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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has shown wastewater (WW) surveillance to be an effective means of tracking the emergence of viral lineages which arrive by many routes of transmission including via transportation hubs. In the Canadian province of Ontario, numerous municipal wastewater treatment plants (WWTPs) participate in WW surveillance of infectious disease targets such as SARS-CoV-2 by qPCR and whole genome sequencing (WGS). The Greater Toronto Airports Authority (GTAA), operator of Toronto Pearson International Airport (Toronto Pearson), has been participating in WW surveillance since January 2022. As a major international airport in Canada and the largest national hub, this airport is an ideal location for tracking globally emerging SARS-CoV-2 variants of concern (VOCs). In this study, WW collected from Toronto Pearson's two terminals and pooled aircraft sewage was processed for WGS using a tiled-amplicon approach targeting the SARS-CoV-2 virus genome. Data generated was analyzed to monitor trends of SARS-CoV-2 lineage frequencies. Initial detections of emerging lineages were compared between Toronto Pearson WW samples, municipal WW samples collected from the surrounding regions, and Ontario clinical data as published by Public Health Ontario. Results enabled the early detection of VOCs and individual mutations emerging in Ontario. On average, the emergence of novel lineages at the airport preceded clinical detections by 1-4 weeks, and up to 16 weeks in one case. This project illustrates the efficacy of WW surveillance at transitory transportation hubs and sets an example that could be applied to other viruses as part of a pandemic preparedness strategy and to provide monitoring on a mass scale., (© 2024. The Author(s).)

Objectives: There are limited data available demonstrating the safety and efficacy of intravenous tenecteplase versus alteplase in patients with acute ischemic stroke in the posterior circulation., Materials and Methods: This is a post-hoc analysis of the Alteplase compared to Tenecteplase (AcT) pragmatic, phase 3, registry-linked randomized controlled trial. Patients with any posterior circulation vessel occlusion on baseline imaging were included. Study outcomes included 90-day modified Rankin Scale (mRS) 0-1, mRS 0-2, ordinal mRS, death within 90 days, 24 h symptomatic intracerebral haemorrhage (sICH) and successful reperfusion/recanalization. Mixed effects regression adjusting for age, sex and stroke severity was used to analyze differences in outcomes between patients administered tenecteplase vs. alteplase. Further, sensitivity analysis was conducted for basilar artery occlusion (BAO) alone., Results: Of 1577 patients, 136 (8.6 %, 77:alteplase, 59:tenecteplase) had posterior circulation stroke. Baseline characteristics were similar[median age 71 (IQR 60-81) vs. 72 (IQR 65-82) years, 57.1 % vs. 67.8 % males, median baseline NIHSS 7 (IQR 4-12) vs. 7 (IQR 4-16) in alteplase vs. tenecteplase arms, respectively]. 28 patients (20.6 %, 16:alteplase, 12:tenecteplase arm) underwent EVT. The median 90-120 days mRS was 2 (IQR 1-4). There were no differences between alteplase and tenecteplase for 90-d mRS 0-1 (adjRR 0.93;95 %CI 0.63-1.36), 90-day mRS 0-2 (adjRR 0.95; 95 %CI 0.72-1.26), sICH (RR 0.65; 95 %CI 0.06-7.02) and mortality (RR 1.21; 95 %CI 0.61-2.38). Successful reperfusion eTICI 2b-3 and successful recanalization rAOL 2b-3 was achieved in 23/28 (82 %, 12:alteplase, 11:tenecteplase) and in 16/28 (57 %, 14:alteplase, 12:tenecteplase), respectively. Similar results were seen in 31 patients (22.8 %) with BAO., Conclusion: Intravenous tenecteplase has a similar effect on outcome as alteplase, without increased safety concerns in patients with acute posterior circulation strokes., Competing Interests: Declaration of competing interest PC has received honoraria from ESMINT. LC has received payments by Servier and consulting fees from Ischaemavie RAPID, Circle NV, and Canadian Medical Protective Association. SBC is principal investigator of the TEMPO-2 trial, for which Boehringer Ingelheim provides the study drug (tenecteplase). MDH has received consulting fees from Sun Pharma and Brainsgate and has stock options in Circle NVI. AYP has received a project research grant from Stryker and honoraria from BMS-Pfizer. RHS has stock options in FollowMD and receives salary support for research from the Heart & Stroke Foundation of Canada, Sandra Black Centre for Brain Resilience & Recovery, and Ontario Brain Institute. BKM has stock options in Circle NVI and has consulted for Biogen and Boehringer Ingelheim. All other authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Functional somatic disorder (FSD) is a prevalent disorder that can be severely disabling for the patient and is associated with major health costs. There are few formalized care programs for these disorders in the country, and their management encounters various difficulties, both in the diagnosis and its announcement and the treatment. Cognitive-behavioural and emotional therapy (CBT) is the standard on psychiatry care, and its efficacy has been demonstrated through several randomised controlled studies on the intensity of physical and psychological symptoms., Intervention: At Lille's University Hospital Center, we have established the "ACSEPT" care pathway for TSF management which consists of a psychiatric consultation followed by an individual referral, including a treatment using repeated transcranial magnetic stimulation (rTMS) or the integration of a CBT-based psychoeducation group. This group had the particularity of caring for all patients presenting FSD regardless of the associated physical symptoms. Educating medical professionals and conducting FSD research were other goals of ACSEPT., Discussion/conclusion: ACSEPT allows an improvement in the care offered to these patients with a defined orientation and interdisciplinary, early, organized cares that are repeatable. Our goal is to study the effectiveness of these different interventions in subsequent studies, to continue the development of ACSEPT and to be able to distribute this intervention at the regional level to establish a clear care program allowing early management of these patients., (Copyright © 2024 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Background: Acetabular and femoral offset play an important role in total hip arthroplasty (THA) for postoperative stability and biomechanical function. However, it is unknown whether offset impacts patient-reported outcomes (PROs). This study evaluated patients undergoing direct anterior (DA) THA with the hypothesis that patients who have a decrease in hip offset postoperatively would have lower physical function scores and higher pain interference., Methods: There were 499 patients who underwent DA THA at a single tertiary academic institution who were retrospectively evaluated. Preoperative and postoperative hip offset was measured by 2 reviewers using the Sundsvall method on standing anteroposterior pelvis radiographs. Postoperative changes in hip offset were categorized as increased (> 5 mm), matched (within 5 mm of the preoperative offset measurement), or decreased ( >5 mm). Postoperative PROs with a minimum 1-year follow-up were recorded. A one-way analysis of variance was utilized to compare postoperative pain and PROs between groups., Results: Patients who had decreased offset had the lowest mean postoperative physical function scores at 39.4 (8.0), followed by the increased offset group at 42.2 (10.4) and the matched offset group at 42.8 (9.8) (P < .01). There were significant differences in postoperative physical function scores between matched offset (42.8) and decreased offset (39.4) groups (P < .01), as well as between increased offset (42.2) and decreased offset (39.4) groups (P = .04). There was no difference between matched and increased offset cohorts., Conclusions: Our data suggests that reducing hip offset may result in worse physical function scores compared to those who have matched or increased hip offset. This should be considered intraoperatively, and efforts should be made to avoid reduced offset even in the presence of hip stability., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Robot-assisted systems offer an opportunity to support the diagnostic and therapeutic treatment of vascular diseases to reduce radiation exposure and support the limited medical staff in vascular medicine. In the diagnosis and follow-up care of vascular pathologies, Doppler ultrasound has become the preferred diagnostic tool. The study presents a robotic system for automatic Doppler ultrasound examinations of patients' leg vessels., Methods: The robotic system consists of a redundant 7 DoF serial manipulator, to which a 3D ultrasound probe is attached. A compliant control was employed, whereby the transducer was guided along the vessel with a defined contact force. Visual servoing was used to correct the position of the probe during the scan so that the vessel can always be properly visualized. To track the vessel's position, methods based on template matching and Doppler sonography were used., Results: Our system was able to successfully scan the femoral artery of seven volunteers automatically for a distance of 20 cm. In particular, our approach using Doppler ultrasound data showed high robustness and an accuracy of 10.7 (±3.1) px in determining the vessel's position and thus outperformed our template matching approach, whereby an accuracy of 13.9 (±6.4) px was achieved., Conclusions: The developed system enables automated robotic ultrasound examinations of vessels and thus represents an opportunity to reduce radiation exposure and staff workload. The integration of Doppler ultrasound improves the accuracy and robustness of vessel tracking, and could thus contribute to the realization of routine robotic vascular examinations and potential endovascular interventions., (© 2024. The Author(s).)

Background: The Association of American Medical Colleges suggests an Experiences-Attributes-Metrics framework for holistic review, but there is minimal research on demographic and personal characteristic attributes and the interplay between these Attributes subcategories. Understanding how personal attributes may vary among students considered represented and those considered underrepresented in one or more categories is critical to avoid unintentionally perpetuating practices that favor represented groups. This study explored differences in six personal characteristics either consistently related to academic performance or deemed positive professional traits based on diversity characteristics (categories of underrepresentation), age, and sex., Methods: Three cohorts of first-year Doctor of Physical Therapy students at a single institution were invited to participate in this prospective, observational study. Participants completed six surveys: PROMIS® General Self-efficacy, PROMIS® Anxiety, 12-item Grit Scale, Perceived Stress Scale-10 (PSS-10), Brief Resilience Scale (BRS), and PROMIS® Positive Affect. T-tests and ANOVAs (or nonparametric equivalents) were used to examine differences in these measures by number of diversity characteristics, age, and sex. Multivariate linear regression was used to determine if diversity characteristics explained additional variance in each of the personal attribute scores after controlling for age and sex., Results: One Hundred and Forty Five students participated (80.7% female, 77.9% < 25 years old, 51% 0 diversity characteristics). Students with more diversity characteristics and males reported higher self-efficacy and resilience (p's < 0.05). Females reported higher anxiety (p's < 0.01). Diversity characteristics explained additional variance in self-efficacy (3.3%, p = 0.02) and resilience (2.5%, p = 0.05) after controlling for age and sex. Grit, perceived stress, and positive affect did not show any group differences., Conclusions: Underrepresented students demonstrated higher self-efficacy and resilience than their represented peers, qualities that may be important to overcome challenges prior to and during graduate school. Males exhibited higher self-efficacy and resilience, but lower anxiety than females which is generally consistent across higher education. Grit, perceived stress, and positive affect were similar across all students and may be less useful to create a diverse learning environment. Further studies should investigate differences in attributes among admitted and unadmitted students and the relationship to future performance for admitted students., (© 2024. The Author(s).)

CRISPR-based genome engineering holds enormous promise for basic science and therapeutic applications. Integrating and editing DNA sequences is still challenging in many cellular contexts, largely due to insufficient control of the repair process. We find that repair at the genome-cargo interface is predictable by deep-learning models and adheres to sequence context specific rules. Based on in silico predictions, we devised a strategy of triplet base-pair repeat repair arms that correspond to microhomologies at double-strand breaks (trimologies), which facilitated integration of large cargo (>2 kb) and protected the targeted locus and transgene from excessive damage. Successful integrations occurred in >30 loci in human cells and in in vivo models. Germline transmissible transgene integration in Xenopus , and endogenous tagging of tubulin in adult mice brains demonstrated integration during early embryonic cleavage and in non-dividing differentiated cells. Further, optimal repair arms for single- or double nucleotide edits were predictable, and facilitated small edits in vitro and in vivo using oligonucleotide templates. We provide a design-tool (Pythia, pythia-editing.org) to optimize custom integration, tagging or editing strategies. Pythia will facilitate genomic integration and editing for experimental and therapeutic purposes for a wider range of target cell types and applications., Competing Interests: Competing Interest Statement T.N. and S.S.L. have filed a patent application (EP23192134.7) in relationship to this work.

Background: Early ischemic changes on baseline imaging are commonly evaluated for acute stroke decision-making and prognostication., Aims: We assess the association of early ischemic changes on clinical outcomes and whether it differs between intravenous tenecteplase and Alteplase., Methods: Data are from the phase 3, Alteplase compared to Tenecteplase (AcT) trial. Subjects with anterior circulation stroke were included. Early ischemic changes were assessed using the Alberta Stroke Program Early CT score (ASPECTS). Efficacy outcomes included modified Rankin scale (mRS) 0-1, mRS 0-2, and ordinal mRS at 90 days. Safety outcomes included 24-h symptomatic intracerebral hemorrhage (sICH), any hemorrhage on follow-up scan, and 90-day mortality rate. Mixed-effects logistic regression was used to assess the association of ASPECTS (continuous and categorical (0-4 vs 5-7 vs 8-10)) with outcomes and if these associations were modified by thrombolytic type after adjusting for age, sex, and baseline stroke severity., Results: Of the 1577 patients in the trial, 901 patients (56.3%; median age 75 years (IQR 65-84), 50.8% females, median National Institute of Health Stroke Scale (NIHSS) 14 (IQR 17-19)) with anterior circulation stroke were included. mRS 0-1 at 90 days was achieved in 1/14 (0.3%), 43/160 (14.7%), and 252/726 (85.1%) in the ASPECTS 0-4, 5-7, and 8-10 groups respectively. Every one-point decrease in ASPECTS was associated with 2.7% and 1.9% decrease in chances of mRS 0-1 and mRS 0-2 at 90 days, respectively, and 1.9% chances of increase in mortality at 90 days. Subgroup analysis in endovascular thrombectomy (EVT)-treated population showed similar results. Thrombolytic type did not modify this association between ASPECTS and 90-day mRS 0-1 (P-interaction 0.75). There was no significant interaction by thrombolytic type with any other outcomes., Conclusion: Similar to prior studies, we found that every one-point decrease in ASPECTS was associated with poorer clinical and safety outcomes. This effect did not differ between alteplase and tenecteplase., Data Access Statement: Data shall made available on reasonable request from the PI (BMM)., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.C. received payments from Servier, consulting fees from iSchemaView RAPID, Circle Neurovascular Imaging (NVI), and Canadian Medical Protective Association. T.T.S. has received consulting fees from Circle NVI. R.H.S. has stock options in FollowMD and gets salary support for research from the Heart and Stroke Foundation of Canada, the Sandra Black Center for Brain Resilience & Recovery, and Ontario Brain Institute. B.M. has stock options in Circle NVI and has consulted for Biogen and Boehringer Ingelheim. M.A. reports grants from Canadian Institute of Health Research during the conduct of the study. No other disclosures are reported. N.S. gets salary support for research from the Heart and Stroke Foundation of Canada, Research Manitoba and University of Manitoba.

The consensus-based guideline "hand antisepsis and hand hygiene" for Germany has the following sections: Prevention of nosocomial infections by hygienic hand antisepsis, prevention of surgical site infections by surgical hand antisepsis, infection prevention in the community by hand antisepsis in epidemic or pandemic situations, hand washing, selection of alcohol-based hand rubs and wash lotions, medical gloves and protective gloves, preconditions for hand hygiene, skin protection and skin care, quality assurance of the implementation of hand hygiene measures and legal aspects. The guideline was developed by the German Society for Hospital Hygiene in cooperation with 22 professional societies, 2 professional organizations, the German Care Council, the Federal Working Group for Self-Help of People with Disabilities and Chronic Illness and their Family Members, the General Accident Insurance Institution Austria and the German-speaking Interest Group of Infection Prevention Experts and Hospital Hygiene Consultants., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024 Kramer et al.)

Objectives : CT-derived fractional flow reserve (CT-FFR) can improve the specificity of coronary CT-angiography (cCTA) for ruling out relevant coronary artery disease (CAD) prior to transcatheter aortic valve replacement (TAVR). However, little is known about the reproducibility of CT-FFR and the influence of diffuse coronary artery calcifications or segment location. The objective was to assess the reliability of machine-learning (ML)-based CT-FFR prior to TAVR in patients without obstructive CAD and to assess the influence of image quality, coronary artery calcium score (CAC), and the location of measurement within the coronary tree. Methods : Patients assessed for TAVR, without obstructive CAD on cCTA were evaluated with ML-based CT-FFR by two observers with differing experience. Differences in absolute values and categorization into hemodynamically relevant CAD (CT-FFR ≤ 0.80) were compared. Results in regard to CAD were also compared against invasive coronary angiography. The influence of segment location, image quality, and CAC was evaluated. Results : Of the screened patients, 109/388 patients did not have obstructive CAD on cCTA and were included. The median (interquartile range) difference of CT-FFR values was -0.005 (-0.09 to 0.04) ( p = 0.47). Differences were smaller with high values. Recategorizations were more frequent in distal segments. Diagnostic accuracy of CT-FFR between both observers was comparable (proximal: Δ0.2%; distal: Δ0.5%) but was lower in distal segments (proximal: 98.9%/99.1%; distal: 81.1%/81.6%). Image quality and CAC had no clinically relevant influence on CT-FFR. Conclusions : ML-based CT-FFR evaluation of proximal segments was more reliable. Distal segments with CT-FFR values close to the given threshold were prone to recategorization, even if absolute differences between observers were minimal and independent of image quality or CAC.

Natural compounds constitute a major resource for the development of medicines for multiple diseases. While many natural compounds show strong biological activity, the mechanisms that confer clinical benefits are often elusive and have been attributed to multiple pathways. Periplogenin (PPG), a natural compound isolated from Cortex periplocae, exhibits strong anti-tumor activities in several human cancer cell lines. However, its molecular mode of action remained unclear. In this study, we leveraged a forward genetic screening approach in DU145 prostate cancer cells to uncover the molecular target of PPG using chemical mutagenesis. Next generation sequencing revealed that a single amino acid substitution at amino acid 804 in ATP1A1 (ATPase Na + /K + Transporting Subunit Alpha 1) confers resistance to the cytotoxic activity of PPG. Mechanistically, ATP1A1 T804 forms a hydrogen bond with PPG which is abolished by the T804A substitution in ATP1A1, resulting in resistance to PPG treatment in vitro. Importantly, in vivo, PPG strongly suppressed tumor development in a DU145 xenograft model whereas DU145 xenograft tumors carrying a ATP1A1-T804A mutation were largely unaffected by the treatment. These findings demonstrate that PPG suppresses the growth of DU145 prostate cancer cells in vitro and in vivo by directly binding to ATP1A1 and highlight the power of our unbiased forward genetic screening approach to uncover direct drug target structures at single amino acid resolution., (© 2024. The Author(s).)

A Europe-wide outbreak of invasive pediatric group A streptococcal infections (iGAS) began in fall 2022. Here, we report the evolution of GAS hospitalizations in children and adolescents during the second outbreak year in 2023-2024 at a tertiary center in Switzerland. Using prospective monitoring of all in-patient GAS cases below 16 years of age, including those with iGAS, we compared case frequencies and clinical characteristics in three time periods (2013-2020; 2022-2023; 2023-2024). Annual GAS hospitalizations increased from a median of 25 cases (range 11-28) in 2013-2020 to 89 and 63 cases, respectively, in 2022-2023 and 2023-2024. iGAS cases evolved similarly (2013-2020, 4 cases (3-8); 2022-2023, 32 cases; 2023-2024, 21 cases). The decline in cases from 2022-2023 to 2023-2024 included all types of GAS organ involvement, except suppurative infections in the head area, which remained largely unchanged (48 vs. 45 cases). Pleural empyema declined from 13 to 7 cases, possibly explained by a poor overlap of the GAS and influenza curves, respectively, in 2023-2024 compared to 2022-2023. These data document the prolongation of the GAS outbreak into its second winter season in 2023-2024.

Despite frequent reports of mental health needs among older women with cancer, depressive symptoms often go unrecognized and untreated, particularly in socially vulnerable survivors. Here, we examined associations of sociodemographic factors and social limitations with depressive symptoms from pre-diagnosis to post-diagnosis in older women diagnosed with breast or gynecological cancer. Using the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey (SEER-MHOS) linked dataset, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between sociodemographic factors (race, ethnicity, marital status, rurality) and social limitations (i.e., health interfering with social activities) on depressive symptoms in women aged ≥65 years with breast or gynecologic cancer ( n  = 1,353). Most participants had breast cancer (82.0%), stage I-II cancer (85.8%), received surgery for their cancer (94.8%), and radiation treatment (50.6%). Prior to diagnosis, 11.8% reported depressive symptoms, which nearly doubled to 22.4% at follow-up. Participants were 2.7 times more likely of reporting depressive symptoms after cancer diagnosis compared with pre-cancer diagnosis (95%CI: 2.10-3.48). Race, ethnicity, rurality, marital status, and social interference were significantly associated with an increased risk of depressive symptoms after cancer diagnosis than before their cancer diagnosis ( p  < 0.05). In summary, depressive symptoms increased following a cancer diagnosis. Our results suggest potential avenues for intervention that could lead to reduced depressive symptoms among older female cancer survivors.

Since the introduction of Haemophilus Influenzae type b (Hib) conjugate vaccines, invasive Hib disease has strongly declined worldwide, yet continued control of Hib disease remains important. In Europe, currently three different hexavalent combination vaccines containing Hib conjugates are marketed. In this phase IV, single-blind, randomized, controlled, multi-country study (NCT04535037), we aimed to compare, in a 2 + 1 vaccination schedule, the immunogenicity and safety and show non-inferiority, as well as superiority, of DTPa-HBV-IPV/Hib (Ih group) versus DTaP5-HB-IPV-Hib (Va group) in terms of anti-polyribosylribitol phosphate (PRP) antibody geometric mean concentrations (GMCs) and proportion of participants reaching anti-PRP antibody concentrations greater than or equal to a threshold of 5 µg/mL. One month after the booster vaccination, the anti-PRP antibody GMC ratio (Ih group/Va group) was 0.917 (95% CI: 0.710-1.185), meeting the non-inferiority criteria. The difference in percentage of participants (Ih group - Va group) reaching GMCs ≥5 µg/mL was -6.3% (95% CI: -14.1% to 1.5%), not reaching the predefined non-inferiority threshold. Interestingly, a slightly higher post-booster antibody avidity was observed in the Ih group versus the Va group. Both vaccines were well tolerated, and no safety concerns were raised. This study illustrates the different kinetics of the anti-PRP antibody response post-primary and post-booster using the two vaccines containing different Hib conjugates and indicates a potential differential impact of concomitant vaccinations on the anti-PRP responses. The clinical implications of these differences should be further studied.

Background: Endovascular procedures are the preferred method for treating peripheral arterial disease. However, limited imaging options during these procedures, such as X-rays and contrast media, expose patients and healthcare professionals to potentially harmful radiation. This study introduces a robotic ultrasound system (RUSS) for navigating endovascular procedures in order to reduce radiation and provide additional information., Methods: The RUSS comprises a seven-degree-of-freedom robotic arm that navigates an ultrasound transducer across a specific region of interest. The system is controlled by a self-programed software designed to navigate the robotic arm in a methodical and reproducible manner using a foot switch., Results: An endovascular surgeon investigated the guidance and visibility of various guidewires and successfully implanted three stents in a vascular leg phantom using the RUSS without further radiation exposure., Conclusions: The innovative set-up has several potential applications, including radiation-free endovascular procedures as well as health screening and diagnostic support in vascular medicine., (© 2024 The Author(s). The International Journal of Medical Robotics and Computer Assisted Surgery published by John Wiley & Sons Ltd.)

Introduction: Evidence-informed decision-making (EIDM) plays a vital role in public health practice. Canada has invested in support for evidence-informed approaches in public health. Despite growing expectations for EIDM, evidence integration has not been thoroughly evaluated., Objective: This study explores EIDM within Canadian public health organizations before the COVID-19 pandemic. A secondary objective is to explore how EIDM in public health was affected by the COVID-19 pandemic., Methods: Using a qualitative descriptive approach, data were collected and analyzed from interviews with public health professionals across Canada., Results: From interviews with 20 participants in four Canadian provinces and one territory, all participants noted that EIDM was valued, but there was considerable variation in implementation. Participants reported differences in consistency of evidence use, resources available at their public health organizations to support EIDM, and staff knowledge and skills in EIDM. Leadership emerged as a strong influencer of EIDM; however, leadership investment in EIDM varied. Changes in evidence use during the COVID-19 pandemic revealed an urgency for decision-making amidst an influx of evidence and reallocated staff roles., Conclusions: Despite gains in the recognized value of EIDM, gaps remain in the integration of evidence into decision-making and adequate resource investment to support EIDM. Time, resources, and skills to adapt processes and implement EIDM are needed for public health organizations in Canada to fully integrate EIDM into all aspects of public health decision-making., Spanish Abstract: http://links.lww.com/IJEBH/A249., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the University of Adelaide, JBI.)

Background: Existing radiological markers of hematoma expansion (HE) show modest predictive accuracy. We aim to investigate a novel radiological marker that co-localizes findings from non-contrast CT (NCCT) and CT angiography (CTA) to predict HE., Methods: Consecutive acute intracerebral hemorrhage patients admitted at Foothills Medical Centre in Calgary, Canada, were included. The Black-&-White sign was defined as any visually identified spot sign on CTA co-localized with a hypodensity sign on the corresponding NCCT. The primary outcome was hematoma expansion (⩾6 mL or ⩾33%). Secondary outcomes included absolute (<3, 3-6, 6-12, ⩾12 mL) and relative (0%, <25%, 25%-50%, 50%-75%, or >75%) hematoma growth scales., Results: Two-hundred patients were included, with 50 (25%) experiencing HE. Forty-four (22%) showed the spot sign, 69 (34.5%) the hypodensity sign, and 14 (7%) co-localized both as the Black-&-White sign. Those with the Black-&-White sign had higher proportions of HE (100% vs 19.4%, p  < 0.001), greater absolute hematoma growth (23.37 mL (IQR = 15.41-30.27) vs 0 mL (IQR = 0-2.39), p  < 0.001) and relative hematoma growth (120% (IQR = 49-192) vs 0% (0-15%), p  < 0.001). The Black-&-White sign had a specificity of 100% (95%CI = 97.6%-100%), a positive predictive value of 100% (95%CI = 76.8%-100%), and an overall accuracy of 82% (95%CI = 76%-87.1%). Among the 14 patients with the Black-&-White sign, 13 showed an absolute hematoma growth ⩾12 mL, and 10 experienced a HE exceeding 75% of the initial volume. The inter-rater agreement was excellent (kappa coefficient = 0.84)., Conclusion: The Black-&-White sign is a robust predictor of hematoma expansion occurrence and severity, yet further validation is needed to confirm these compelling findings., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Virus-induced accelerated aging has been proposed as a potential mechanism underlying the persistence of HIV-associated neurocognitive disorders (HAND) despite advances in access and adherence to combination antiretroviral therapies (cART). While some studies have demonstrated evidence of accelerated aging in PLWH, studies examining acute infection, and cART intervention are limited, with most studies being in vitro or utilizing small animal models. Here, we utilized FFPE tissues from Simian immunodeficiency virus (SIV) infected rhesus macaques to assess the levels of two proteins commonly associated with aging - the cellular senescence marker p16 INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Our central hypothesis was that SIV infection induces accelerated aging phenotypes in the brain characterized by increased expression of p16 and altered expression of SIRT1 that correlate with increased neurodegeneration, and that cART inhibits this process. We found that SIV infection induced increased GFAP, p16, SIRT1, and neurodegeneration in multiple brain regions, and treatment with cART reduced GFAP expression in SIV-infected animals and thus likely decreases inflammation in the brain. Importantly, cART reversed SIV-induced accelerated aging (p16 and SIRT1) and neurodegeneration in the frontal lobe and hippocampus. Combined, these data suggest that cART is both safe and effective in reducing neuroinflammation and age-associated alterations in astrocytes that contribute to neurodegeneration, providing possible therapeutic targets in the treatment of HAND., Competing Interests: Additional Declarations: The authors have declared there is NO conflict of interest to disclose Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Purpose: The massive increase of infections with Group A Streptococcus (GAS) in 2022-2023 coincided in Switzerland with a change of the recommendations for the management of GAS pharyngitis. Therefore, the objective of the present study was to investigate whether the clinical manifestations and management before hospitalization for GAS infection differed in 2022-2023 compared with 2013-2022., Methods: Retrospective study of GAS infections requiring hospitalization in patients below 16 years. Preadmission illness (modified McIsaac score), oral antibiotic use, and outcome in 2022-2023 were compared with 2013-2022. Time series were compared with surveillance data for respiratory viruses., Results: In 2022-2023, the median modified McIsaac score was lower (2 [IQR 2-3] vs. 3 [IQR 2-4], p =  < 0.0001) and the duration of preadmission illness was longer (4 days [3-7] vs. 3 [2-6], p = 0.004) than in 2013-2022. In both periods, withholding of preadmission oral antibiotics despite a modified McIsaac score ≥ 3 (12% vs. 18%, n.s.) or ≥ 4 (2.4% vs. 10.0%, p = 0.027) was rare. Respiratory disease, skeletal/muscle infection, and invasive GAS disease were significantly more frequent in 2022-2023, but there were no differences in clinical outcome. The time course of GAS cases in 2022-2023 coincided with the activity of influenza A/B., Conclusion: We found no evidence supporting the hypothesis that the 2022-2023 GAS outbreak was associated with a change in preadmission management possibly induced by the new recommendation for GAS pharyngitis. However, clinical manifestations before admission and comparative examination of time-series strongly suggest that viral co-circulation played an important role in this outbreak., (© 2024. The Author(s).)

Personalized medicine promises the ability to improve patient outcomes by tailoring treatment recommendations to the likelihood that any given patient will respond well to a given treatment. It is important that predictions of treatment response be validated and replicated in independent data to support their use in clinical practice. In this paper, we propose and test an approach for validating predictions of individual treatment effects with continuous outcomes across samples that uses matching in a test (validation) sample to match individuals in the treatment and control arms based on their predicted treatment response and their predicted response under control. To examine the proposed validation approach, we conducted simulations where test data is generated from either an identical, similar, or unrelated process to the training data. We also examined the impact of nuisance variables. To demonstrate the use of this validation procedure in the context of predicting individual treatment effects in the treatment of alcohol use disorder, we apply our validation procedure using data from a clinical trial of combined behavioral and pharmacotherapy treatments. We find that the validation algorithm accurately confirms validation and lack of validation, and also provides insights into cases where test data were generated under similar, but not identical conditions. We also show that the presence of nuisance variables detrimentally impacts algorithm performance, which can be partially reduced though the use of variable selection methods. An advantage of the approach is that it can be widely applied to different predictive methods., (© 2024 John Wiley & Sons Ltd.)

Changes in the abundance of certain bacterial species within the colorectal microbiota correlate with colorectal cancer (CRC) development. While carcinogenic mechanisms of single pathogenic bacteria have been characterized in vitro , limited tools are available to investigate interactions between pathogenic bacteria and both commensal microbiota and colonocytes in a physiologically relevant tumor microenvironment. To address this, we developed a microfluidic device that can be used to co-culture colonocyte spheroids and colorectal microbiota. The device was used to explore the effect of Fusobacterium nucleatum , an opportunistic pathogen associated with colorectal cancer development in humans, on colonocyte gene expression and microbiota composition. F. nucleatum altered the transcription of genes involved in cytokine production, epithelial-to-mesenchymal transition, and proliferation in colonocytes in a contact-independent manner; however, most of these effects were significantly diminished by the presence of commensal microbiota. Interestingly, F. nucleatum significantly altered the abundance of multiple bacterial clades associated with mucosal immune responses and cancer development in the colon. Our results highlight the importance of evaluating the potential carcinogenic activity of pathogens in the context of a commensal microbiota, and the potential to discover novel inter-species microbial interactions in the CRC microenvironment.

Inhibitory phosphatases, such as the inositol-5-phosphatase SHIP1 could potentially contribute to B-cell acute lymphoblastic leukemia (B-ALL) by raising the threshold for activation of the autoimmunity checkpoint, allowing malignant cells with strong oncogenic B-cell receptor signaling to escape negative selection. Here, we show that SHIP1 is differentially expressed across B-ALL subtypes and that high versus low SHIP1 expression is associated with specific B-ALL subgroups. In particular, we found high SHIP1 expression in both, Philadelphia chromosome (Ph)-positive and ETV6-RUNX1-rearranged B-ALL cells. As demonstrated by targeted knockdown of SHIP1 by RNA interference, proliferation of B-ALL cells in vitro and their tumorigenic spread in vivo depended in part on SHIP1 expression. We investigated the regulation of SHIP1, as an important antagonist of the AKT signaling pathway, by the B-cell-specific transcription factor Ikaros. Targeted restoration of Ikaros and pharmacological inhibition of the antagonistic casein kinase 2, led to a strong reduction in SHIP1 expression and at the same time to a significant inhibition of AKT activation and cell growth. Importantly, the tumor suppressive function of Ikaros was enhanced by a SHIP1-dependent additive effect. Furthermore, our study shows that all three AKT isoforms contribute to the pro-mitogenic and anti-apoptotic signaling in B-ALL cells. Conversely, hyperactivation of a single AKT isoform is sufficient to induce negative selection by increased oxidative stress. In summary, our study demonstrates the regulatory function of Ikaros on SHIP1 expression in B-ALL and highlights the relevance of sustained SHIP1 expression to prevent cells with hyperactivated PI3K/AKT/mTOR signaling from undergoing negative selection., (© 2024. The Author(s).)

Measuring self-efficacy can be a valuable means for instructors to predict student performance. However, it is crucial to measure self-efficacy within specific contexts to effectively gauge students' perceptions of their capabilities. This study evaluated the factors comprising the Anatomical Self-Efficacy Instrument (ASEI) and determined whether these factors could predict performance in gross anatomy. Three cohorts of Doctor Physical Therapy (DPT) students completed the ASEI at the start of gross anatomy. An exploratory factor analysis (EFA) analyzed the ASEI's dimensionality, and Cronbach's alpha evaluated the internal consistency of the extracted factors. Linear regression was used to determine whether ASEI's total or subdomain scores predicted final anatomy course performance scores. In total, 142 of 287 (49.5%) DPT students completed the ASEI. EFA revealed three distinct factors, including "cognitive," "psychomotor," and "clinical anatomy self-efficacy", and explained 44.9%, 13.7%, and 5.2% of the total variance, respectively. Only cognitive self-efficacy predicted final gross anatomy course performance (β = 0.34; R 2  = 0.071; F(3,138) = 3.51; p < 0.05). Overall, the ASEI's 3-factor solution implies its multidimensionality, a finding that could inform the development of more comprehensive self-efficacy measures. Notably, "cognitive self-efficacy" was the only subdomain that predicted DPT student performance in anatomy, suggesting its potential as a tool for identifying students in need of additional learning support. The ASEI's practical usability should be further explored through additional psychometric testing., (© 2024 American Association for Anatomy.)

Brachyspira pilosicoli ( B. pilosicoli ) is a pathogen in pigs, poultry, and humans causing colitis, diarrhea, and poor growth rates. Its role as a canine pathogen is controversial, and the seroprevalence of specific IgG antibodies against B. pilosicoli in dogs is unknown. A further, not yet officially recognized Brachyspira species in dogs is " Brachyspira canis " (" B. canis "), which is proposed to be apathogenic. This study evaluates enzyme-linked immunosorbent assays (ELISAs) measuring serum IgG antibodies specific for B. pilosicoli or " B. canis " and investigates levels of specific IgG antibodies against B. pilosicoli and " B. canis " in a cohort of clinical patients presented at an animal referral clinic. These ELISAs use detergent-extracted antigens from B. pilosicoli and " B. canis ". To increase analytic specificity, we precipitated the antigens with trichloroacetic acid (TCA) to isolate and concentrate the respective protein fraction. Our results indicate that a large number of serum IgG antibodies bind to shared epitopes of detergent-extracted antigens of the two spirochaetes. Our data also suggest that dogs might not only carry B. pilosicoli but also have " B. canis "-specific serum IgG antibodies.

Background: The COVID-19 pandemic has had a significant impact on mental health, with evidence suggesting an enduring mental health crisis. Studies worldwide observed increased usage of antidepressants, anxiolytics, and hypnotics during the pandemic, notably among young people and women. However, few studies tracked consumption post-2021. Our study aimed to fill this gap by investigating whether the surge in the number psychotropic drug consumers in France persisted 2 years after the first lockdown, particularly focusing on age and gender differences., Methods: We conducted a national retrospective observational study based on the French national insurance database. We retrieved all prescriptions of anxiolytics, hypnotics, and antidepressants dispensed in pharmacies in France for the period 2015-2022. We performed interrupted time series analyses based on Poisson models for five age classes (12-18; 19-25; 26-50; 51-75; 76 and more) to assess the trend before lockdown, the gap induced and the change in trend after., Results: In the overall population, the number of consumers remained constant for antidepressants while it decreased for anxiolytics and hypnotics. Despite this global trend, a long-term increase was observed in the 12-18 and 19-25 groups for the three drug classes. Moreover, for these age classes, the increases were more pronounced for women than men, except for hypnotics where the trends were similar., Conclusions: The number of people using antidepressants continues to increase more than 2 years after the first lockdown, showing a prolonged effect on mental health. This effect is particularly striking among adolescents and young adults confirming the devastating long-term impact of the pandemic on their mental health., (© 2024. The Author(s).)

Background: Early ischemic change and collateral extent are colinear with ischemic core volume (ICV). We investigated the relationship between a combined score using the Alberta Stroke Program Early Computed Tomography Score and multiphase computed tomography angiography (mCTA) collateral extent, named mCTA-ACE score, on functional outcomes in endovascular therapy-treated patients., Methods: We performed a post hoc analysis of a subset of endovascular therapy-treated patients from the Alteplase Compared to Tenecteplase trial which was conducted between December 2019 and January 2022 at 22 centers across Canada. Ten-point mCTA collateral corresponding to M2 to M6 regions of the Alberta Stroke Program Early Computed Tomography Score grid was evaluated as 0 (poor), 1 (moderate), or 2 (normal) and additively combined with the 10-point Alberta Stroke Program Early Computed Tomography Score to produce a 20-point mCTA-ACE score. We investigated the association of mCTA-ACE score with modified Rankin Scale score ≤2 and return to prestroke level of function at 90 to 120 days using mixed-effects logistic regression. In the subset of patients who underwent baseline computed tomography perfusion imaging, we compared the mCTA-ACE score and ICV for outcome prediction., Results: Among 1577 intention-to-treat population in the trial, 368 (23%; 179 men; median age, 73 years) were included, with Alberta Stroke Program Early Computed Tomography Score, mCTA collateral, and combination of both (mCTA-ACE score: median [interquartile range], 8 [7-10], 9 [8-10], and 17 [16-19], respectively). The probability of modified Rankin Scale score ≤2 and return to prestroke level of function increased for each 1-point increase in mCTA-ACE score (odds ratio, 1.16 [95% CI, 1.06-1.28] and 1.22 [95% CI, 1.06-1.40], respectively). Among 173 patients in whom computed tomography perfusion data was assessable, the mCTA-ACE score was inversely correlated with ICV (ρ=-0.46; P <0.01). The mCTA-ACE score was comparable to ICV to predict a modified Rankin Scale score ≤2 and return to prestroke level of function (C statistics 0.71 versus 0.69 and 0.68 versus 0.64, respectively)., Conclusions: The mCTA-ACE score had a significant positive association with functional outcomes after endovascular therapy and had a similar predictive performance as ICV., Competing Interests: Disclosures Dr Catanese reports compensation from Roche. Dr Shankar reports a grant from Medtronic. Dr Poppe reports grants from the Heart and Stroke Foundation of Canada, the Fondation Brain Canada, and Stryker and compensation from Roche. Dr Swartz reports grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada; compensation from Roche and the Sunnybrook Research Institute; and stock holdings in FollowMD, Inc. Dr Hill reports grants from the Canadian Institutes of Health Research, Roche, Medtronic, MicroVention, Inc, Boehringer Ingelheim, and NoNO, Inc; compensation from Brainsgate and Merck; and a patent issued for Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients licensed to Circle Neurovascular Imaging. Dr Sajobi reports the role as a consultant to Circle Neurovascular Imaging. Dr Menon reports stock holdings in Circle Neurovascular Imaging and compensation from Roche and Boehringer Ingelheim. Dr Demchuk reports compensation from Roche, Lumosa, Boehringer Ingelheim, NovaSignal, Philips, and Medtronic; stock holdings in Circle Neurovascular Imaging; and a patent issued for Stroke imaging software licensed to Circle Neurovascular Imaging. Dr Ganesh reports grants from the Canadian Institutes of Health Research, the Alzheimer Society of Canada, the Heart and Stroke Foundation of Canada, the Fondation Brain Canada, the Sunnybrook Research Institute, the Canadian Cardiovascular Society, Alberta Innovates, Campus Alberta Neuroscience, the Government of Canada, Wellcome Trust, MicroVention, Inc, and Panmure House; compensation from the Canadian Association of Neuroscience Nurses, Biogen, and Atheneum for consultant services; MD Analytics, Creative Research Designs, CTC Communications, Corporation, Alexion Pharmaceuticals, Figure 1, Rhodes Scholarships, MyMedicalPanel, and DeepBench; and stock holdings in Collavidence, Inc, and SnapDx, Inc. Dr Ganesh is a Review Editor of Stroke for Frontiers in Neurology and an Editorial Board Member of Stroke of the American Heart Association and Neurology and Neurology: Clinical Practice of American Academy of Neurology and reports travel supports from the American Heart Association, the American Academy of Neurology, and the University of Calgary. The other authors report no conflicts.

Wnt signaling is a crucial developmental pathway involved in early development as well as stem-cell maintenance in adults and its misregulation leads to numerous diseases. Thus, understanding the regulation of this pathway becomes vitally important. Axin2 and Nkd1 are widely utilized negative feedback regulators in Wnt signaling where Axin2 functions to destabilize cytoplasmic β-catenin, and Nkd1 functions to inhibit the nuclear localization of β-catenin. Here, we set out to further understand how Axin2 and Nkd1 regulate Wnt signaling by creating axin2 gh1/gh1 , nkd1 gh2/gh2 single mutants and axin2 gh1/gh1 ;nkd1 gh2/gh2 double mutant zebrafish using sgRNA/Cas9. All three Wnt regulator mutants were viable and had impaired heart looping, neuromast migration defects, and behavior abnormalities in common, but there were no signs of synergy in the axin2 gh1/gh1 ;nkd1 gh2/gh2 double mutants. Further, Wnt target gene expression by qRT-PCR and RNA-seq, and protein expression by mass spectrometry demonstrated that the double axin2 gh1/gh1 ;nkd1 gh2/gh2 mutant resembled the nkd1 gh2/gh2 phenotype demonstrating that Nkd1 functions downstream of Axin2. In support of this, the data further demonstrates that Axin2 uniquely alters the properties of β-catenin-dependent transcription having novel readouts of Wnt activity compared with nkd1 gh2/gh2 or the axin2 gh1/gh1 ;nkd1 gh2/gh2 double mutant. We also investigated the sensitivity of the Wnt regulator mutants to exacerbated Wnt signaling, where the single mutants displayed characteristic heightened Wnt sensitivity, resulting in an eyeless phenotype. Surprisingly, this phenotype was rescued in the double mutant, where we speculate that cross-talk between Wnt/β-catenin and Wnt/Planar Cell Polarity pathways could lead to altered Wnt signaling in some scenarios. Collectively, the data emphasizes both the commonality and the complexity in the feedback regulation of Wnt signaling.

Background: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality., Methods: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual., Findings: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059)., Interpretation: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis., Funding: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation., Competing Interests: Declaration of interests SBC received grant funding from the Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada (HSFC), and the British Heart Foundation (BHF) to complete the TEMPO-2 study. Boehringer Ingelheim provided off-the-shelf study drug (tenecteplase) for the study. JFA has received public research grants from the Spanish Ministry of Science, the regional health department, the European Commission, and a private research grant from AstraZeneca. He has received consultant or speaker fees from Pfizer-BMS, Medtronic, and Amgen, and travel support from Daiichi-Sankyo. KSB reports speaker fees from Boehringer Ingelheim and AstraZeneca. LC has received consulting or speakers fees from Roche. JF reports speaker fees from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Pfizer, Sankyo, and Daiichi. AG reports a grant from Microvention; speaker fees from Alexion, Biogen, and Servier Canada; and stock options for SnapDx and Collavidence. DG reports honoraria from Boehringer Ingelheim, Ipsen, and Eisai. MG reports grant funding from Medtronic and Cerenovus and consulting fees from Mentice, CSL Behring, MicroVention, and Medtronic. TSF participated in an advisory board for Roche. FL reports speaker fees and travel support from Boehringer Ingelheim. BKM has been paid honoraria from Boehringer Ingelheim and Roche. MM has received honoraria from Boehringer Ingelheim for participation at an advisory board on the approval of tenecteplase for treatment of acute ischaemic stroke. SOM has received speaker fees from Boehringer, Medtronic, Penumbra, Bayer, Pfizer, Novartis, Novo Nordisk, Servier, and Daiichi Sankyo. KWM reports grant funding from the BHF, and the Stroke Association; consultancy fees from Boehringer Ingelheim, Biogen, IschaemaView; lecture fees from Boehringer Ingelheim, IschaemaView, and Brainomix; and non-financial support (drug supply for ATTEST-2 trial) from Boehringer Ingelheim. MWP is on Boehringer Ingelheim Advisory Board for Metalyse in stroke. AP received speaker fees from Boehringer Ingelheim and travel support from AstraZeneca for attending a meeting. OMP-N has received speaker fees from Boehringer Ingelheim and AstraZeneca. RS is part funded by the UCLH Biomedical Research Centre. DS reports an unrestricted educational grant from Boehringer Ingelheim. MIW reports sponsorship or financial assistance to support attendance at scientific meetings from Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo UK, and Bayer; honoraria for lectures given at education meetings from Boehringer Ingelheim, Bristol Myers Squibb, and AstraZeneca; and payment for participation in advisory panels from Boehringer Ingelheim and Daiichi Sankyo UK. DJW is the Co-principal Investigator for Health Research Board of Ireland, Award–Improving Pathways for Acute Stroke and Rehabilitation. AYXY reports salary support from the HSFC. MDH reports grant funding from CIHR, HSFC, Alberta Innovates, and study drug from Boehringer Ingelheim; grants from NoNo and Medtronic; consulting fees from Sun Pharma Brainsgate; and a DSMB member role on many stroke clinical trials., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Schistosomiasis, caused by a parasitic blood fluke of the genus Schistosoma, is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni. Against cultured S. mansoni schistosomula and adult worms, many of the gallinamides generated a range of deleterious phenotypic responses. Imaging with a fluorescent-activity-based probe derived from gallinamide A demonstrated that SmCB1 is the primary target for gallinamides in the parasite. Furthermore, we solved the high-resolution crystal structures of SmCB1 in complex with gallinamide A and its two analogs and describe the acrylamide covalent warhead and binding mode in the active site. Quantum chemical calculations evaluated the contribution of individual positions in the peptidomimetic scaffold to the inhibition of the target and demonstrated the importance of the P1' and P2 positions. Our study introduces gallinamides as a powerful chemotype that can be exploited for the development of novel antischistosomal chemotherapeutics.

Background and Purpose: The presence of spot sign is associated with a high risk of hematoma growth. Our aim was to investigate the timing of the appearance, volume, and leakage rate of the spot sign for predicting hematoma growth in acute intracerebral hemorrhage using multiphase CTA., Materials and Methods: In this single-center retrospective study, multiphase CTA in 3 phases was performed in acute intracerebral hemorrhage (defined as intraparenchymal ± intraventricular hemorrhages). Phases of the spot sign first appearance, spot sign volumes (microliter), and leakage rates among phases (microliter/second) were measured. Associations between baseline clinical and imaging variables including spot sign volume parameters (volume and leakage rate divided by median) and hematoma growth (>6 mL) were investigated using regression models. Receiver operating characteristic analysis was used as appropriate., Results: Two hundred seventeen patients (131 men; median age, 70 years) were included. The spot sign was detected in 21.7%, 30.0%, and 29.0% in the first, second, and third phases, respectively, with median volumes of 19.7, 31.4, and 34.8 μl in these phases. Hematoma growth was seen in 44 patients (20.3%). By means of modeling, the following variables, namely the spot sign appearing in the first phase, first phase spot sign volume, spot sign appearing in the second or third phase, and spot sign positive and negative leakage rates, were associated with hematoma growth. Among patients with a spot sign, the absolute leakage rate accounting for both positive and negative leakage rates was also associated with hematoma growth (per 1-μl/s increase; OR, 1.26; 95% CI, 1.04-1.52). Other hematoma growth predictors were stroke history, baseline NIHSS score, onset-to-imaging time, and baseline hematoma volume (all P values < .05)., Conclusions: The timing of the appearance of the spot sign, volume, and leakage rate were all associated with hematoma growth. Development of automated software to generate these spot sign volumetric parameters would be an important next step to maximize the potential of temporal intracerebral hemorrhage imaging such as multiphase CTA for identifying those most at risk of hematoma growth., (© 2024 by American Journal of Neuroradiology.)

Background: Catatonia is a highly prevalent syndrome in patients presenting with major neurocognitive disorders (dementia). In this study, we aim to provide a comprehensive description of the clinical and therapeutic aspects of catatonia in patients with dementia., Method: This descriptive study, conducted between September 2015 and June 2022, collected data from 25 patients diagnosed with dementia, out of 143 patients treated for catatonia in our specialized psychiatry department. We collected sociodemographic, clinical and treatment data for each patient., Results: Dementia patients constituted 17% of the catatonic cases. Predominantly female, the cohort had a mean age of 65. Diagnoses included Alzheimer's (4 patients, 17%) and Parkinson's (1 patient, 4%) diseases, Lewy body dementia (5 patients, 21%), vascular dementia (4 patients, 17%) and frontotemporal lobar degeneration (10 patients, 41%). The mean Bush-Francis Catatonia Rating Scale score upon admission was 20/69. Overall, complete remission of catatonia was achieved in 75% of patients (n=18), with only 13% (n=3) responding to lorazepam alone, while others required additional interventions such as electroconvulsive therapy (ECT) and/or amantadine. Vascular dementia was predominantly observed in cases resistant to treatment., Conclusion: The findings indicate a frequent co-occurrence of catatonia and dementia, highlighting treatability yet suggesting a potential for resistance to lorazepam, which varies by dementia diagnosis. Investigating the mechanisms underlying this resistance and the variability in treatment response is crucial for developing more precise therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors report no financial disclosures or conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: In patients with congenital diaphragmatic hernia (CDH) the exact functional outcome of the affected lung side is still unknown, mainly due to the lack of spatially resolved diagnostic tools. Functional matrix-pencil decomposition (MP-) lung MRI fills this gap as it measures side-specific ventilation and perfusion. We aimed to assess the overall and side-specific pulmonary long-term outcomes of patients with CDH using lung function tests and MP-MRI., Methods: Thirteen school-aged children with CDH (seven with small and six with large defect-sized CDH, defined as > 50% of the chest wall circumference being devoid of diaphragm tissue) and thirteen healthy matched controls underwent spirometry, multiple-breath washout, and MP-MRI. The main outcomes were forced expiratory volume in 1 second (FEV 1 ), lung clearance index (LCI 2.5 ), ventilation defect percentage (VDP), and perfusion defect percentage (QDP)., Results: Patients with a large CDH showed significantly reduced overall lung function compared to healthy controls (mean difference [95%-CI adjusted ]: FEV 1 (z-score) -4.26 [-5.61, -2.92], FVC (z-score) -3.97 [-5.68, -2.26], LCI 2.5 (TO) 1.12 [0.47, 1.76], VDP (%) 8.59 [3.58, 13.60], QDP (%) 17.22 [13.16, 21.27]) and to patients with a small CDH. Side-specific examination by MP-MRI revealed particularly reduced ipsilateral ventilation and perfusion in patients with a large CDH (mean difference to contralateral side [95%-CI adjusted ]: VDP (%) 14.80 [10.50, 19.00], QDP (%) 23.50 [1.75, 45.20])., Conclusions: Data indicate impaired overall lung function with particular limitation of the ipsilateral side in patients with a large CDH. MP-MRI is a promising tool to provide valuable side-specific functional information in the follow-up of patients with CDH., Clinical Relevance Statement: In patients with congenital diaphragmatic hernia, easily applicable MP-MRI allows specific examination of the lung side affected by the hernia and provides valuable information on ventilation and perfusion with implications for clinical practice, making it a promising tool for routine follow-up., Key Points: • Functional matrix pencil decomposition (MP) MRI data from a small sample indicate reduced ipsilateral pulmonary ventilation and perfusion in children with large congenital diaphragmatic hernia (CDH). • Easily applicable pencil decomposition MRI provides valuable side-specific diagnostic information on lung ventilation and perfusion. This is a clear advantage over conventional lung function tests, helping to comprehensively follow up patients with congenital diaphragmatic hernia and monitor therapy effects., (© 2023. The Author(s).)

Climate change and population densities accelerated transmission of highly pathogenic viruses to humans, including the Crimean-Congo haemorrhagic fever virus (CCHFV). Here we report that the Low Density Lipoprotein Receptor (LDLR) is a critical receptor for CCHFV cell entry, playing a vital role in CCHFV infection in cell culture and blood vessel organoids. The interaction between CCHFV and LDLR is highly specific, with other members of the LDLR protein family failing to bind to or neutralize the virus. Biosensor experiments demonstrate that LDLR specifically binds the surface glycoproteins of CCHFV. Importantly, mice lacking LDLR exhibit a delay in CCHFV-induced disease. Furthermore, we identified the presence of Apolipoprotein E (ApoE) on CCHFV particles. Our findings highlight the essential role of LDLR in CCHFV infection, irrespective of ApoE presence, when the virus is produced in tick cells. This discovery holds profound implications for the development of future therapies against CCHFV., (© 2024. The Author(s).)

Traditional operation modes, such as running the production processes at constant process settings or within a narrow design space, do not fully exploit the advantages of continuous pharmaceutical manufacturing. Integrating Quality by Control (QbC) algorithms as a standard component of production processes can mitigate the effect of diverse process disturbances and enhance process efficiency, particularly in terms of production costs and environmental footprint. This paper explores the potential of QbC algorithms for optimizing twin-screw wet granulation in the ConsiGma TM -25 manufacturing line, specifically addressing granule size. It represents the second part of a study (Celikovic et al. (2024)) focused on granule composition. The concepts proposed in this work rely on process analytical technology (PAT) equipment for real-time monitoring of the granulation CQAs and a dynamic process model linking the granulation process parameters and the monitored CQAs. The granule size model identified via the local-linear-model-tree (LoLiMoT) algorithm is used to develop both a model predictive controller (MPC) and a granule size soft sensor. The MPC employs this model as a core component for selecting optimal granulation parameters to ensure the production of granules with target size. A digital operator assistant is developed to address disturbances that cannot be mitigated via MPC but can be eliminated by the plant operators. This study systematically outlines a workflow, starting from conceptualization, moving through simulation development, and finally ending with real-world application on a production line. In this final step, all proposed concepts are transferred to the ConsiGma TM -25 manufacturing line, where their performance is validated through selected disturbance scenarios., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Continuous manufacturing of pharmaceuticals offers several benefits, such as increased production efficiency, enhanced product quality control, and lower environmental footprint. To fully exploit these benefits, standard operation mode (production processes with no or minimal disturbance mitigation measures) should be supported by adopting novel quality-by-control (QbC) methodologies. The paper at hand is the first part of a study focused on developing QbC algorithms for optimizing twin-screw wet granulation in the industrial manufacturing line ConsiGma TM -25, specifically addressing granule composition. This work relies on previously established process-analytical-technology (PAT) equipment for real-time monitoring of the granule composition, i.e., the active pharmaceutical ingredient (API) and liquid content in wet granules. The developed control platform integrates model-based process control algorithms that aim to keep the API- and liquid content at target values through real-time adjustments of the process parameters. Furthermore, the platform integrates a digital operator assistant, which aims to detect and classify granulation disturbances and provides messages and instructions for the plant operator. The present manuscript systematically outlines all design steps from the development phase in the simulation environment to the final real system application and validation. The control platform's performance is demonstrated through selected test scenarios on the ConsiGma TM -25 manufacturing line. The obtained results indicate improved disturbance robustness and an increase in intermediate/final product quality (compared to conventional operating modes): The process control algorithms successfully maintained the API- and liquid content at target values despite process disturbances. Furthermore, realistic disturbances (feeder, pump, and material) were accurately detected and classified by the digital assistant algorithm. The information was provided through a user interface, offering real-time support for plant personnel., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Purpose: The ANNEXA-4 trial measured hemostatic efficacy of andexanet alfa in patients with major bleeding taking factor Xa inhibitors. A proportion of this was traumatic and nontraumatic intracranial bleeding. Different measurements were applied in the trial including volumetrics to assess for intracranial bleeding depending on the compartment involved. We aimed to determine the most reliable way to measure intracranial hemorrhage (ICrH) volume by comparing individual brain compartment and total ICrH volume., Methods: Thirty patients were randomly selected from the ANNEXA-4 database to assess measurement of ICrH volume by compartment and in total. Total and compartmental hemorrhage volumes were measured by five readers using Quantomo software. Each reader measured baseline hemorrhage volumes twice separated by 1 week. Twenty-eight different ANNEXA-4 subjects were also randomly selected to assess intra-rater reliability of total ICrH volume measurement change at baseline and 12-h follow up, performed by three readers twice to assess hemostatic efficacy categories used in ANNEXA-4., Results: Compartmental minimal detectable change percentages (MDC%) ranged between 9.72 and 224.13, with the greatest measurement error occurring in patients with a subdural hemorrhage. Total ICrH volume measurements had the lowest MDC%, which ranged between 6.57 and 33.52 depending on the reader., Conclusion: Measurement of total ICrH volumes is more accurate than volume by compartment with less measurement error. Determination of hemostatic efficacy was consistent across readers, and within the same reader, as well as when compared to consensus read. Volumetric analysis of intracranial hemostatic efficacy is feasible and reliable when using total ICrH volumes., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background and Purpose: The safety and efficacy of tenecteplase in patients with ischemic stroke due to medium vessel occlusion (MeVO) are not well studied. We aimed to compare tenecteplase with alteplase in stroke due to MeVO., Methods: Patients with baseline M2-middle cerebral artery (MCA), M3/M4-MCA, P2/P3/P4-posterior cerebral artery (PCA), A2/A3/A4-anterior cerebral artery (ACA) occlusions from the Alteplase Compared to Tenecteplase (AcT) trial were included. Primary outcome was the proportion of 90-day modified Rankin Scale (mRS) 0-1. Secondary outcomes were 90-day mRS 0-2, ordinal mRS, mortality, quality of life measures (EuroQol 5-Dimension 5-Level, EuroQol visual analog scale), and symptomatic intracerebral hemorrhage (sICH). Initial and final successful reperfusion were reported in patients undergoing endovascular thrombectomy (EVT)., Results: Among 1,558 patients with available baseline computed tomography angiography; 455 (29.2%) had MeVO of which 27.5% (125/455) were proximal M2; 16.3% (74/455) were distal M2; 35.2% (160/455) were M3/M4; 7.5% (34/455) were A2/A3/A4; and 13.6% (62/455) were P2/P3/P4 occlusions. EVT was performed in 87/455 (19.1%) patients. mRS 0-1 at 90 days was achieved in 37.9% in the tenecteplase versus 34.7% in the alteplase group (adjusted risk ratio [aRR] 1.07; 95% confidence interval [CI] 0.91-1.25). Rates of 90-day mRS 0-2, sICH, and mortality were similar in both groups. No statistical difference was noted in initial successful reperfusion rates (13.0% vs. 7.5%) among the 87 patients who underwent endovascular thrombectomy. However, final successful reperfusion was higher in the tenecteplase group (71.7% vs. 60.0%, aRR 1.29, 95% CI 1.04-1.61)., Conclusion: Intravenous tenecteplase had comparable safety, functional outcomes and quality of life compared to intravenous alteplase among patients with MeVO. Among those treated with EVT, tenecteplase was associated with higher successful reperfusion rates than alteplase.

For dosimetry of radiopharmaceutical therapies, it is essential to determine the volume of relevant structures exposed to therapeutic radiation. For many radiopharmaceuticals, the kidneys represent an important organ-at-risk. To reduce the time required for kidney segmentation, which is often still performed manually, numerous approaches have been presented in recent years to apply deep learning-based methods for CT-based automated segmentation. While the automatic segmentation methods presented so far have been based solely on CT information, the aim of this work is to examine the added value of incorporating PSMA-PET data in the automatic kidney segmentation., Methods: A total of 108 PET/CT examinations (53 [ 68 Ga]Ga-PSMA-I&T and 55 [ 18 F]F-PSMA-1007 examinations) were grouped to create a reference data set of manual segmentations of the kidney. These segmentations were performed by a human examiner. For each subject, two segmentations were carried out: one CT-based (detailed) segmentation and one PET-based (coarser) segmentation. Five different u-net based approaches were applied to the data set to perform an automated segmentation of the kidney: CT images only, PET images only (coarse segmentation), a combination of CT and PET images, a combination of CT images and a PET-based coarse mask, and a CT image, which had been pre-segmented using a PET-based coarse mask. A quantitative assessment of these approaches was performed based on a test data set of 20 patients, including Dice score, volume deviation and average Hausdorff distance between automated and manual segmentations. Additionally, a visual evaluation of automated segmentations for 100 additional (i.e., exclusively automatically segmented) patients was performed by a nuclear physician., Results: Out of all approaches, the best results were achieved by using CT images which had been pre-segmented using a PET-based coarse mask as input. In addition, this method performed significantly better than the segmentation based solely on CT, which was supported by the visual examination of the additional segmentations. In 80% of the cases, the segmentations created by exploiting the PET-based pre-segmentation were preferred by the nuclear physician., Conclusion: This study shows that deep-learning based kidney segmentation can be significantly improved through the addition of a PET-based pre-segmentation. The presented method was shown to be especially beneficial for kidneys with cysts or kidneys that are closely adjacent to other organs such as the spleen, liver or pancreas. In the future, this could lead to a considerable reduction in the time required for dosimetry calculations as well as an improvement in the results., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael Lassmann has received institutional grants by IPSEN Pharma, Nordic Nanovector, and Novartis. No other potential conflicts of interest relevant to this article exist., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Giant viruses (Nucleocytoviricota) are significant lethality agents of various eukaryotic hosts. Although metagenomics indicates their ubiquitous distribution, available giant virus isolates are restricted to a very small number of protist and algal hosts. Here we report on the first viral isolate that replicates in the amoeboflagellate Naegleria. This genus comprises the notorious human pathogen Naegleria fowleri, the causative agent of the rare but fatal primary amoebic meningoencephalitis. We have elucidated the structure and infection cycle of this giant virus, Catovirus naegleriensis (a.k.a. Naegleriavirus, NiV), and show its unique adaptations to its Naegleria host using fluorescence in situ hybridization, electron microscopy, genomics, and proteomics. Naegleriavirus is only the fourth isolate of the highly diverse subfamily Klosneuvirinae, and like its relatives the NiV genome contains a large number of translation genes, but lacks transfer RNAs (tRNAs). NiV has acquired genes from its Naegleria host, which code for heat shock proteins and apoptosis inhibiting factors, presumably for host interactions. Notably, NiV infection was lethal to all Naegleria species tested, including the human pathogen N. fowleri. This study expands our experimental framework for investigating giant viruses and may help to better understand the basic biology of the human pathogen N. fowleri., (© 2024. The Author(s).)

The NIMH-funded Multilevel Community-Based Mental Health Intervention to Address Structural Inequities and Adverse Disparate Consequences of COVID-19 Pandemic on Latinx Immigrants and African Refugees study aims to advance the science of multilevel interventions to reduce the disparate, adverse mental health, behavioral, and socioeconomic consequences of the COVID-19 pandemic that are a result of complex interactions between underlying structural inequities and barriers to health care. The study tests three nested levels of intervention: 1) an efficacious 4-month advocacy and mutual learning model (Refugee and Immigrant Well-being Project, RIWP); 2) engagement with community-based organizations (CBOs); and 3) structural policy changes enacted in response to the pandemic. This community-based participatory research (CBPR) study builds on long-standing collaboration with five CBOs. By including 240 Latinx immigrants and 60 African refugees recruited from CBO partners who are randomly assigned to treatment-as-usual CBO involvement or the RIWP intervention and a comparison group comprised of a random sample of 300 Latinx immigrants, this mixed methods longitudinal waitlist control group design study with seven time points over 36 months tests the effectiveness of the RIWP intervention and engagement with CBOs to reduce psychological distress, daily stressors, and economic precarity and increase protective factors (social support, access to resources, English proficiency, cultural connectedness). The study also tests the ability of the RIWP intervention and engagement with CBOs to increase access to the direct benefits of structural interventions. This paper reports on the theoretical basis, design, qualitative and quantitative analysis plan, and power for the study., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Jessica R. Goodkind is an unpaid Board Member of United Voices for Newcomer Rights, a partner organization in the study., (Copyright: © 2024 Goodkind et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cnidarians, such as corals and sea anemones, associate with a wide range of bacteria that have essential functions, including nutrient cycling and the production of antimicrobial compounds. Within cnidarians, bacteria can colonize all microhabitats including the tissues. Among them are obligate intracellular bacteria of the phylum Chlamydiota (chlamydiae) whose impact on cnidarian hosts and holobionts, especially corals, remain unknown. Here, we conducted a meta-analysis of previously published 16S rRNA gene metabarcoding data from cnidarians (e.g. coral, jellyfish, and anemones), eight metagenome-assembled genomes (MAGs) of coral-associated chlamydiae, and one MAG of jellyfish-associated chlamydiae to decipher their diversity and functional potential. While the metabarcoding dataset showed an enormous diversity of cnidarian-associated chlamydiae, six out of nine MAGs were affiliated with the Simkaniaceae family. The other three MAGs were assigned to the Parasimkaniaceae, Rhabdochlamydiaceae, and Anoxychlamydiaceae, respectively. All MAGs lacked the genes necessary for an independent existence, lacking any nucleotide or vitamin and most amino acid biosynthesis pathways. Hallmark chlamydial genes, such as a type III secretion system, nucleotide transporters, and genes for host interaction, were encoded in all MAGs. Together these observations suggest an obligate intracellular lifestyle of coral-associated chlamydiae. No unique genes were found in coral-associated chlamydiae, suggesting a lack of host specificity. Additional studies are needed to understand how chlamydiae interact with their coral host, and other microbes in coral holobionts. This first study of the diversity and functional potential of coral-associated chlamydiae improves our understanding of both the coral microbiome and the chlamydial lifestyle and host range., Competing Interests: The authors declare they have no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Society for Microbial Ecology.)

Bioluminescence imaging (BLI) is a non-invasive state-of-the-art-method for longitudinal tracking of tumor cells in mice. The technique is commonly used to determine bone metastatic burden in vivo and also suitable ex vivo to detect even smallest bone micro-metastases in spontaneous metastasis xenograft models. However, it is unclear to which extent ex vivo BLI correlates with alternative methods for metastasis quantification. Here, we compared ex vivo BLI, human DNA-based Alu-qPCR, and histology for the quantification of bone vs. lung metastases, which are amongst the most common sites of metastasis in prostate cancer (PCa) patients and spontaneous PCa xenograft models. Data from 93 immunodeficient mice were considered, each of which were subcutaneously injected with luciferase/RGB-labeled human PCa PC-3 cells. The primary tumors were resected at ~ 0.75 cm³ and mice were sacrificed ~ 3 weeks after surgery and immediately examined by ex vivo BLI. Afterwards, the right lungs and hind limbs with the higher BLI signal (BLI Hi bone) were processed for histology, whereas the left lung lobes and hind limbs with the lower BLI signal (BLI Lo bone) were prepared for Alu-qPCR. Our data demonstrate remarkable differences in the correlation coefficients of the different methods for lung metastasis detection (r ~ 0.8) vs. bone metastasis detection (r ~ 0.4). However, the BLI values of the BLI Hi and BLI Lo bones correlated very strongly (r ~ 0.9), indicating that the method per se was reliable under identical limitations; the overall level of metastasis to contralateral bones was astonishingly similar. Instead, the level of lung metastasis only weakly to moderately correlated with the level of bone metastasis formation. Summarized, we observed a considerable discrepancy between ex vivo BLI and histology/Alu-qPCR in the quantification of bone metastases, which was not observed in the case of lung metastases. Future studies using ex vivo BLI for bone metastasis quantification should combine multiple methods to accurately determine metastatic load in bone samples., (© 2024. The Author(s).)

This clinical review examines the treatment of status epilepticus, a condition in which epileptic seizures are prolonged and pose a significant risk of brain damage and death. International guidelines recommend the use of benzodiazepines as first-line treatment, and these should be administered promptly and in appropriate doses. Second-line treatment involves the use of high-dose anti-seizure medications to stop and prevent seizures. If seizure activity persists, general anaesthesia should be administered as soon as possible. All neurological hospital departments should have established and rehearsed protocols for treating status epilepticus.

Background: Carotid tandem lesions ((TL) ⩾70% stenosis or occlusion) account for 15-20% of acute stroke with large vessel occlusion., Aims: We investigated the safety and efficacy of intravenous tenecteplase (0.25 mg/kg) versus intravenous alteplase (0.9 mg/kg) in patients with carotid TL., Methods: This is a substudy of the alteplase compared with the tenecteplase trial. Patients with ⩾70% stenosis of the extracranial internal carotid artery (ICA) and concomitant occlusion of the intracranial ICA, M1 or M2 segments of the middle cerebral artery on baseline computed tomography angiography (CTA) were included. Primary outcome was 90-day-modified Rankin Scale (mRS) 0-1. Secondary outcomes were mRS 0-2, mortality, and symptomatic ICH (sICH). Angiographic outcomes were successful recanalization (revised Arterial Occlusive Lesion (rAOL) 2b-3) on first and successful reperfusion (eTICI 2b-3) on final angiographic acquisitions. Multivariable mixed-effects logistic regression was performed., Results: Among 1577 alteplase versus tenecteplase randomized controlled trial (AcT) patients, 128 (18.8%) had carotid TL. Of these, 93 (72.7%) underwent intravenous thrombolysis plus endovascular thrombectomy (IVT + EVT), while 35 (27.3%) were treated with IVT alone. In the IVT + EVT group, tenecteplase was associated with higher odds of 90-day-mRS 0-1 (46.0% vs. 32.6%, adjusted OR (aOR) 3.21; 95% CI = 1.06-9.71) compared with alteplase. No statistically significant differences in rates of mRS 0-2 (aOR 1.53; 95% CI = 0.51-4.55), initial rAOL 2b-3 (16.3% vs. 28.6%), final eTICI 2b-3 (83.7% vs. 85.7%), and mortality (18.0% vs. 16.3%) were found. SICH only occurred in one patient. There were no differences in outcomes between thrombolytic agents in the IVT-only group., Conclusion: In patients with carotid TL treated with EVT, intravenous tenecteplase may be associated with similar or better clinical outcomes, similar angiographic reperfusion rates, and safety outcomes as compared with alteplase., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.Y.P. is the Principal investigator of the EASI-TOC trial of carotid stenting, partially funded by Stryker, Brain Canada, Heart and Stroke Foundation of Canada, and the Canadian Stroke Consortium and is in the advisory board of and receives speaker honoraria from Roche Canada. Other authors report no conflict of interest.

Bertolt Brecht's poem "A Worker's Speech to a Doctor" is frequently cited as a means to raise awareness among health workers of the health effects of living and working conditions. Less cited is his Call to Arms trilogy of poems, which calls for class-based action to transform the capitalist economic system that sickens and kills so many. In this article, we show how "A Worker's Speech to a Doctor," with its plea for empathy for the ill, contrasts with the more activist and often militant tone of the Call to Arms trilogy: "Call to a Sick Communist," "The Sick Communist's Answer to the Comrades," and "Call to the Doctors and Nurses." We also show that, while "A Worker's Speech to a Doctor" has been applied in the training of health workers, its accusatorial tone towards health workers' complicity in the system the poem is critiquing risks alienating such workers. In contrast, the Call to Arms trilogy seeks common ground, inviting these same workers into the broader political and social fight against injustice. While we contend that the description of the sick worker as a "Communist" risks estranging these health workers, our analysis of the Call to Arms poems nevertheless indicates that their use can contribute to moving health workers' educational discourse beyond a laudable but fleeting elicitation of empathy for the ill towards a structural critique and deeper systemic understanding in order to prompt action by health workers to reform or even replace the capitalist economic system that sickens and kills so many., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days., Methods: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient ( r ) with 95% CI., Results: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase ( P =0.10). Older age ( P <0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale ( P <0.01), and longer stroke onset-to-needle time ( P =0.004) were associated with lower EQ5D index and VAS scores. There was a strong association ( r , 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index ( r , 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores ( r , 0.42 [95% CI, 0.37-0.46])., Conclusions: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249., Competing Interests: Disclosures Dr Menon reports stock in Circle NVI and patents for systems of triage in acute stroke. Dr Sajobi reports consulting fees received from Circle NVI and employment at the University of Calgary. Dr Almekhlafi reports to be on the medical advisory board of Palmera Medical, Inc. Dr Deschaintre reports being part of the Association des neurologues du Québec, the Société des Sciences Vasculaires du Québec, and the Université de Montréal. Dr Coutts reports that Boehringer Ingelheim provided a study drug (tenecteplase) for the TEMPO-2 trial. Dr Catanese reports employment with Hamilton Health Sciences and McMaster University, consulting fees from Hoffmann-La Roche Ltd, and a grant/contract from Servier Pharmaceuticals LLC. Dr Field reports consulting fees from AstraZeneca Canada, Bayer, HLS Therapeutics, and Roche; stock and being a fiduciary officer (board member) in Destine Health; grants/contracts from Boehringer Ingelheim and Bayer; and being an expert witness for the Canadian Medical Protective Association. Dr Siddiqui reports a grant/contract from Allergan and other interests from Bayer and Boehringer Ingelheim. Dr Demchuk reports stock in Circle NVI and patents for stroke imaging software; consulting fees from Servier Pharmaceuticals LLC, NovaSignal, Boehringer Ingelheim, HLS Therapeutics, Inc, Hoffmann-La Roche Ltd, and Medtronic; data and safety monitoring with Philips; and other interests from AstraZeneca Canada, Novo Nordisk AS, and Pfizer Canada, Inc. Dr Hill reports employment with the University of Calgary; consulting fees from Brainsgate Ltd; grants/contracts from Biogen, Inc, Boehringer Ingelheim, the Canadian Institutes of Health Research, Medtronic, MicroVention, Inc, and NoNO, Inc; being part of the end point review committee at Merck; stock in Circle NVI; and patents for systems of triage in acute stroke. Dr Poppe reports grant funding from the Fondation Brain Canada and the Heart and Stroke Foundation of Canada and research funding from Stryker. Dr Swartz reports stock in FollowMD, Inc, and grants/contracts from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the National Institutes of Health, the Ontario Brain Institute, and the Sunnybrook Research Institute. The other authors report no conflicts.

Introduction: Suicide is a major health issue. Its prevalence is particularly high in subjects presenting major depression disorder (MDD), making this a key suicide-related risk factor. Suicide attempts in severe forms of MDD were assumed to be linked to impulsivity and loss of control. Nevertheless, we failed to find data specifically investigating the link between impulsivity and suicide risk in treatment-resistant depression (TRD). This study seeks to review this relationship., Method: Patients were recruited for a prospective cohort. Suicide risk and impulsivity were assessed using the International Neuropsychiatric Interview and Barratt Impulsiveness Scale, Version 10, respectively, while the severity of depressive symptoms was assessed using the Montgomery-Asberg Depression Rating Scale, anxiety with the State-Trait Anxiety Inventory and childhood maltreatment using the Childhood Trauma Questionnaire., Results: 220 TRD patients were enrolled in the study. The impulsivity score was correlated with self-esteem, marital status, professional status and anxiety. There was no direct link to suicide risk. However, impulsivity was associated with self-esteem (coefficient: -0.24; p value 0.043) and depressive symptom severity (coefficient: 0.; p value 0.045). The suicide risk was significantly correlated with depressive symptom severity (coefficient = 0.38, p < 0.001) and self-esteem (coefficient = -0.34, p = 0.01). Considering these correlations, we postulated that the effect of impulsivity on suicide risk could be mediated by self-esteem in terms of depressive symptom severity and we finally found a relevant mediation model within impulsivity having an indirect effect on suicide risk by impacting self-esteem and depressive symptoms with anxiety also playing a significant role as a covariable., Conclusion: We found that impulsivity could play an indirect role with the involvement of self-esteem and depressive symptoms and the contributing role of anxiety., Competing Interests: Declaration of competing interest AY received speaker's honoraria from AstraZeneca, Janssen, Lundbeck, Otsuka and Servier, and carried out clinical studies in relation to the development of Janssen and Lundbeck medicines unrelated to this work. J-BG received a speaker's honorarium from Servier. P-ML received grants, honoraria and consulting fees from Allergan, Gedeon Richter, Janssen- Cilag, Lundbeck, Otsuka, Recordati, Sanofi-Aventis and Teva. RRi received a speaker's honorarium from Janssen Cilag. FS received honoraria from Otsuka. EH acted in an advisory capacity, carried out clinical studies in relation to the development of a medicine, received funding for research and studies along with travel allowances, gave presentations at meetings and received remuneration for input from the following pharmaceutical companies: AstraZeneca, BMS, Cellgene, Euthérapie-Servier, Janssen, Elli Lilly, Lundbeck, LivaNova, Otsuka, Pfizer and Sanofi. WE-H received speaker's honoraria from Chugai, Eisai, Lundbeck, Janssen-Cilag, Otsuka and UCB unrelated to this work. BA received speaker's honoraria and/or a travel allowance from Lundbeck, Sanofi, Janssen-Cilag and Eli Lilly. He has also served on the advisory board of Janssen-Cilag. BE received honoraria for consulting activities for Sanofi. The remaining authors have no commercial or financial relationships to declare that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)