirin at reducing recurrent stroke in patients with recent embolic strokes of undetermined source (ESUS) and left ventricular (LV) dysfunction., Objective: To determine whether anticoagulation is superior to aspirin in reducing recurrent stroke in patients with ESUS and LV dysfunction., Design, Setting, and Participants: Post hoc exploratory analysis of data from the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) trial, a randomized, phase 3 clinical trial with enrollment from December 2014 to September 2017. The study setting included 459 stroke recruitment centers in 31 countries. Patients 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of the 7213 NAVIGATE ESUS participants, 7107 (98.5%) had a documented assessment of LV function at study entry and were included in the present analysis. Data were analyzed in January 2021., Interventions: Participants were randomized to receive either 15 mg of rivaroxaban or 100 mg of aspirin once daily., Main Outcomes and Measures: The study examined whether rivaroxaban was superior to aspirin at reducing the risk of (1) the trial primary outcome of recurrent stroke or systemic embolism and (2) the trial secondary outcome of recurrent stroke, systemic embolism, myocardial infarction, or cardiovascular mortality during a median follow-up of 10.4 months. LV dysfunction was identified locally through echocardiography and defined as moderate to severe global impairment in LV contractility and/or a regional wall motion abnormality. A Cox proportional hazards model was used to assess for treatment interaction and to estimate the hazard ratios for those randomized to rivaroxaban vs aspirin by LV dysfunction status., Results: LV dysfunction was present in 502 participants (7.1%). Of participants with LV dysfunction, the mean (SD) age was 67 (10) years, and 130 (26%) were women. Among participants with LV dysfunction, annualized primary event rates were 2.4% (95% CI, 1.1-5.4) in those assigned to rivaroxaban vs 6.5% (95% CI, 4.0-11.0) in those assigned aspirin. Among the 6605 participants without LV dysfunction, rates were similar between those assigned to rivaroxaban (5.3%; 95% CI, 4.5-6.2) vs aspirin (4.5%; 95% CI, 3.8-5.3). Participants with LV dysfunction assigned to rivaroxaban vs aspirin had a lower risk of the primary outcome (hazard ratio, 0.36; 95% CI, 0.14-0.93), unlike those without LV dysfunction (hazard ratio, 1.16; 95% CI, 0.93-1.46) (P for treatment interaction = .03). Results were similar for the secondary outcome., Conclusions and Relevance: In this post hoc exploratory analysis, rivaroxaban was superior to aspirin in reducing the risk of recurrent stroke or systemic embolism among NAVIGATE ESUS participants with LV dysfunction., Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.

Background: With over 11 million people incarcerated globally, prevention and control of COVID-19 in custodial settings is a critical component of the public health response. Given the risk of rapid transmission in these settings, it is important to know what guidance existed for responding to COVID-19 in the early stages of the pandemic. We sought to identify, collate, and summarise guidance for the prevention and control of COVID-19 in custodial settings in the first six months of 2020. We conducted a systematic search of peer-reviewed and grey literature, and manually searched relevant websites to identify publications up to 30 June 2020 outlining recommendations to prevent and/or control COVID-19 in custodial settings. We inductively developed a coding framework and assessed recommendations using conventional content analysis., Results: We identified 201 eligible publications containing 374 unique recommendations across 19 domains including: preparedness; physical environments; case identification, screening, and management; communication; external access and visitation; psychological and emotional support; recreation, legal, and health service adaptation; decarceration; release and community reintegration; workforce logistics; surveillance and information sharing; independent monitoring; compensatory measures; lifting control measures; evaluation; and key populations/settings. We identified few conflicting recommendations., Conclusions: The breadth of recommendations identified in this review reflects the complexity of COVID-19 response in custodial settings. Despite the availability of comprehensive guidance early in the pandemic, important gaps remain in the implementation of recommended prevention and control measures globally, and in the availability of evidence assessing their effectiveness on reducing COVID-19 disease, impact on people in custody and staff, and implementation., (© 2021. The Author(s).)

Optimal cytoreduction for ovarian cancer is often challenging because of aggressive tumor biology and advanced stage. It is a critical issue since the extent of residual disease after surgery is the key predictor of ovarian cancer patient survival. For a limited number of cancers, fluorescence-guided surgery has emerged as an effective aid for tumor delineation and effective cytoreduction. The intravenously administered fluorescent agent, most commonly indocyanine green (ICG), accumulates preferentially in tumors, which are visualized under a fluorescent light source to aid surgery. Insufficient tumor specificity has limited the broad application of these agents in surgical oncology including for ovarian cancer. In this study, we developed a novel tumor-selective fluorescent agent by chemically linking ICG to mouse monoclonal antibody 10D7 that specifically recognizes an ovarian cancer-enriched cell surface receptor, CUB-domain-containing protein 1 (CDCP1). 10D7 ICG has high affinity for purified recombinant CDCP1 and CDCP1 that is located on the surface of ovarian cancer cells in vitro and in vivo. Our results show that intravenously administered 10D7 ICG accumulates preferentially in ovarian cancer, permitting visualization of xenograft tumors in mice. The data suggest CDCP1 as a rational target for tumor-specific fluorescence-guided surgery for ovarian cancer.

Background and Purpose: Subdural hematomas are an uncommon, but a serious, bleeding complication of antithrombotic therapies. We update our previous inconclusive meta-analysis to better estimate the risk of subdural hematoma associated with aspirin use., Methods: For the initial meta-analysis, nine randomized trials published between1980 and 2012 comparing aspirin with placebo/control were considered. Additional data from four large primary prevention trials were added. Two reviewers independently extracted data on subdural hematomas, with differences resolved by joint review and consensus., Results: Numbers of subdural hematoma were available from thirteen randomized trials involving 155,554 participants comparing aspirin (dosage range 25 mg twice daily to 325 mg daily) to placebo (ten double-blind trials) or no aspirin (three trials). Participants included healthy healthcare providers, older people with vascular risk factors without manifest vascular disease, and those with atrial fibrillation or chronic angina. Pooling all trials, subdural hematomas were identified in 93 of 77,698 participants assigned to aspirin versus 62 of 77,856 participants assigned to placebo/no aspirin. By meta-analysis, the relative risk ratio meta of subdural hematoma associated with assignment to aspirin was 1.5 (95%CI 1.1, 2.0, p = 0.01; p = 0.9 for heterogeneity, I 2 index = 0%). Based on recent primary prevention trials, subdural hematoma diagnosis averaged 1 per 3,125 people per year without aspirin use; the absolute increase associated with aspirin use was estimated as one additional subdural hematoma per 6,500 patients annually., Conclusions: This meta-analysis confirms that aspirin use increases the relative risk of subdural hematoma, but the absolute increased rate associated with aspirin therapy is very low for most people., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Research about the sexual exploitation of homeless and street-involved boys is limited and often combined with that of girls. As aggregation can distort unique issues among genders which are exploited, this study provides information about the context of exploitation for homeless boys. Boys participated in the anonymous, multi-city British Columbia (BC), Canada Homeless and Street-Involved Youth Health paper surveys of 2006 and 2014. Measures included questions about trading sex for money, shelter, or other consideration; age first exploited; for whom; where they were living when first traded sex; gender of exploiters; and demographics. Analyses, separately for younger/older boys, explored the prevalence, timing of exploitation vs. homelessness, and ANOVAs to evaluate the patterns of the age of first exploitation by the genders of exploiters. Just over one in four boys reported exploitation (n = 132), with a median age of 14-15 in most groups. Most were runaway or homeless before their first exploitation, but 25.5% (2006) and 41% (2014) were living with family. Most boys were exploited by women (78%-85%), with 62%-65% were exclusively exploited by women.

Identification of tumors which over-express Epidermal Growth Factor Receptor (EGFR) is important in selecting patients for anti-EGFR therapies. Enzymatic bioconjugation was used to introduce positron-emitting radionuclides ( 89 Zr, 64 Cu) into an anti-EGFR antibody fragment for Positron Emission Tomography (PET) imaging the same day as injection. A monovalent antibody fragment with high affinity for EGFR was engineered to include a sequence that is recognized by the transpeptidase sortase A. Two different metal chelators, one for 89 Zr IV and one for 64 Cu II , were modified with a N-terminal glycine to enable them to act as substrates in sortase A mediated bioconjugation to the antibody fragment. Both fragments provided high-quality PET images of EGFR positive tumors in a mouse model at 3 hours post-injection, a significant advantage when compared to radiolabeled full antibodies that require several days between injection of the tracer and imaging. The use of enzymatic bioconjugation gives reproducible homogeneous products with the metal complexes selectively installed on the C-terminus of the antibody potentially simplifying regulatory approval., Competing Interests: Stacey E. Rudd and Paul S. Donnelly are inventors on intellectual property relating to the use of DFOSq that have been licenced from the University of Melbourne to Telix Pharmaceuticals. Paul S. Donnelly is an inventor of intellectual property relating to this area of research that has been licensed from the University of Melbourne to Clarity Pharmaceuticals. Paul S. Donnelly serves on the Scientific Advisory board and has a financial interest in Clarity Pharmaceuticals. Rodney J. Hicks has shares in Telix Pharmaceuticals., (This journal is © The Royal Society of Chemistry.)

Background and Aim: The diagnosis of embolic stroke of undetermined source (ESUS) is based on excluding other more likely stroke etiologies, and therefore diagnostic testing plays an especially crucial role. Our objective was to compare the diagnostic testing by region, sex, and age among the participants of NAVIGATE-ESUS trial., Methods: Participants were grouped according to five global regions (North America, Latin America, Western Europe, Eastern Europe and East Asia), age (<60, 60-74, and >75 years), and sex. Frequencies of each diagnostic test within areas of echocardiography, cardiac rhythm monitoring, and arterial imaging were described and compared across groups. A multivariable logistic regression model for each diagnostic test was fit to assess the independent influence of each of region, age, and sex and likelihood of testing., Results: We included 6985 patients in the analysis (918 from North America; 746 from Latin America; 2853 from Western Europe; 1118 from Eastern Europe; 1350 from East Asia). Average age (highest in Western Europe (69 years), lowest in Eastern Europe (65 years)), % females (highest in Latin America (44%) and lowest in East Asia (31%)), and use of each diagnostic test varied significantly across regions. Region, but not sex, was independently associated with use of each diagnostic test examined. Transesophageal echocardiography and either CT or MR angiogram were more often used in younger patients., Conclusion: Diagnostic testing differed by region, and less frequently by age, but not by sex. Our findings reflect the existing variations in global practice in diagnostic testing in ESUS patients.

Background: An epidemic of opioid overdose has spread across North America, with illicit drug-related overdose emerging as a leading cause of death in recent years. Estimates of opioid use disorder (OUD) prevalence at the level of the public health service delivery area are needed to project resource needs and identify priority areas for targeted intervention. Our objective is to estimate the annual prevalence of OUD in British Columbia (BC), Canada, from 2000 to 2017., Methods: We performed a multi-sample stratified capture-recapture analysis to estimate OUD prevalence in BC. The analysis included individuals identified from 3 administrative databases for 2000-2011 and 4 databases for 2012-2017, linked at the individual level. Negative binomial regression models on the counts of individuals within these strata were used to estimate prevalence, adjusting for dependency between databases., Results: OUD prevalence in BC among people aged 12 years or older was 1.00 % (N = 34,663 individuals) in 2000 and increased to 1.54 % (N = 61,080) in 2011. Between 2013 and 2017 prevalence increased from 1.57 % (95 % confidence interval: 1.56-1.58) to 1.92 % (1.89-1.95; N = 83,760; 82,492-84,855). The greatest increases in prevalence were observed among males 12-30 years old and 31-44 years old, with 43.2 % and 40.2 % increases from 2013 to 2017., Conclusions: In BC, the OUD prevalence was 1.92 % among people 12 years or older in 2017. We estimated that prevalence has nearly doubled since 2000, with the highest increases in prevalence observed among males under 45., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Importance: The concept of embolic stroke of undetermined source (ESUS) unifies a subgroup of cryptogenic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of certain causes. Despite an annual stroke recurrence rate of 5%, little is known about the etiology underlying recurrent stroke after ESUS., Objective: To identify the stroke subtype of recurrent ischemic strokes after ESUS, to explore the interaction with treatment assignment in each category, and to examine the consistency of cerebral location of qualifying ESUS and recurrent ischemic stroke., Design, Setting, and Participants: The NAVIGATE-ESUS trial was a randomized clinical trial conducted from December 23, 2014, to October 5, 2017. The trial compared the efficacy and safety of rivaroxaban and aspirin in patients with recent ESUS (n = 7213). Ischemic stroke was validated in 309 of the 7213 patients by adjudicators blinded to treatment assignment and classified by local investigators into the categories ESUS or non-ESUS (ie, cardioembolic, atherosclerotic, lacunar, other determined cause, or insufficient testing). Five patients with recurrent strokes that could not be defined as ischemic or hemorrhagic in absence of neuroimaging or autopsy were excluded. Data for this secondary post hoc analysis were analyzed from March to June 2019., Interventions: Patients were randomly assigned to receive rivaroxaban, 15 mg/d, or aspirin, 100 mg/d., Main Outcomes and Measures: Association of recurrent ESUS with stroke characteristics., Results: A total of 309 patients (205 men [66%]; mean [SD] age, 68 [10] years) had ischemic stroke identified during the median follow-up of 11 (interquartile range [IQR], 12) months (annualized rate, 4.6%). Diagnostic testing was insufficient for etiological classification in 39 patients (13%). Of 270 classifiable ischemic strokes, 156 (58%) were ESUS and 114 (42%) were non-ESUS (37 [32%] cardioembolic, 26 [23%] atherosclerotic, 35 [31%] lacunar, and 16 [14%] other determined cause). Atrial fibrillation was found in 27 patients (9%) with recurrent ischemic stroke and was associated with higher morbidity (median change in modified Rankin scale score 2 [IQR, 3] vs 0 (IQR, 1]) and mortality (15% vs 1%) than other causes. Risk of recurrence did not differ significantly by subtype between treatment groups. For both the qualifying and recurrent strokes, location of infarct was more often in the left (46% and 54%, respectively) than right hemisphere (40% and 37%, respectively) or brainstem or cerebellum (14% and 9%, respectively)., Conclusions and Relevance: In this secondary analysis of randomized clinical trial data, most recurrent strokes after ESUS were embolic and of undetermined source. Recurrences associated with atrial fibrillation were a minority but were more often disabling and fatal. More extensive investigation to identify the embolic source is important toward an effective antithrombotic strategy., Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.

Background: Illicit drug use is associated with severe health-related harms, yet people who use drugs (PWUD) face substantial barriers to healthcare. We sought to identify factors associated with disclosure of drug use to a healthcare provider and describe differences in self-reported quality of care received based on disclosure status., Methods: A client-reported experience questionnaire on healthcare access and quality, adapted from the World Health Organization Survey on Health and Health System Responsiveness, was administered within two ongoing prospective cohort studies of PWUD in Vancouver, Canada. Respondents not currently receiving addiction treatment were asked about experience of care and drug use disclosure to their most commonly accessed outpatient healthcare provider in the past 6 months. We used an adjusted logistic regression model to identify client characteristics associated with disclosure., Results: From a total of 261 respondents (34.1% female), less than half (n = 125, 47.8%) reported disclosing drug use to their healthcare provider. Indigenous participants were less likely to disclose compared to non-Indigenous participants (adjusted OR: 0.55, 95% confidence interval: 0.30, 0.97). Disclosure was associated with lower self-reported quality of care (overall rating: disclosed 8.2 vs. did not disclose 8.8, p = 0.04)., Conclusions: In a sample of PWUD accessing outpatient healthcare services, we observed low rates of drug use disclosure, particularly for Indigenous respondents, and reduced quality of care for those who disclosed. These findings highlight the need for culturally safe and non-stigmatizing care to address pervasive stereotyping in the healthcare system and improved screening for substance use disorder in outpatient healthcare services., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020. Published by Elsevier B.V.)

Saturn's moon Titan is the only extraterrestrial body known to host stable lakes and a hydrological cycle. Titan's lakes predominantly contain liquid methane, ethane, and nitrogen, with methane evaporation driving its hydrological cycle. Molecular interactions between these three species lead to non-ideal behavior that causes Titan's lakes to behave differently than Earth's lakes. Here, we numerically investigate how methane evaporation and non-ideal interactions affect the physical properties, structure, dynamics, and evolution of shallow lakes on Titan. We find that, under certain temperature regimes, methane-rich mixtures are denser than relatively ethane-rich mixtures. This allows methane evaporation to stratify Titan's lakes into ethane-rich upper layers and methane-rich lower layers, separated by a strong compositional gradient. At temperatures above 86K, lakes remain well-mixed and unstratified. Between 84 and 86K, lakes can stratify episodically. Below 84K, lakes permanently stratify, and develop very methane-depleted epilimnia. Despite small seasonal and diurnal deviations (<5K) from typical surface temperatures, Titan's rain-filled ephemeral lakes and "phantom lakes" may nevertheless experience significantly larger temperature fluctuations, resulting in polymictic or even meromictic stratification, which may trigger ethane ice precipitation.

Astronomers have discovered thousands of planets outside the Solar System 1 , most of which orbit stars that will eventually evolve into red giants and then into white dwarfs. During the red giant phase, any close-orbiting planets will be engulfed by the star 2 , but more distant planets can survive this phase and remain in orbit around the white dwarf 3,4 . Some white dwarfs show evidence for rocky material floating in their atmospheres 5 , in warm debris disks 6-9 or orbiting very closely 10-12 , which has been interpreted as the debris of rocky planets that were scattered inwards and tidally disrupted 13 . Recently, the discovery of a gaseous debris disk with a composition similar to that of ice giant planets 14 demonstrated that massive planets might also find their way into tight orbits around white dwarfs, but it is unclear whether these planets can survive the journey. So far, no intact planets have been detected in close orbits around white dwarfs. Here we report the observation of a giant planet candidate transiting the white dwarf WD 1856+534 (TIC 267574918) every 1.4 days. We observed and modelled the periodic dimming of the white dwarf caused by the planet candidate passing in front of the star in its orbit. The planet candidate is roughly the same size as Jupiter and is no more than 14 times as massive (with 95 per cent confidence). Other cases of white dwarfs with close brown dwarf or stellar companions are explained as the consequence of common-envelope evolution, wherein the original orbit is enveloped during the red giant phase and shrinks owing to friction. In this case, however, the long orbital period (compared with other white dwarfs with close brown dwarf or stellar companions) and low mass of the planet candidate make common-envelope evolution less likely. Instead, our findings for the WD 1856+534 system indicate that giant planets can be scattered into tight orbits without being tidally disrupted, motivating the search for smaller transiting planets around white dwarfs.

Objective: To compare the efficacy and safety of oral anticoagulants vs antiplatelets in patients with stroke and atherosclerotic plaques in the aortic arch or cervical or intracranial arteries, collectively described as supracardiac atherosclerosis., Methods: We searched PubMed and Scopus until August 28, 2019, for randomized trials comparing oral anticoagulants vs antiplatelets in patients with stroke and supracardiac atherosclerosis using the terms "anticoagulant or anticoagulation" and "antiplatelet or aspirin" and "randomized controlled trial or RCT" and "stroke or cerebral ischemia" and "aortic or carotid or vertebrobasilar or intracranial or atherosclerosis or stenosis or arterial." Four outcomes were assessed: recurrent ischemic stroke, major ischemic event or death, major bleeding, and intracranial bleeding. Treatment effects (relative risk [RR] and 95% confidence interval [CI]) were estimated by meta-analysis using random-effects models., Results: Among 1,117 articles identified in the literature search, results from 10 randomized controlled trials involving 6,068 patients with stroke/TIA with supracardiac atherosclerosis were included in the meta-analysis. Recurrent ischemic stroke rates were 2.94 per 100 patient-years in the anticoagulant-assigned patients vs 3.30 per 100 patient-years in the antiplatelet-assigned patients (RR, 0.91; 95% CI, 0.70-1.18 for the SJ estimator, I 2 = 26%). Major ischemic event or death rates were 4.39 per 100 patient-years in anticoagulant-assigned patients vs 4.32 in antiplatelet-assigned patients (RR, 1.03; 95% CI, 0.79-1.35; I 2 = 54.5%). Major bleeding rates were 2.88 per 100 patient-years in anticoagulant-assigned patients vs 0.82 in antiplatelet-assigned patients (RR, 3.21; 95% CI, 1.96-5.24; I 2 = 46%)., Conclusion: This systematic review and meta-analysis showed that anticoagulant-assigned patients with stroke and supracardiac atherosclerosis were not at different risk of ischemic stroke recurrence and increased risk of major bleeding compared to antiplatelet-assigned patients., (© 2020 American Academy of Neurology.)

Background and Purpose: Optimal secondary prevention for patients with embolic stroke of undetermined source (ESUS) remains unknown. We aimed to assess whether high-sensitivity cardiac troponin T (hs-cTnT) levels are associated with major vascular events and whether hs-cTnT may identify patients who benefit from anticoagulation following ESUS., Methods: Data were obtained from the biomarker substudy of the NAVIGATE ESUS trial, a randomized controlled trial testing the efficacy of rivaroxaban versus aspirin for secondary stroke prevention in ESUS. Patients were dichotomized at the hs-cTnT upper reference limit (14 ng/L, Gen V, Roche Diagnostics). Cox proportional hazard models were computed to explore the association between hs-cTnT, the combined cardiovascular end point (recurrent stroke, myocardial infarction, systemic embolism, cardiovascular death), and recurrent ischemic stroke., Results: Among 1337 patients enrolled at 111 participating centers in 18 countries (mean age 67±9 years, 61% male), hs-cTnT was detectable in 95% and at/above the upper reference limit in 21%. During a median follow-up of 11 months, the combined cardiovascular end point occurred in 68 patients (5.0%/y, rivaroxaban 28 events, aspirin 40 events; hazard ratio, 0.67 [95% CI, 0.41-1.1]), and recurrent ischemic stroke occurred in 50 patients (4.0%/y, rivaroxaban 16 events, aspirin 34 events, hazard ratio 0.45 [95% CI, 0.25-0.81]). Annualized combined cardiovascular end point rates were 8.2% (9.5% rivaroxaban, 7.0% aspirin) for those above hs-cTnT upper reference limit and 4.8% (3.1% rivaroxaban, 6.6% aspirin) below with a significant treatment modification ( P =0.04). Annualized ischemic stroke rates were 4.7% above hs-cTnT upper reference limit and 3.9% below, with no suggestion of an interaction between hs-cTnT and treatment ( P =0.3)., Conclusions: In patients with ESUS, hs-cTnT was associated with increased cardiovascular event rates. While fewer recurrent strokes occurred in patients receiving rivaroxaban, outcomes were not stratified by hs-cTn results. Our findings support using hs-cTnT for cardiovascular risk stratification but not for decision-making regarding anticoagulation therapy in patients with ESUS. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Background and Aims: The 'cascade of care' framework, measuring attrition at various stages of care engagement, has been proposed to guide the public health response to the opioid overdose public health emergency in British Columbia, Canada. We estimated the cascade of care for opioid use disorder and identified factors associated with care engagement for people with opioid use disorder (PWOUD) provincially., Design: Retrospective study using a provincial-level linkage of four health administrative databases., Setting and Participants: All PWOUD in BC from 1 January 1996 to 30 November 2017., Measurements: The eight-stage cascade of care included diagnosed PWOUD, ever on opioid agonist treatment (OAT), recently on OAT, currently on OAT and retained on OAT: ≥ 1, ≥ 3, ≥ 12 and ≥ 24 months). Health-care use, homelessness and other demographics were obtained from physician billing records, hospitalizations, and drug dispensation records. Receipt of income assistance was indicated by enrollment in Pharmacare Plan C., Findings: A total of 55 470 diagnosed PWOUD were alive at end of follow-up. As of 2017, a majority of the population (n = 39 456; 71%) received OAT during follow-up; however, only 33% (n = 18 519) were currently engaged in treatment and 16% (n = 8960) had been retained for at least 1 year. Compared with those never on OAT, those currently engaged in OAT were more likely to be aged under 45 years [adjusted odds ratio (aOR) = 1.75, 95% confidence interval (CI) = 1.64, 1.89], male (aOR = 1.72, 95% CI = 1.64, 1.82), with concurrent substance use disorders (aOR = 2.56, 95% CI = 2.44, 2.70), hepatitis C virus (HCV) (aOR = 1.22, 95% CI = 1.14, 1.33) and either homeless or receiving income-assistance (aOR = 4.35, 95% CI = 4.17, 4.55). Regular contact with the health-care system-either in out-patient or acute care settings-was common among PWOUD not engaged in OAT, regardless of time since diagnosis or treatment discontinuation., Conclusions: People with opioid use disorder in British Columbia, Canada show high levels of out-patient care prior to diagnosis. Younger age, male sex, urban residence, lower income level and homelessness appear to be independently associated with increased opioid agonist treatment engagement., (© 2020 Society for the Study of Addiction.)

Background: Non-stenotic intracranial and systemic atherosclerosis are associated with ischemic stroke. We report frequency and response to anticoagulant vs. antiplatelet prophylaxis of patients with embolic stroke of undetermined source (ESUS) who have non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis., Methods: Exploratory analysis of the international NAVIGATE ESUS randomized trial comparing rivaroxaban 15mg daily with aspirin 100mg daily in 7213 patients with recent ESUS. Among participants with results of intracranial arterial imaging with either computed tomographic angiography (CTA) or magnetic resonance angiography (MRA), the frequency and predictors of non-stenotic intracranial and systemic atherosclerosis and responses to antithrombotic therapy were assessed., Results: Among 4723 participants with available intracranial CTA or MRA results (65% of the trial cohort), the prevalence of intracranial atherosclerosis was 16% (n=739). Patient features independently associated with intracranial atherosclerosis included East Asian region (odds ratio 2.7, 95%CI 2.2,3.3) and cervical carotid plaque (odds ratio 2.3, 95%CI 1.9,2.7), among others. The rate of recurrent ischemic stroke averaged 4.8%/year among those with intracranial atherosclerosis vs. 5.0.%/year for those without (HR 0.95, 95%CI 0.65, 1.4). Among those with intracranial atherosclerosis, the recurrent ischemic stroke rate was higher if assigned to rivaroxaban (5.8%/year) vs. aspirin (3.7%/year), but the difference was not statistically significant (HR 1.6, 95%CI 0.78, 3.3). There was trend for the effect of antithrombotic treatments to be different according to the presence or absence of intracranial atherosclerosis (p interaction =0.09). Among participants with evidence of systemic atherosclerosis by either history or imaging (n=3820), recurrent ischemic stroke rates were similar among those assigned to rivaroxaban (5.5%/year) vs. aspirin (4.9%/year)(HR 1.1, 95%CI 0.84, 1.5)., Conclusions: East Asia region was the strongest factor associated with intracranial atherosclerosis. There were no statistically significant differences between rivaroxaban and aspirin prophylaxis for recurrent ischemic stroke in patients with non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis., (Copyright © 2020. Published by Elsevier Inc.)

Background and Purpose: Risks, sites, and predictors of major bleeding during antithrombotic therapies have not been well defined for patients with recent embolic stroke of undetermined source., Methods: Exploratory analysis of major bleeds defined by International Society of Thrombosis and Hemostasis criteria occurring among 7213 participants in international NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial) embolic stroke of undetermined source randomized trial comparing rivaroxaban 15 mg daily with aspirin 100 mg daily., Results: During a median follow-up of 11 months, 85 major bleeds occurred. The most frequent site was gastrointestinal (38%), followed by intracranial (29%). Assignment to rivaroxaban (hazard ratio [HR], 2.7 [95% CI, 1.7-4.3]), East Asia region (HR, 2.5 [95% CI, 1.6-3.9]), systolic blood pressure ≥160 mm Hg (HR, 2.2 [95% CI, 1.2-3.8]), and reduced estimated glomerular filtration rate (HR, 1.2 per 10 mL/min per 1.73 m 2 decrease, [95% CI, 1.0-1.3]) were independently associated with presence of major bleeds. Five (6%) were fatal. Among 15 patients with intracerebral hemorrhage, 2 (13%) were fatal. There was no evidence of an early high-risk period following initiation of rivaroxaban. The annualized rate of intracerebral hemorrhage was 6-fold higher among East Asian participants (0.67%) versus all other regions (0.11%; HR, 6.3 [95% CI, 2.2-18.0]). Distribution of bleeding sites was similar for rivaroxaban and aspirin., Conclusions: Among embolic stroke of undetermined source patients participating in an international randomized trial, independent predictors of major bleeding were assignment to rivaroxaban, East Asia region, increased systolic blood pressure, and impaired renal function. East Asia as a region was strongly associated with risk of intracerebral hemorrhage. Estimated glomerular filtration rate should be a consideration for stratifying bleeding risk. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Background and Purpose- Emboli in embolic stroke of undetermined source (ESUS) may originate from various potential embolic sources (PES), some of which may respond better to anticoagulation, whereas others to antiplatelets. We analyzed whether rivaroxaban is associated with reduction of recurrent stroke compared with aspirin in patients with ESUS across different PES and by number of PES. Methods- We assessed the presence/absence of each PES (atrial cardiopathy, atrial fibrillation, arterial atherosclerosis, left ventricular dysfunction, cardiac valvulopathy, patent foramen ovale, cancer) in NAVIGATE-ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) participants. Prevalence of each PES, as well as treatment effect and risk of event for each PES were determined. Results by number of PES were also determined. The outcomes were ischemic stroke, all-cause mortality, cardiovascular mortality, and myocardial infarction. Results- In 7213 patients (38% women, mean age 67years) followed for a median of 11 months, the 3 most prevalent PES were atrial cardiopathy (37%), left ventricular disease (36%), and arterial atherosclerosis (29%). Forty-one percent of all patients had multiple PES, with 15% having ≥3 PES. None or a single PES was present in 23% and 36%, respectively. Recurrent ischemic stroke risk was similar for rivaroxaban- and aspirin-assigned patients for each PES, except for those with cardiac valvular disease which was marginally higher in rivaroxaban-assigned patients (hazard ratio, 1.8 [95% CI, 1.0-3.0]). All-cause mortality risks were similar across treatment groups for each PES while too few myocardial infarctions and cardiovascular deaths occurred for meaningful assessment. Increasing number of PES was not associated with increased stroke recurrence nor all-cause mortality, and outcomes did not vary between rivaroxaban- and aspirin-assigned patients by number of PES. Conclusions- A large proportion of patients with ESUS had multiple PES which could explain the neutral results of NAVIGATE-ESUS. Recurrence rates between rivaroxaban- and aspirin-assigned patients were similar across the spectrum of PES. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02313909.

Background and Purpose- Atrial cardiopathy and atherosclerotic plaque are two potential mechanisms underlying embolic strokes of undetermined source (ESUS). The relationship between these two mechanisms among ESUS patients remains unclear. A better understanding of their association may inform targeted secondary prevention strategies. Methods- We examined the association between atrial cardiopathy and atherosclerotic plaque in the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), which enrolled 7213 patients with recent ESUS during 2014 to 2017. For this analysis, we included patients with data on left atrial dimension, location of brain infarction, and cervical large artery plaque. The variables of primary interest were left atrial diameter and cervical plaque ipsilateral to brain infarction. Secondary markers of atrial cardiopathy were premature atrial contractions on Holter monitoring and newly diagnosed atrial fibrillation. For descriptive purposes, left atrial enlargement was defined as ≥4.7 cm. Multivariable logistic regression was used to examine the association between atrial cardiopathy markers and ipsilateral plaque after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, current smoking, and hyperlipidemia. Results- Among 3983 eligible patients, 235 (5.9%) had left atrial enlargement, 939 (23.6%) had ipsilateral plaque, and 94 (2.4%) had both. Shared risk factors for left atrial enlargement and ipsilateral plaque were male sex, white race, hypertension, tobacco use, and coronary artery disease. Despite shared risk factors, increasing left atrial dimension was not associated with ipsilateral plaque after adjustment for covariates (odds ratio per cm, 1.1 [95% CI, 1.0-1.2]; P =0.08). We found no consistent associations between secondary markers of atrial cardiopathy and ipsilateral plaque. Conclusions- In a large population of patients with ESUS, we did not observe a notable association between atrial cardiopathy and atherosclerotic plaque, and few patients had both conditions. These findings suggest that atrial cardiopathy and atherosclerotic plaque may be distinct, nonoverlapping risk factors for stroke among ESUS patients.

Background: Studies assessing the comparative effectiveness of methadone versus buprenorphine/naloxone for opioid use disorder in real-world settings are rare - challenged by structural differences in delivery across settings and factors influencing treatment selection. We identified determinants of selection into buprenorphine/naloxone and quantified contributions of individual and provider-level covariates in a setting delivering both medications within the same healthcare settings., Methods: Utilizing linked health administrative datasets, we conducted a retrospective cohort study of people with opioid use disorder (PWOUD) receiving opioid agonist treatment (OAT) in British Columbia, Canada, from 2008-2017. Determinants of buprenorphine/naloxone selection were identified using a generalized linear mixed model with random intercept terms for providers and individuals. We determined the influence of individual demographics, clinical history, measures of provider experience and preference, and dates of key policy changes., Results: A total of 39,605 individuals experienced 178,976 OAT episodes (methadone:139,439(77.9 %);buprenorphine/naloxone:39,537(22.1 %)). Male sex, less OAT experience, younger age, mental health conditions and chronic pain were associated with higher odds of buprenorphine/naloxone prescription. For providers, higher client-attachment, more complex OAT case-mixes, and higher buprenorphine/naloxone prescribing-preference were also associated with higher odds of buprenorphine/naloxone prescription. Observed individual-level covariates explained 9.7 % of variance in odds of buprenorphine/naloxone selection, while observed provider-level covariates explained 20.0 %. Controlling for covariates, residual unmeasured between-individual variance accounted for 18.5 % of the explained variation in the odds of buprenorphine/naloxone selection, while unmeasured between-provider variance accounted for 28.4 %., Conclusion: Provider characteristics were more influential in selection of buprenorphine/naloxone over methadone informing subsequent analyses of comparative effectiveness of these regimens., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose- Aortic arch atherosclerosis (AAA) is a possible source of embolism in patients with embolic stroke of undetermined source. Previous studies reported high rates of embolic events in patients with AAA, especially those with high-risk AAA. This exploratory analysis of NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) focused on patients with AAA and assessed their characteristics, stroke recurrence rates, and response to treatment. Methods- The detection of AAA and the assessment of its features were based on transesophageal echocardiography that was done in 19% of participants. AAA plaques were considered to have complex features when reported as complex or ulcerated or were ≥4 mm in thickness or had a mobile thrombus present. Results- Among 1382 participants who had transesophageal echocardiography, 397 (29%) had AAA and 112 (8%) had complex AAA. Mean (SD) age (63 [10] versus 67 [9] versus 69 [9]; P <0.001), prevalence of diabetes mellitus (19% versus 26%, versus 32%; P =0.002), and aortic valvulopathy (10 versus 20 versus 20; P <0.001) increased across no versus noncomplex versus complex AAA, respectively. In multivariable analyses, increasing age, diabetes mellitus, aortic valvulopathy, statin use before randomization, chronic infarcts on imaging, and region were independently associated with any AAA versus no AAA and also with complex AAA versus no AAA. Multiterritorial qualifying infarcts rather than single-territory infarcts were observed in 21% with complex AAA versus 17% noncomplex versus 13% no AAA ( P =0.07). Annualized rates of ischemic stroke recurrence were 7.2% versus 4.2% versus 5.6% for complex versus noncomplex versus no AAA, respectively. While prevalence of complex AAA increased with increasing risk score, after adjusting for risk score, we did not observe increased risk of recurrent stroke for patients with complex AAA (hazard ratio, 1.1; 95% CI, 0.53-2.4), although the number of outcomes was limited. In patients with complex AAA, 4 strokes occurred among rivaroxaban-assigned patients and 4 strokes among aspirin-assigned patients. Conclusions- Complex AAA is prevalent in embolic stroke of undetermined source patients and is associated with atherosclerotic burden. Whether complex AAA independently increases recurrent stroke risk and whether a non-vitamin-K oral anticoagulant as compared with aspirin may be effective for reducing recurrent stroke requires additional study. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

The functionalization of proteins with different cargo molecules is highly desirable for a broad range of applications. However, the reproducible production of defined conjugates with multiple functionalities is a significant challenge. Herein, we report the dual site-specific labeling of an antibody fragment, utilizing the orthogonal Sortase A and π-clamp conjugation methods, and demonstrate that binding of the antibody fragment to its target receptor is retained after dual labeling.

Objectives: Administrative data are increasingly being used for surveillance and monitoring of mental health and substance use disorders (MHSUD) across Canada. However, the validity of the diagnostic codes specific to MHSUD is unknown in emergency departments (EDs). Our objective was to determine the concordance, and individual-level and hospital-level factors associated with concordance, between diagnosis codes assigned in ED and at discharge from hospital for MHSUD-related conditions., Design: Population-based retrospective cohort study., Setting: EDs and hospitals within Vancouver Coastal Health Authority (VCH), British Columbia, Canada., Participants: 16 926 individuals who were admitted into a VCH hospital following an ED visit from 1 April 2009 to 31 March 2017, contributing to 48 116 pairs of ED and hospital discharge diagnoses., Primary and Secondary Outcome Measures: We examined concordance in identifying MHSUD between the primary discharge diagnosis codes based on the International Statistical Classification of Diseases, 9th and 10th Revisions (Canada) assigned in the ED and those assigned in the hospital among all ED visits resulting in a hospital admission. We calculated the percent overall agreement, positive agreement, negative agreement and Cohen's kappa coefficient. We performed multiple regression analyses to identify factors independently associated with discordance., Results: We found a high level of concordance for broad categories of MH conditions (overall agreement=0.89, positive agreement=0.74 and kappa=0.67), and a fair level of concordance for SUDs (overall agreement=0.89, positive agreement=0.31 and kappa=0.27). SUDs were less likely to be indicated as the primary cause in ED as opposed to in hospital (3.8% vs 11.7%). In multiple regression analyses, ED visits occurring during holidays, weekends and overnight (21:00-8:59 hours) were associated with increased odds of discordance in identifying MH conditions (adjusted OR 1.47, 95% CI 1.11 to 1.93; 1.27, 95% CI 1.16 to 1.40; 1.30, 95% CI 1.19 to 1.42, respectively)., Conclusions: ED data could be used to improve surveillance and monitoring of MHSUD. Future efforts are needed to improve screening for individuals with MHSUD and subsequently connect them to treatment and follow-up care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To understand how the Take Home Naloxone (THN) program is implemented in two pilot correctional facilities in British Columbia (BC), Canada, in order to identify areas for program improvement and inform the expansion of the program to other Canadian correctional facilities The paper aims to discuss these issues., Design/methodology/approach: Two focus groups and one interview were conducted with healthcare staff at two pilot correctional facilities. Sessions were audio recorded, transcribed verbatim and divergent and convergent experiences within and between the facilities were explored in an iterative process. Key themes and lessons learned were identified and later validated by focus group participants., Findings: Key themes that emerged included: challenges and importance of the train-the-trainer program for healthcare staff conducting participant training sessions; potential for improved prison population engagement and awareness of the program; tailoring program resources to the unique needs of an incarcerated population; challenges connecting participants to community harm reduction resources following release; and clarifying and enhancing the role of correctional officers to support the program., Research Limitations/implications: The correctional setting presents unique challenges and opportunities for the THN program that must be considered for program effectiveness., Originality/value: This evaluation was conducted to inform program expansion amidst a historic opioid overdose epidemic in BC, and adds to the limited yet growing body of literature on the implementation and evaluation of this program in correctional settings globally.

Pearce, LA, Sinclair, WH, Leicht, AS, and Woods, CT. Physical, anthropometric, and athletic movement qualities discriminate development level in a rugby league talent pathway. J Strength Cond Res 32(11): 3169-3176, 2018-This study compared the physical, anthropometric, and athletic movement qualities of talent-identified rugby league (RL) players within a development pathway. From a total of 174 players, 3 developmental levels were defined: under 18 (U18; n = 52), under 20 (U20; n = 53), and state league (SL; n = 69). All players performed a test battery that consisted of 5 physical assessments, 2 anthropometric measurements, and an athletic movement assessment. A multivariate analysis of variance modeled the main effect of developmental level (3 levels: U18, U20, and SL) on test criterion variables. Receiver-operating characteristic (ROC) curves were then built for the criterion variables that showed a significant developmental level effect. A significant effect was noted (V = 0.775, F = 5.43, p ≤ 0.05), with the SL players outperforming their U18 and U20 counterparts for measures of body mass, peak and average lower limb power, double lunge (left side), single-leg Romanian deadlift (left and right sides), the push-up, and total athletic ability assessment score (p ≤ 0.05; d = 0.35-1.21). The ROC curves generated an area under the curve of greater than 65% for each test criterion, indicating greater than chance discrimination. These results highlight the physical, anthropometric, and athletic movement qualities discriminant of development level within a RL talent pathway. Practitioners are encouraged to consider the thresholds from the ROC curves as an objective guide to assist with the development of physical performance qualities that may augment player progression in Australian RL.

CD52, a glycophosphatidylinositol (GPI)-anchored glycoprotein, is released in a soluble form following T cell activation and binds to the Siglec (sialic acid-binding Ig-like lectin)-10 receptor on T cells to suppress their function. We show that binding of CD52-Fc to Siglec-10 and T cell suppression requires the damage-associated molecular pattern (DAMP) protein, high-mobility group box 1 (HMGB1). CD52-Fc bound specifically to the proinflammatory Box B domain of HMGB1, and this in turn promoted binding of the CD52 N-linked glycan, in α-2,3 sialic acid linkage with galactose, to Siglec-10. Suppression of T cell function was blocked by anti-HMGB1 antibody or the antiinflammatory Box A domain of HMGB1. CD52-Fc induced tyrosine phosphorylation of Siglec-10 and was recovered from T cells complexed with HMGB1 and Siglec-10 in association with SHP1 phosphatase and the T cell receptor (TCR). Thus, soluble CD52 exerts a concerted immunosuppressive effect by first sequestering HMGB1 to nullify its proinflammatory Box B, followed by binding to the inhibitory Siglec-10 receptor, triggering recruitment of SHP1 to the intracellular immunoreceptor tyrosine-based inhibitory motif of Siglec-10 and its interaction with the TCR. This mechanism may contribute to immune-inflammatory homeostasis in pathophysiologic states and underscores the potential of soluble CD52 as a therapeutic agent., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

The mortality rate of most patients with atrial fibrillation (AF) exceeds the stroke rate, but predictors of mortality have not been well defined. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE A) recruited patients with AF who were unsuitable to receive vitamin K-antagonists and were randomized to aspirin alone versus aspirin plus clopidogrel. We investigated independent predictors of all-cause mortality by multivariable Cox regression analysis and explored interactions with assigned antiplatelet therapy. Of the 7,554 patients enrolled with a mean age of 71 years, 1,687 (22%) patients died during the median follow-up of 3.7 years (annualized mortality rate 6.4%/year). Assignment to dual antiplatelet therapy had no effect on mortality (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.90 to 1.1) or on vascular and nonvascular death. Independent predictors of all-cause mortality were advancing age, lower body mass index (HR 1.4 < 25 kg/m 2 , 95% CI 1.3 to 1.6), diabetes mellitus, Latin American ethnicity (HR 1.4, 95% CI 1.1 to 1.6), previous stroke or transient ischemic attack, peripheral artery disease, increased resting heart rate (HR 1.3, 95% CI 1.1 to 1.4 per 30 bpm), lower diastolic blood pressure, coronary artery disease, heart failure, left ventricular systolic dysfunction, hemoglobin level of <13 mg/dl, and reduced estimated glomerular filtration rate. In conclusion, in this large clinical trial cohort of patients with AF, treatment with clopidogrel plus aspirin versus aspirin monotherapy did not affect all-cause mortality, vascular death, or nonvascular death. Novel independent predictors of increased mortality included lower diastolic blood pressure and Latin American ethnicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment., Methods: SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent magnetic resonance imaging (MRI)-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (130-149mmHg vs <130mmHg; open label) and to antiplatelet treatment (aspirin/clopidogrel vs aspirin/placebo; double-blinded). The current analysis involves 1,278 trial participants who had a baseline axial T2*-weighted gradient echo MRI sequence allowing for CMB detection., Results: CMBs were present in 30% of 1,278 patients (mean age = 63 years). Male gender (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.3-2.3), history of hypertension (OR = 1.6, 95% CI = 1.2-2.3), increased systolic blood pressure (1.2 per 20mmHg, 95% CI = 1.1-1.4), nondiabetic status (OR = 1.4, 95% CI = 1.1-1.9), multiple old lacunar infarcts (OR = 1.9, 95% CI = 1.5-2.5), and moderate (OR = 1.7, 95% CI = 1.2-2.3) or severe (OR = 4.2, 95% CI = 3.0-5.9) white matter hyperintensities on MRI were independently associated with CMBs. During a mean follow-up of 3.3 years, overall stroke recurrence was 2.5% per patient-year. Patients with CMBs had an adjusted 2-fold increased risk of recurrent stroke (hazard ratio = 2.1, 95% CI = 1.4-3.1). CMBs were not a risk factor for death. There were no statistically significant interactions between CMBs and treatment assignments., Interpretation: Patients with lacunar stroke and CMBs likely harbor a more advanced form of cerebral small vessel disease in need of efficacious therapeutic strategies. Ann Neurol 2017;82:196-207., (© 2017 American Neurological Association.)