Comparison of electrogram characteristics in persistent atrial fibrillation.

INTRODUCTION: Multiple analysis techniques evaluate electrograms during atrial fibrillation (AF), but none have been established to guide catheter ablation. This study compares electrogram properties recorded from multiple right (RA) and left atrial (LA) sites. METHODS: Multisite LA/RA mapping (281 ± 176/239 ± 166 sites/patient) was performed in 42 patients (30 males, age 63 ± 9 years) undergoing first (n = 32) or redo-AF ablation (n = 10). All electrogram recordings were visually reviewed and artifactual signals were excluded leaving a total of 21 846 for analysis. Electrogram characteristics evaluated were cycle length (CL), amplitude, Shannon's entropy (ShEn), fractionation interval, dominant frequency, organizational index, and cycle length of most recurrent morphology (CLR ) from morphology recurrence plot analysis. RESULTS: Electrogram characteristics were correlated to each other. All pairwise comparisons were significant (p < .001) except for dominant frequency and CLR (p = .59), and amplitude and dominant frequency (p = .38). Only ShEn and fractionation interval demonstrated a strong negative correlation (r = -.94). All other pairwise comparisons were poor to moderately correlated. The relationships are highly conserved among patients, in the RA versus LA, and in those undergoing initial versus redo ablations. Antiarrhythmic drug therapy did not have a significant effect on electrogram characteristics, except minimum ShEn. Electrogram characteristics associated with ablation outcome were shorter minimum CLR , lower minimum ShEn, and longer mimimum CL. There was minimal overlap between the top 10 sites identified by one electrogram characteristic and the top 10 sites identified by the other 10 characteristics. CONCLUSION: Multiple techniques can be employed for electrogram analysis in AF. In this analysis of eight different electrogram characteristics, seven were poorly to moderately correlated and do not identify similar locations. Only some characteristics were predictive of ablation outcome. Further studies to consider electrogram properties, perhaps in combination, for categorizing and/or mapping AF are warranted.

The Next Frontier in Tuberculosis Investigation: Automated Whole Genome Sequencing for Mycobacterium tuberculosis Analysis.

A fully automated bacteria whole genome sequencing (WGS) assay was evaluated to characterize Mycobacterium tuberculosis (MTB) and non-tuberculosis Mycobacterium (NTM) clinical isolates. The results generated were highly reproducible, with 100% concordance in species and sub-lineage classification and 92% concordance between antimicrobial resistance (AMR) genotypic and phenotypic profiles. Using extracted deoxyribonucleic acid (DNA) from MTB clinical isolates as starting material, these findings demonstrate that a fully automated WGS assay, with a short turnaround time of 24.5 hours, provides timely and valuable insights into MTB outbreak investigation while providing reliable genotypic AMR profiling consistent with traditional antimicrobial susceptibility tests (AST). This study establishes a favorable proposition for the adoption of end-to-end fully automated WGS solutions for decentralized MTB diagnostics, thereby aiding in World Health Organization's (WHO) vision of tuberculosis eradication.

Membrane Potential-Dependent Uptake of Cationic Oligoimidazolium Mediates Bacterial DNA Damage and Death.

The treatment of bacterial infections is becoming increasingly challenging with the emergence of antimicrobial resistance. Thus, the development of antimicrobials with novel mechanisms of action is much needed. Previously, we designed several cationic main-chain imidazolium compounds and identified the polyimidazolium PIM1 as a potent antibacterial against a wide panel of multidrug-resistant nosocomial pathogens, and it had relatively low toxicity against mammalian epithelial cells. However, little is known about the mechanism of action of PIM1. Using an oligomeric version of PIM1 with precisely six repeating units (OIM1-6) to control for consistency, we showed that OIM1-6 relies on an intact membrane potential for entry into the bacterial cytoplasm, as resistant mutants to OIM1-6 have mutations in their electron transport chains. These mutants demonstrate reduced uptake of the compound, which can be circumvented through the addition of a sub-MIC dose of colistin. Once taken up intracellularly, OIM1-6 exerts double-stranded DNA breaks. Its potency and ability to kill represents a promising class of drugs that can be combined with membrane-penetrating drugs to potentiate activity and hedge against the rise of resistant mutants. In summary, we discovered that cationic antimicrobial OIM1-6 exhibits an antimicrobial property that is dissimilar to the conventional cationic antimicrobial compounds. Its killing mechanism does not involve membrane disruption but instead depends on the membrane potential for uptake into bacterial cells so that it can exert its antibacterial effect intracellularly.

Phase 1 Trial of a Therapeutic Anti-Yellow Fever Virus Human Antibody.

BACKGROUND: Insufficient vaccine doses and the lack of therapeutic agents for yellow fever put global health at risk, should this virus emerge from sub-Saharan Africa and South America. METHODS: In phase 1a of this clinical trial, we assessed the safety, side-effect profile, and pharmacokinetics of TY014, a fully human IgG1 anti-yellow fever virus monoclonal antibody. In a double-blind, phase 1b clinical trial, we assessed the efficacy of TY014, as compared with placebo, in abrogating viremia related to the administration of live yellow fever vaccine (YF17D-204; Stamaril). The primary safety outcomes were adverse events reported 1 hour after the infusion and throughout the trial. The primary efficacy outcome was the dose of TY014 at which 100% of the participants tested negative for viremia within 48 hours after infusion. RESULTS: A total of 27 healthy participants were enrolled in phase 1a, and 10 participants in phase 1b. During phase 1a, TY014 dose escalation to a maximum of 20 mg per kilogram of body weight occurred in 22 participants. During phases 1a and 1b, adverse events within 1 hour after infusion occurred in 1 of 27 participants who received TY014 and in none of the 10 participants who received placebo. At least one adverse event occurred during the trial in 22 participants who received TY014 and in 8 who received placebo. The mean half-life of TY014 was approximately 12.8 days. At 48 hours after the infusion, none of the 5 participants who received the starting dose of TY014 of 2 mg per kilogram had detectable YF17D-204 viremia; these participants remained aviremic throughout the trial. Viremia was observed at 48 hours after the infusion in 2 of 5 participants who received placebo and at 72 hours in 2 more placebo recipients. Symptoms associated with yellow fever vaccine were less frequent in the TY014 group than in the placebo group. CONCLUSIONS: This phase 1 trial of TY014 did not identify worrisome safety signals and suggested potential clinical benefit, which requires further assessment in a phase 2 trial. (Funded by Tysana; ClinicalTrials.gov number, NCT03776786.).

Guidance on take-home naloxone distribution and use by community overdose responders in Canada.

BACKGROUND: The increasing toxicity of opioids in the unregulated drug market has led to escalating numbers of overdoses in Canada and worldwide; takehome naloxone (THN) is an evidence-based intervention that distributes kits containing naloxone to people in the community who may witness an overdose. The purpose of this guidance is to provide policy recommendations for territorial, provincial and federal THN programs, using evidence from scientific and grey literature and community evidence that reflects 11 years of THN distribution in Canada. METHODS: The Naloxone Guidance Development Group - a multidisciplinary team including people with lived and living experience and expertise of drug use - used the Appraisal of Guidelines for Research & Evaluation (AGREE II) instrument to inform development of this guidance. We considered published evidence identified through systematic reviews of all literature types, along with community evidence and expertise, to generate recommendations between December 2021 and September 2022. We solicited feedback on preliminary recommendations through an External Review Committee and a public input process. The project was funded by the Canadian Institutes of Health Research through the Canadian Research Initiative in Substance Misuse. We used the Guideline International Network principles for managing competing interests. RECOMMENDATIONS: Existing evidence from the literature on THN was of low quality. We incorporated evidence from scientific and grey literature, and community expertise to develop our recommendations. These were in 3 areas: routes of naloxone administration, THN kit contents and overdose response. Take-home naloxone programs should offer the choice of both intramuscular and intranasal formulations of naloxone in THN kits. Recommended kit contents include naloxone, a naloxone delivery device, personal protective equipment, instructions and a carrying case. Trained community overdose responders should prioritize rescue breathing in the case of respiratory depression, and conventional cardiopulmonary resuscitation in the case of cardiac arrest, among other interventions. INTERPRETATION: This guidance development project provides direction for THN programs in Canada in the context of limited published evidence, with recommendations developed in collaboration with diverse stakeholders.

A scoping review of qualitative studies on pre-hospital analgesia administration and practice.

BACKGROUND: Pain is an exceedingly common complaint in the pre-hospital setting. Despite advancements in organizational protocols and guidelines, many emergency medical services (EMS) systems still fail to provide optimal pain management. This scoping review thus aimed to map the body of qualitative literature pertaining to factors influencing pre-hospital analgesia administration and practice in order to clarify concepts and understanding as well as to identify any knowledge gaps. METHODS: The review protocol was guided by the framework outlined by Arksey and O'Malley and ensuing recommendations made by Levac and colleagues. Five databases were searched from inception till October 26, 2021, namely MEDLINE, EMBASE, CINAHL, The Cochrane Library, and Scopus. The search strategy was developed in consultation with a medical information specialist. A total of 5848 records were screened by abstract and title by four independent researchers. 199 records were included for full text review. From these, 15 articles were eligible for thematic analysis based on pre-defined inclusion criteria. RESULTS: Included studies found that practitioner, patient, and environmental factors influenced the administration and practice of pre-hospital analgesia. Key barriers included the difficulty in assessing pain, poor inter-professional relationship, knowledge deficits, stress and anxiety, and miscellaneous factors, such as concerns over drug-seeking behaviours. Some possible solutions were proposed, and pre-hospital EMS systems and healthcare institutions could consider bridging some of these gaps. There was a notable paucity of Asian studies, and a variety of EMS settings with different protocols and workflows were examined, hence systemic factors including guidelines and legislations cannot and should not be generalized across every healthcare system. CONCLUSION: The factors influencing pre-hospital analgesia administration and practice remain incompletely understood. Existing tools and practice guidelines were also inadequate. This scoping review provided an overarching perspective of the extant literature, highlighting some of the significant barriers, enablers, and areas for further research.

Priority setting for Canadian Take-Home Naloxone best practice guideline development: an adapted online Delphi method.

BACKGROUND: Take-Home Naloxone (THN) is a core intervention aimed at addressing the toxic illicit opioid drug supply crisis. Although THN programs are available in all provinces and territories throughout Canada, there are currently no standardized guidelines for THN programs. The Delphi method is a tool for consensus building often used in policy development that allows for engagement of stakeholders. METHODS: We used an adapted anonymous online Delphi method to elicit priorities for a Canadian guideline on THN as a means of facilitating meaningful stakeholder engagement. A guideline development group generated a series of key questions that were then brought to a 15-member voting panel. The voting panel was comprised of people with lived and living experience of substance use, academics specializing in harm reduction, and clinicians and public health professionals from across Canada. Two rounds of voting were undertaken to score questions on importance for inclusion in the guideline. RESULTS: Nine questions that were identified as most important include what equipment should be in THN kits, whether there are important differences between intramuscular and intranasal naloxone administration, how stigma impacts access to distribution programs, how effective THN programs are at saving lives, what distribution models are most effective and equitable, storage considerations for naloxone in a community setting, the role of CPR and rescue breathing in overdose response, client preference of naloxone distribution program type, and what aftercare should be provided for people who respond to overdoses. CONCLUSIONS: The Delphi method is an equitable consensus building process that generated priorities to guide guideline development.

Noncentrifugal activation patterns in focal RVOT PVC/VT: New insights from high density multielectrode mapping.

BACKGROUND: Activation from an automatic focus is thought to show centrifugal spread. In patients with premature ventricular complex/ventricular tachycardia (PVC/VT) from the right ventricular outflow tract (RVOT), the presence of preferential conduction and epicardial connections could however also lead to noncentrifugal wavefront propagation. OBJECTIVE: To study endocardial activation in RVOT PVC/VT using high-resolution 3D activation mapping. METHODS: Consecutive patients with frequent idiopathic PVC/VT were studied. High-resolution 3D activation maps were acquired using a multielectrode mapping catheter (Orion, Rhythmia, Boston Scientific). Noncentrifugal activation was defined as a pattern of wavefront propagation which does not show uniform propagation in all directions from one focus. Patients without sustained ablation success and patients with a left-sided PVC origin or with insufficient map density were excluded from the analysis. RESULTS: Sixteen patients (44% female) with a median age of 54 years (interquartile range [IQR], 47-64) and a median PVC burden of 19% (IQR, 15-27) were studied. High-resolution activation maps consisting of a median number of 1863 mapping points (IQR, 1195-2463 points) demonstrated a centrifugal activation in 6/16 (38%) and a noncentrifugal activation in 10/16 (62%). When comparing patients with centrifugal and noncentrifugal activation, patients with centrifugal activation were older (p = .01), but no differences were found in age, gender, QRS duration of the PVC's and sites of origin in the RVOT. No procedural complications occurred. CONCLUSIONS: High-resolution multielectrode mapping demonstrates the presence of noncentrifugal activation patterns in some of the patients with idiopathic RVOT PVC/VT. This may indicate the presence of preferential conduction and or epicardial/intramural connections in the outflow tract.

A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in vitro.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008µM and 9.453 µM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19.

Take-home naloxone programs for suspected opioid overdose in community settings: a scoping umbrella review.

BACKGROUND: Opioid related overdoses and overdose deaths continue to constitute an urgent public health crisis. The implementation of naloxone programs, such as 'take-home naloxone' (THN), has emerged as a key intervention in reducing opioid overdose deaths. These programs aim to train individuals at risk of witnessing or experiencing an opioid overdose to recognize an opioid overdose and respond with naloxone. Naloxone effectively reverses opioid overdoses on a physiological level; however, there are outstanding questions on community THN program effectiveness (adverse events, dosing requirements, dose-response between routes of administration) and implementation (accessibility, availability, and affordability). The objective of this scoping review is to identify existing systematic reviews and best practice guidelines relevant to clinical and operational guidance on the distribution of THN. METHODS: Using the Arksey & O'Malley framework for scoping reviews, we searched both academic literature and grey literature databases using keywords (Naloxone) AND (Overdose) AND (Guideline OR Review OR Recommendation OR Toolkit). Only documents which had a structured review of evidence and/or provided summaries or recommendations based on evidence were included (systematic reviews, meta-analyses, scoping reviews, short-cut or rapid reviews, practice/clinical guidelines, and reports). Data were extracted from selected evidence in two key areas: (1) study identifiers; and (2) methodological characteristics. RESULTS: A total of 47 articles met inclusion criteria: 20 systematic reviews; 10 grey literature articles; 8 short-cut or rapid reviews; 4 scoping reviews; and 5 other review types (e.g. mapping review and comprehensive reviews). The most common subject themes were: naloxone effectiveness, safety, provision feasibility/acceptability of naloxone distribution, dosing and routes of administration, overdose response after naloxone administration, cost-effectiveness, naloxone training and education, and recommendations for policy, practice and gaps in knowledge. CONCLUSIONS: Several recent systematic reviews address the effectiveness of take-home naloxone programs, naloxone dosing/route of administration, and naloxone provision models. Gaps remain in the evidence around evaluating cost-effectiveness, training parameters and strategies, and adverse events following naloxone administration. As THN programs continue to expand in response to opioid overdose deaths, this review will contribute to understanding the evidence base for policy and THN program development and expansion.

Structural and computational examination of the Arabidopsis profilin-Poly-P complex reveals mechanistic details in profilin-regulated actin assembly.

Profilins are abundant cytosolic proteins that are universally expressed in eukaryotes and that regulate actin filament elongation by binding to both monomeric actin (G-actin) and formin proteins. The atypical profilin Arabidopsis AtPRF3 has been reported to cooperate with canonical profilin isoforms in suppressing formin-mediated actin polymerization during plant innate immunity responses. AtPRF3 has a 37-amino acid-long N-terminal extension (NTE), and its suppressive effect on actin assembly is derived from enhanced interaction with the polyproline (Poly-P) of the formin AtFH1. However, the molecular mechanism remains unclear. Here, we solved the crystal structures of AtPRF3Δ22 and AtPRF3Δ37, as well as AtPRF2 apo form and in complex with AtFH1 Poly-P at 1.5-3.6 Å resolutions. By combining these structures with molecular modeling, we found that AtPRF3Δ22 NTE has high plasticity, with a primary "closed" conformation that can adopt an open conformation that enables Poly-P binding. Furthermore, using molecular dynamics simulation and free-energy calculations of protein-protein binding, along with experimental validation, we show that the AtPRF3Δ22 binds to Poly-P in an adaptive manner, thereby enabling different binding modes that maintain the interaction through disordered sequences. Together, our structural and simulation results suggest that the dynamic conformational changes of the AtPRF3 NTE upon Poly-P binding modulate their interactions to fine-tune formin-mediated actin assembly.

Increasing prevalence of primary biliary cholangitis in Victoria, Australia.

BACKGROUND AND AIM: The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and in some parts of the world appears to be increasing. The aim of this study was to determine the 2013 prevalence of PBC in Victoria, Australia, and to determine the time trend by comparing it with previous studies undertaken in 1991 and 2002. METHODS: Four case-finding methods were used to identify cases of PBC in Victoria: (1) physicians' survey; (2) tertiary hospital search; (3) liver transplant database search; and (4) private pathology antimitochondrial antibody search. RESULTS: The prevalence of PBC in Victoria, Australia, is 189.0 per million using all four methods. The average annual increase in prevalence from 1991 to 2013 was 7.7 per million per year. Using the same case-finding methods as the 1991 Victorian prevalence study (methods 1 and 2), the prevalence of PBC increased from 19.1 per million in 1991 to 49.4 per million in 2002 (P < 0.001) and to 80.7 per million in 2013 (P < 0.001). CONCLUSIONS: The current prevalence of PBC in Victoria is significantly higher than previously reported. The use of private pathology-based case-finding methods is important in identifying the maximum number of PBC cases.

Plasticity of the 340-Loop in Influenza Neuraminidase Offers New Insight for Antiviral Drug Development.

The recently discovered 340-cavity in influenza neuraminidase (NA) N6 and N7 subtypes has introduced new possibilities for rational structure-based drug design. However, the plasticity of the 340-loop (residues 342-347) and the role of the 340-loop in NA activity and substrate binding have not been deeply exploited. Here, we investigate the mechanism of 340-cavity formation and demonstrate for the first time that seven of nine NA subtypes are able to adopt an open 340-cavity over 1.8 µs total molecular dynamics simulation time. The finding that the 340-loop plays a role in the sialic acid binding pathway suggests that the 340-cavity can function as a druggable pocket. Comparing the open and closed conformations of the 340-loop, the side chain orientation of residue 344 was found to govern the formation of the 340-cavity. Additionally, the conserved calcium ion was found to substantially influence the stability of the 340-loop. Our study provides dynamical evidence supporting the 340-cavity as a druggable hotspot at the atomic level and offers new structural insight in designing antiviral drugs.

Effects of surgery on neurocognitive function in patients with glioma: a meta-analysis of immediate post-operative and long-term follow-up neurocognitive outcomes.

PURPOSE: This study aims to identify the neuropsychological tests commonly used for assessment in each neurocognitive domain, and quantify the post-operative changes in neurocognitive function in the immediate post-operation and follow-up. METHODS: With the use of the PubMed, a comprehensive search of the English literature was performed following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. There were 1021 publications identified for screening. Standardized mean differences (SMD) in neuropsychological task performance were calculated both for immediate post-operation (up to 1 week) and follow-up (up to 6 months). RESULTS: Out of 12 studies which met the inclusion criteria, 11 studies were analyzed in this meta-analysis, with a total of 313 patients (age range 18-82, 50% males) with intracranial gliomas (45% high-grade, 55% low-grade). Complex attention, language and executive function were the most frequently tested neurocognitive domains. Surgery had a positive impact in the domains of complex attention, language, learning and memory tasks in the immediate post-operative period and sustained improvement at follow-up. In contrast, surgery was found to negatively impact performance for executive function in the immediate post-operative period with sustained decline in performance in the long term. CONCLUSIONS: This meta-analysis suggests that surgery for glioma confers a benefit for the domains of complex attention, language, learning and memory, while negatively affecting executive function, in the periods immediately after surgery and at 6 months follow-up. In addition, awake surgery seemed to confer a beneficial effect on neurocognitive functions. Future research should attempt to standardize a battery of neuropsychological tests for patients undergoing surgical resection for glioma, perhaps with a particular focus on executive function.

Contraction of the type I IFN locus and unusual constitutive expression of IFN-α in bats.

Bats harbor many emerging and reemerging viruses, several of which are highly pathogenic in other mammals but cause no clinical signs of disease in bats. To determine the role of interferons (IFNs) in the ability of bats to coexist with viruses, we sequenced the type I IFN locus of the Australian black flying fox, Pteropus alecto, providing what is, to our knowledge, the first gene map of the IFN region of any bat species. Our results reveal a highly contracted type I IFN family consisting of only 10 IFNs, including three functional IFN-α loci. Furthermore, the three IFN-α genes are constitutively expressed in unstimulated bat tissues and cells and their expression is unaffected by viral infection. Constitutively expressed IFN-α results in the induction of a subset of IFN-stimulated genes associated with antiviral activity and resistance to DNA damage, providing evidence for a unique IFN system that may be linked to the ability of bats to coexist with viruses.

Ischaemic Stroke and the Echocardiographic "Bubble Study": Are We Screening the Right Patients?

BACKGROUND: Patent foramen ovale (PFO) is a potential mechanism for paradoxical embolism in cryptogenic ischaemic stroke or transient ischaemic attack (TIA). PFO is typically demonstrated with agitated saline ("bubble study", BS) during echocardiography. We hypothesised that the BS is frequently requested in patients that have a readily identifiable cause of stroke, that any PFO detected is likely incidental, and its detection often does not alter management. METHODS: This was a retrospective observational study of patients with recent ischaemic stroke/TIA referred for a BS. Patient demographics, stroke risk factors, vascular/cerebral imaging results and transoesophageal echocardiogram (TOE) reports were recorded. A "modified" Risk of Paradoxical Embolism (RoPE) score was calculated. Change in management was defined as antiplatelet/anticoagulant therapy alteration or referral for PFO closure. Bubble Study complications were recorded. RESULTS: Among 715 patients with ischaemic stroke/TIA referred for a BS, 8.7% had atrial fibrillation and 9.2% had carotid stenosis ≥70%. At least three stroke risk factors were present in 39.3% and only 47.1% of patients screened had a "modified" RoPE score of >5. A PFO was detected in 248 patients of whom only 31% (77/248) had a subsequent change in management. Of BS performed, 1/924 patients (0.1%) suffered a TIA as a complication. CONCLUSIONS: The echocardiographic BS is frequently performed in patients that have a readily identifiable cause of stroke and whose PFO unlikely relates to the stroke/TIA. Bubble Study findings resulted in a change in management in the minority. The procedure is safe but the complication rate warrants informed consent.

Document d'orientation sur la distribution et l'utilisation de trousses de naloxone à emporter par les intervenants et intervenantes communautaires en cas de surdose au Canada.

CONTEXTE: La toxicité croissante des opioïdes dans le marché illicite des drogues a fait exploser le nombre de surdoses au Canada et ailleurs dans le monde; le programme de naloxone à emporter (NàE) est une intervention fondée sur des données probantes qui consiste à distribuer des trousses contenant de la naloxone aux membres de la communauté susceptibles d'être témoins d'une surdose. L'objectif du présent document d'orientation est de formuler des recommandations stratégiques à l'intention des programmes fédéraux, provinciaux et territoriaux de NàE, en s'appuyant sur des données probantes issues de la documentation scientifique, de la littérature grise et des communautés, à la lumière de 11 années de distribution de NàE au Canada. MÉTHODES : Le groupe d'élaboration des documents d'orientation sur la naloxone, une équipe multidisciplinaire composée de personnes ayant une expertise et une expérience vécue en matière de toxicomanie, a appliqué l'outil AGREE II (Appraisal of Guidelines for Research & Evaluation) afin d'éclairer l'élaboration du présent document d'orientation. En vue de l'élaboration de nos recommandations, nous avons procédé entre décembre 2021 et septembre 2022 à une revue systématique de tous les types d'ouvrages dans le but de recueillir les données probantes publiées, ainsi que les données probantes et l'expertise issues de la communauté. Nous avons sollicité des commentaires sur nos recommandations préliminaires par le biais d'un comité de révision externe et d'un processus de participation du public. Le projet a été financé par les Instituts de recherche en santé du Canada dans le cadre de l'Initiative canadienne de recherche sur l'abus de substances (ICRAS). Nous avons appliqué les principes du Réseau international en matière de lignes directrices (Guidelines International Network) pour gérer les intérêts concurrents. RECOMMANDATIONS: Les données probantes existantes issues de la documentation sur la NàE étaient de faible qualité. Pour élaborer nos recommandations, nous avons incorporé des données probantes tirées de la documentation scientifique et de la littérature grise, ainsi que l'expertise de la communauté. Nos recommandations portent sur 3 volets : les voies d'administration de la naloxone, le contenu des trousses de NàE et les interventions en cas de situations de surdose. Les trousses distribuées par les programmes de naloxone à emporter doivent offrir le choix entre les préparations intramusculaire et intranasale. Le contenu recommandé de la trousse comprend la naloxone, un dispositif d'administration de la naloxone, un équipement de protection individuelle, des instructions et un étui de transport. Les intervenants et intervenantes communautaires formés à la réponse aux surdoses doivent prioriser la respiration artificielle en cas de dépression respiratoire, et la réanimation cardiorespiratoire (RCR) conventionnelle en cas d'arrêt cardiaque, entre autres interventions. INTERPRÉTATION : Ce projet d'élaboration d'un document d'orientation vise à guider les programmes de NàE au Canada dans un contexte où les données probantes publiées sont rares; les recommandations ont été élaborées en collaboration avec diverses parties prenantes.

Characterization of the Antigen Processing Machinery and Endogenous Peptide Presentation of a Bat MHC Class I Molecule.

Bats are a major reservoir of emerging and re-emerging infectious diseases, including severe acute respiratory syndrome-like coronaviruses, henipaviruses, and Ebola virus. Although highly pathogenic to their spillover hosts, bats harbor these viruses, and a large number of other viruses, with little or no clinical signs of disease. How bats asymptomatically coexist with these viruses is unknown. In particular, little is known about bat adaptive immunity, and the presence of functional MHC molecules is mostly inferred from recently described genomes. In this study, we used an affinity purification/mass spectrometry approach to demonstrate that a bat MHC class I molecule, Ptal-N*01:01, binds antigenic peptides and associates with peptide-loading complex components. We identified several bat MHC class I-binding partners, including calnexin, calreticulin, protein disulfide isomerase A3, tapasin, TAP1, and TAP2. Additionally, endogenous peptide ligands isolated from Ptal-N*01:01 displayed a relatively broad length distribution and an unusual preference for a C-terminal proline residue. Finally, we demonstrate that this preference for C-terminal proline residues was observed in Hendra virus-derived peptides presented by Ptal-N*01:01 on the surface of infected cells. To our knowledge, this is the first study to identify endogenous and viral MHC class I ligands for any bat species and, as such, provides an important avenue for monitoring and development of vaccines against major bat-borne viruses both in the reservoir and spillover hosts. Additionally, it will provide a foundation to understand the role of adaptive immunity in bat antiviral responses.

Helicobacter pylori infection and the risk of upper gastrointestinal bleeding in low dose aspirin users: systematic review and meta-analysis.

OBJECTIVE: To determine whether the risk of upper gastrointestinal bleeding in patients taking low dose aspirin (≤ 325 mg/day) is increased in people with Helicobacter pylori infections. STUDY DESIGN: A systematic search for all publications since 1989 (when H. pylori was named) using search term equivalents for "upper gastrointestinal haemorrhage" and "aspirin". Articles were assessed individually for inclusion of data on H. pylori infection, as not all relevant papers were indexed with this term. Data that could be pooled were then subjected to meta-analysis, using a random effects model. DATA SOURCES: MEDLINE, Embase, Scopus, the Cochrane Library. DATA SYNTHESIS: Of 7599 retrieved publications, reports for seven case-control studies contained data suitable for meta-analysis; four were deemed high quality on the Newcastle-Ottawa scale. Upper gastrointestinal haemorrhage was more frequent in aspirin users infected with H. pylori than in those who were not (odds ratio [OR], 2.32; 95% CI, 1.25-4.33; P = 0.008). The heterogeneity of the studies was significant (Q = 19.3, P = 0.004; I2 = 68.9%, 95% CI, 31.5-85.9%), but the pooled odds ratio was similar after removing the two studies that contributed most to heterogeneity (OR, 2.34; 95% CI, 1.56-3.53; P < 0.001). The number needed to treat to prevent one bleeding event annually was estimated to be between 100 and more than 1000. CONCLUSIONS: The odds of upper gastrointestinal bleeding in patients taking low dose aspirin is about twice as great in those infected with H. pylori. Testing for and treating the infection should be considered in such patients, especially if their underlying risk of peptic ulcer bleeding is already high.