Molecular cell types as functional units of the efferent vagus nerve.

The vagus nerve vitally connects the brain and body to coordinate digestive, cardiorespiratory, and immune functions. Its efferent neurons, which project their axons from the brainstem to the viscera, are thought to comprise "functional units" - neuron populations dedicated to the control of specific vagal reflexes or organ functions. Previous research indicates that these functional units differ from one another anatomically, neurochemically, and physiologically but have yet to define their identity in an experimentally tractable way. However, recent work with genetic technology and single-cell genomics suggests that genetically distinct subtypes of neurons may be the functional units of the efferent vagus. Here we review how these approaches are revealing the organizational principles of the efferent vagus in unprecedented detail.

Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

Molecular organization of autonomic, respiratory, and spinally-projecting neurons in the mouse ventrolateral medulla.

The ventrolateral medulla (VLM) is a crucial region in the brain for visceral and somatic control, serving as a significant source of synaptic input to the spinal cord. Experimental studies have shown that gene expression in individual VLM neurons is predictive of their function. However, the molecular and cellular organization of the VLM has remained uncertain. This study aimed to create a comprehensive dataset of VLM cells using single-cell RNA sequencing in male and female mice. The dataset was enriched with targeted sequencing of spinally-projecting and adrenergic/noradrenergic VLM neurons. Based on differentially expressed genes, the resulting dataset of 114,805 VLM cells identifies 23 subtypes of neurons, excluding those in the inferior olive, and 5 subtypes of astrocytes. Spinally-projecting neurons were found to be abundant in 7 subtypes of neurons, which were validated through in-situ hybridization. These subtypes included adrenergic/noradrenergic neurons, serotonergic neurons, and neurons expressing gene markers associated with pre-motor neurons in the ventromedial medulla. Further analysis of adrenergic/noradrenergic neurons and serotonergic neurons identified 9 and 6 subtypes, respectively, within each class of monoaminergic neurons. Marker genes that identify the neural network responsible for breathing were concentrated in 2 subtypes of neurons, delineated from each other by markers for excitatory and inhibitory neurons. These datasets are available for public download and for analysis with a user-friendly interface. Collectively, this study provides a fine-scale molecular identification of cells in the VLM, forming the foundation for a better understanding of the VLM's role in vital functions and motor control.Significance statement The ventrolateral medulla (VLM) is an anatomically complex region of the brain that plays a crucial role in regulating vital functions, including autonomic and respiratory control, sleep-wake behaviors, cranial motor functions, and locomotion. This study comprehensively classifies VLM cell types and neuronal subtypes based on their molecular and anatomical features, by leveraging single-nuclei RNA sequencing, RNA fluorescence in situ hybridization, and axonal tract tracing. We present a dataset comprising 114,805 single-nuclei transcriptomes that identifies and validates the precise molecular characteristics of neurons involved in autonomic and motor systems functions. This publicly-available dataset offers new opportunities for comprehensive experimental studies to dissect the central organization of vital homeostatic functions and body movement.

Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER.

PURPOSE: Evaluate long-term efficacy and safety of elamipretide during the open-label extension (OLE) of the TAZPOWER trial in individuals with Barth syndrome (BTHS). METHODS: TAZPOWER was a 28-week randomized, double-blind, and placebo-controlled trial followed by a 168-week OLE. Patients entering the OLE continued elamipretide 40 mg subcutaneous daily. OLE primary endpoints were safety and tolerability; secondary endpoints included change from baseline in the 6-minute walk test (6MWT) and BarTH Syndrome Symptom Assessment (BTHS-SA) Total Fatigue score. Muscle strength, physician- and patient-assessed outcomes, echocardiographic parameters, and biomarkers, including cardiolipin (CL) and monolysocardiolipin (MLCL), were assessed. RESULTS: Ten patients entered the OLE; 8 reached the week 168 visit. Elamipretide was well tolerated, with injection-site reactions being the most common adverse events. Significant improvements from OLE baseline on 6MWT occurred at all OLE time points (cumulative 96.1 m of improvement [week 168, P = .003]). Mean BTHS-SA Total Fatigue scores were below baseline (improved) at all OLE time points. Three-dimensional (3D) left ventricular stroke, end-diastolic, and end-systolic volumes improved, showing significant trends for improvement from baseline to week 168. MLCL/CL values showed improvement, correlating to important clinical outcomes. CONCLUSION: Elamipretide was associated with sustained long-term tolerability and efficacy, with improvements in functional assessments and cardiac function in BTHS.

Identification of genetic markers of resistance to macrolide class antibiotics in Mannheimia haemolytica isolates from a Saskatchewan feedlot.

Mannheimia haemolytica is a major contributor to bovine respiratory disease (BRD), which causes substantial economic losses to the beef industry, and there is an urgent need for rapid and accurate diagnostic tests to provide evidence for treatment decisions and support antimicrobial stewardship. Diagnostic sequencing can provide information about antimicrobial resistance genes in M. haemolytica more rapidly than conventional diagnostics. Realizing the full potential of diagnostic sequencing requires a comprehensive understanding of the genetic markers of antimicrobial resistance. We identified genetic markers of resistance in M. haemolytica to macrolide class antibiotics commonly used for control of BRD. Genome sequences were determined for 99 M. haemolytica isolates with six different susceptibility phenotypes collected over 2 years from a feedlot in Saskatchewan, Canada. Known macrolide resistance genes estT, msr(E), and mph(E) were identified in most resistant isolates within predicted integrative and conjugative elements (ICEs). ICE sequences lacking antibiotic resistance genes were detected in 10 of 47 susceptible isolates. No resistance-associated polymorphisms were detected in ribosomal RNA genes, although previously unreported mutations in the L22 and L23 ribosomal proteins were identified in 12 and 27 resistant isolates, respectively. Pangenome analysis led to the identification of 79 genes associated with resistance to gamithromycin, of which 95% (75 of 79) had no functional annotation. Most of the observed phenotypic resistance was explained by previously identified antibiotic resistance genes, although resistance to the macrolides gamithromycin and tulathromycin was not explained in 39 of 47 isolates, demonstrating the need for continued surveillance for novel determinants of macrolide resistance.IMPORTANCEBovine respiratory disease is the costliest disease of beef cattle in North America and the most common reason for injectable antibiotic use in beef cattle. Metagenomic sequencing offers the potential to make economically significant reductions in turnaround time for diagnostic information for evidence-based selection of antibiotics for use in the feedlot. The success of diagnostic sequencing depends on a comprehensive catalog of antimicrobial resistance genes and other genome features associated with reduced susceptibility. We analyzed the genome sequences of isolates of Mannheimia haemolytica, a major bovine respiratory disease pathogen, and identified both previously known and novel genes associated with reduced susceptibility to macrolide class antimicrobials. These findings reinforce the need for ongoing surveillance for markers of antimicrobial resistance to support improved diagnostics and antimicrobial stewardship.

A single bout of vigorous intensity exercise enhances the efficacy of rituximab against human chronic lymphocytic leukaemia B-cells ex vivo.

Chronic lymphocytic leukaemia (CLL) is characterised by the clonal proliferation and accumulation of mature B-cells and is often treated with rituximab, an anti-CD20 monoclonal antibody immunotherapy. Rituximab often fails to induce stringent disease eradication, due in part to failure of antibody-dependent cellular cytotoxicity (ADCC) which relies on natural killer (NK)-cells binding to rituximab-bound CD20 on B-cells. CLL cells are diffusely spread across lymphoid and other bodily tissues, and ADCC resistance in survival niches may be due to several factors including low NK-cell frequency and a suppressive stromal environment that promotes CLL cell survival. It is well established that exercise bouts induce a transient relocation of NK-cells and B-cells into peripheral blood, which could be harnessed to enhance the efficacy of rituximab in CLL by relocating both target and effector cells together with rituximab in blood. In this pilot study, n = 20 patients with treatment-naïve CLL completed a bout of cycling 15 % above anaerobic threshold for âˆ¼ 30-minutes, with blood samples collected pre-, immediately post-, and 1-hour post-exercise. Flow cytometry revealed that exercise evoked a 254 % increase in effector (CD3-CD56+CD16+) NK-cells in blood, and a 67 % increase in CD5+CD19+CD20+ CLL cells in blood (all p < 0.005). NK-cells were isolated from blood samples pre-, and immediately post-exercise and incubated with primary isolated CLL cells with or without the presence of rituximab to determine specific lysis using a calcein-release assay. Rituximab-mediated cell lysis increased by 129 % following exercise (p < 0.001). Direct NK-cell lysis of CLL cells - independent of rituximab - was unchanged following exercise (p = 0.25). We conclude that exercise improved the efficacy of rituximab-mediated ADCC against autologous CLL cells ex vivo and propose that exercise should be explored as a means of enhancing clinical responses in patients receiving anti-CD20 immunotherapy.

What Can Current Biomarker Data Tell Us About the Risks of Lung Cancer Posed by Heated Tobacco Products?

INTRODUCTION: Heated tobacco products (HTPs) are marketed as less harmful alternatives to cigarettes, but the lung cancer risk of HTPs is unknown. In the absence of epidemiological data, assessing the risks of HTPs relies on biomarker data from clinical trials. This study examined existing biomarker data to determine what it tells us about the lung cancer risk posed by HTPs. AIMS AND METHODS: We identified all biomarkers of exposure and potential harm measured in HTP trials and evaluated their appropriateness based on ideal characteristics for measuring lung cancer risk and tobacco use. The effects of HTPs on the most appropriate biomarkers within cigarette smokers switched to HTPs and compared to continued cigarette smoking or cessation were synthesized. RESULTS: Sixteen out of eighty-two biomarkers (7 exposure and 9 potential harm) measured in HTP trials have been associated with tobacco use and lung cancer, dose-dependently correlated with smoking, modifiable upon cessation, measured within an appropriate timeframe, and had results published. Three of the exposure biomarkers significantly improved in smokers who switched to HTPs and were not significantly different from cessation. The remaining 13 biomarkers did not improve-in some instances worsening upon switching to HTPs-or were inconsistently affected across studies. There were no appropriate data to estimate the lung cancer risk of HTPs in non-smokers. CONCLUSIONS: The appropriateness of existing biomarker data in assessing lung cancer risk of HTPs, both relative to cigarettes and their absolute risk, is limited. Furthermore, findings on the most appropriate biomarkers were conflicting across studies and largely showed no improvement following a switch to HTPs. IMPLICATIONS: Biomarker data are fundamental to assessing the reduced risk potential of HTPs. Our evaluation suggests much of the existing biomarker data on HTPs is inappropriate for determining the risk of lung cancer posed by HTPs. In particular, there is a paucity of data on the absolute lung cancer risk of HTPs, which could be obtained from comparisons to smokers who quit and never smokers exposed to or using HTPs. There is an urgent need for further exploration of the lung cancer risks posed by HTPs, via clinical trials and, in the long-term, confirmation of these risks via epidemiological studies. However, careful consideration should be given to biomarker selection and study design to ensure both are appropriate and will provide valuable data.

Implementation of optical coherence tomography in retinopathy of prematurity screening.

PURPOSE OF REVIEW: In this review, we explore the investigational applications of optical coherence tomography (OCT) in retinopathy of prematurity (ROP), the insights they have delivered thus far, and key milestones for its integration into the standard of care. RECENT FINDINGS: While OCT has been widely integrated into clinical management of common retinal diseases, its use in pediatric contexts has been undermined by limitations in ergonomics, image acquisition time, and field of view. Recently, investigational handheld OCT devices have been reported with advancements including ultra-widefield view, noncontact use, and high-speed image capture permitting real-time en face visualization. These developments are compelling for OCT as a more objective alternative with reduced neonatal stress compared to indirect ophthalmoscopy and/or fundus photography as a means of classifying and monitoring ROP. SUMMARY: OCT may become a viable modality in management of ROP. Ongoing innovation surrounding handheld devices should aim to optimize patient comfort and image resolution in the retinal periphery. Future clinical investigations may seek to objectively characterize features of peripheral stage and explore novel biomarkers of disease activity.

Antimicrobial resistance in Enterococcus isolated from western Canadian cow-calf herds.

BACKGROUND: Data on antimicrobial resistance (AMR) in cow-calf herds is limited and there have been no Canadian studies examining AMR in Enterococcus in cow-calf herds. Enterococcus is a ubiquitous Gram-positive indicator of AMR for enteric organisms that is also important in human health. The objective of this study was to describe AMR in specific Enterococcus species of interest from cow-calf herds; highlighting differences in AMR among isolates from cows and calves and samples collected in the spring and fall. Isolates (n = 1505) were examined from 349 calves and 385 cows from 39 herds in the spring of 2021 and 413 calves from 39 herds and 358 cows from 36 herds in the fall of 2021. Enterococcus species were identified using Matrix-Assisted Laser Desorption Ionization Time-Of-Flight mass spectrometry (MALDI-TOF MS) and antimicrobial susceptibility testing was completed based on a prioritization scheme for importance to human health and using the National Antimicrobial Resistance Monitoring System (NARMS) Gram positive Sensititre broth microdilution panel. RESULTS: Resistance was observed to at least one antimicrobial in 86% (630/734) of isolates from the spring and 84% (644/771) of isolates from the fall. The most common types of resistance across all species were: lincomycin, quinupristin/dalfopristin, daptomycin, ciprofloxacin, and tetracycline. However, the proportion of isolates with AMR varied substantially based on species. Multiclass resistance, defined as resistance to ≥3 antimicrobial classes after excluding intrinsic resistance, was highest in isolates from calves in the spring (6.9%) (24/349) and cows in the fall (6.7%) (24/357). Differences in resistance were seen between cows and calves in the spring and fall as well as across seasons, with no differences seen between cows and calves in the fall. CONCLUSIONS: While most Enterococcus isolates were resistant to at least one antimicrobial, questions remain regarding species differences in intrinsic resistance and the accuracy of certain antimicrobial breakpoints for specific Enterococcus spp. As a result, some species-specific AMR profiles should be interpreted with caution. Despite these constraints, Enterococcus species are important indicator organisms for AMR and resulting data can be used to inform stewardship initiatives.

Perfusion education and training in Europe anno 2023.

Background: In the absence of uniform European regulations, there have been many differences in the training of perfusionists across Europe. Furthermore, there has been no uniform or single European accreditation of the profession. One of the objectives of The European Board of Cardiovascular Perfusion (EBCP) is to standardise and monitor training of perfusionists across Europe whilst offering support in accordance with national regulations. This goal is particularly imminent as there have been numerous newly founded National perfusion societies, particularly from Eastern European countries, which are now established members of EBCP.Purpose: In this article, we provide an updated overview or 'snapshot' of current European perfusion training programs that were accessible in 2022. Nationally acquired data refers to 2022 unless stated otherwise. The last overview of Perfusion education in Europe was reported over 15 years ago including 20 countries.Research Design: For this report thirty-two national EBCP delegates plus representatives from Austria were contacted at the beginning of 2023 to complete a pro forma questionnaire about their national perfusion training programmes. The data has been summarized in this article and five additional derived parameters were calculated.Results: We received responses from 31 countries, providing specific national training characteristics which are summarized, listed and benchmarked by country in this article.Conclusion: There have been several national and supranational initiatives towards the recognition of perfusion as a profession in Europe, however so far without success for the majority of countries. For this reason, it remains essential for EBCP, as the only European professional perfusionist body, to define education standards and competencies for perfusionists and to monitor training by accreditation of dedicated perfusion schools across Europe.

Development of Good Manufacturing Practice-Compatible Isolation and Culture Methods for Human Olfactory Mucosa-Derived Mesenchymal Stromal Cells.

Demyelination in the central nervous system (CNS) resulting from injury or disease can cause loss of nerve function and paralysis. Cell therapies intended to promote remyelination of axons are a promising avenue of treatment, with mesenchymal stromal cells (MSCs) a prominent candidate. We have previously demonstrated that MSCs derived from human olfactory mucosa (hOM-MSCs) promote myelination to a greater extent than bone marrow-derived MSCs (hBM-MSCs). However, hOM-MSCs were developed using methods and materials that were not good manufacturing practice (GMP)-compliant. Before considering these cells for clinical use, it is necessary to develop a method for their isolation and expansion that is readily adaptable to a GMP-compliant environment. We demonstrate here that hOM-MSCs can be derived without enzymatic tissue digestion or cell sorting and without culture antibiotics. They grow readily in GMP-compliant media and express typical MSC surface markers. They robustly produce CXCL12 (a key secretory factor in promoting myelination) and are pro-myelinating in in vitro rodent CNS cultures. GMP-compliant hOM-MSCs are comparable in this respect to those grown in non-GMP conditions. However, when assessed in an in vivo model of demyelinating disease (experimental autoimmune encephalitis, EAE), they do not significantly improve disease scores compared with controls, indicating further pre-clinical evaluation is necessary before their advancement to clinical trials.

Trace mineral concentrations in Canadian beef calves at weaning.

Objective: To describe the copper and selenium statuses of beef calves at weaning. Animal: Calves (n = 1998) were sampled from 106 Canadian cow-calf herds in the fall of 2021. Procedure: Serum samples from calves were tested for copper, selenium, and molybdenum concentrations. Results: Although the percentages of calves classified as selenium deficient (< 0.025 ppm) were relatively low (0.5% western Canada, 3% eastern Canada), 53% of calves from western Canada and 77% of calves from eastern Canada were classified as having less than adequate selenium concentrations (< 0.08 ppm). Copper deficiency (< 0.5 ppm) was common in calves from both western (17%) and eastern (14%) Canada. High molybdenum concentrations (> 0.10 ppm) were identified in 6% of calves from western Canada and 7% of calves from eastern Canada. Conclusion: Selenium concentrations were higher in calves from western Canada than from those in eastern Canada (P < 0.001). Copper and molybdenum concentrations were not significantly different between western and eastern Canada. Less-than-adequate serum copper was the most common deficiency identified in Canadian beef calves at weaning. Clinical relevance: Trace minerals are important for immune system function in calves at weaning. Selenium concentrations in calves at weaning were lower than in cows from the same herds collected at pregnancy testing 2 y earlier. Copper deficiency was also identified, though less frequently than for mature cows. Supplementation programs for calves should be customized based on testing and recognize both regional and age differences in risk.

Concentrations d'oligo-éléments minéraux chez les veaux de boucherie canadiens au sevrage. Objectif: Décrire les statuts en cuivre et en sélénium des veaux de boucherie au sevrage. Animal: Des veaux (n = 1998) ont été échantillonnés dans 106 troupeaux de type vache-veau canadiens à l'automne 2021. Procédure: Des échantillons de sérum de veaux ont été testés pour déterminer les concentrations de cuivre, de sélénium et de molybdène. Résultats: Même si les pourcentages de veaux classés comme déficients en sélénium (< 0,025 ppm) étaient relativement faibles (0,5 % dans l'ouest du Canada, 3 % dans l'est du Canada), 53 % des veaux de l'ouest du Canada et 77 % des veaux de l'est du Canada étaient classés comme ayant moins des concentrations de sélénium moins qu'adéquates (< 0,08 ppm). Une carence en cuivre (< 0,5 ppm) était courante chez les veaux de l'ouest (17 %) et de l'est (14 %) du Canada. Des concentrations élevées de molybdène (> 0,10 ppm) ont été identifiées chez 6 % des veaux de l'ouest du Canada et 7 % des veaux de l'est du Canada. Conclusion: Les concentrations de sélénium étaient plus élevées chez les veaux de l'ouest du Canada que chez ceux de l'est du Canada (P < 0,001). Les concentrations de cuivre et de molybdène n'étaient pas significativement différentes entre l'ouest et l'est du Canada. Un taux de cuivre sérique nettement insuffisamment était la carence la plus courante identifiée chez les veaux de boucherie canadiens au sevrage. Pertinence clinique: Les oligo-éléments sont importants pour le fonctionnement du système immunitaire des veaux au sevrage. Les concentrations de sélénium chez les veaux au sevrage étaient inférieures à celles des vaches des mêmes troupeaux collectées lors des tests de gestation deux ans plus tôt. Des carences en cuivre ont également été identifiées, quoique moins fréquemment que chez les vaches matures. Les programmes de supplémentation pour les veaux doivent être personnalisés en fonction des tests et reconnaître les différences de risque selon la région et l'âge.(Traduit par Dr Serge Messier).

Antimicrobial resistance in generic E. coli isolated from western Canadian cow-calf herds.

Objective: To examine antimicrobial resistance (AMR) in commensal fecal Escherichia coli (E. coli) from extensively managed beef calves and cows in western Canada and describe the differences among cows and calves in the spring and fall. Animal: Beef cattle, cow-calf. Procedure: Antimicrobial susceptibility testing was conducted on generic E. coli isolates collected from 388 calves and 387 cows from 39 herds following calving in 2021, 419 calves from 39 herds near weaning, and 357 cows from 36 herds at pregnancy testing. Minimum inhibitory concentrations were measured with the NARMS CMV5AGNF plate for Gram-negative bacteria and interpreted using Clinical and Laboratory Standards Institute standard breakpoints for humans. Results: Only 16% (242/1551) of all isolates from 97% (38/39) of herds were resistant to ≥ 1 antimicrobial. Generic E. coli isolates were most commonly resistant to sulfisoxazole (11%, 175/1551), followed by tetracycline (9.3%, 145/1551) and chloramphenicol (3.5%, 55/1551). Isolates from calves in the spring were more likely to be resistant to sulfisoxazole, tetracycline, and chloramphenicol than those from cows in the spring or calves in the fall. Multiclass-resistant isolates were identified in 5% (39/807) of calves. Only 2 isolates recovered from cows were resistant to antimicrobials of very high importance for human health. Conclusion and clinical relevance: Most generic E. coli isolates were pansusceptible. The observed resistance patterns were consistent with earlier studies of AMR from commensal E. coli in this region. Baseline AMR data for cow-calf herds are not currently collected as part of routine surveillance, but are essential to inform antimicrobial use policy and stewardship.

Résistance aux antimicrobiens chez E. coli générique isolé dans des troupeaux vache-veau de l'Ouest canadien. Objectif: Examiner la résistance aux antimicrobiens (RAM) chez Escherichia coli de la flore fécale commensale (E. coli) provenant de veaux et de vaches de boucherie en élevage extensif dans l'ouest du Canada et décrire les différences entre les vaches et les veaux au printemps et à l'automne. Animal: Bovins de boucherie, vache-veau. Procédure: Des tests de sensibilité aux antimicrobiens ont été effectués sur des isolats génériques d'E. coli collectés auprès de 388 veaux et 387 vaches de 39 troupeaux après le vêlage en 2021, de 419 veaux de 39 troupeaux à l'approche du sevrage et de 357 vaches de 36 troupeaux lors des tests de gestation. Les concentrations minimales inhibitrices ont été mesurées avec la plaque NARMS CMV5AGNF pour les bactéries à Gram négatif et interprétées à l'aide des seuils standard pour les humains du Clinical and Laboratory Standards Institute. Résultats: Seulement 16 % (242/1 551) de tous les isolats provenant de 97 % (38/39) des troupeaux étaient résistants à ≥ 1 antimicrobien. Les isolats génériques d'E. coli étaient le plus souvent résistants au sulfisoxazole (11 %, 175/1 551), suivi de la tétracycline (9,3 %, 145/1 551) et du chloramphénicol (3,5 %, 55/1 551). Les isolats provenant des veaux au printemps étaient plus susceptibles d'être résistants au sulfisoxazole, à la tétracycline et au chloramphénicol que ceux provenant des vaches au printemps ou des veaux à l'automne. Des isolats résistants à plusieurs classes ont été identifiés chez 5 % (39/807) des veaux. Seuls deux isolats récupérés chez des vaches étaient résistants à des antimicrobiens de très haute importance pour la santé humaine. Conclusion et pertinence clinique: La plupart des isolats génériques d'E. coli étaient sensibles à l'ensemble des antimicrobiens. Les profils de résistance observés concordaient avec les études antérieures sur la RAM provenant d'E. coli commensal dans cette région. Les données de base sur la RAM pour les troupeaux vache-veau ne sont pas actuellement recueillies dans le cadre de la surveillance de routine, mais elles sont essentielles pour éclairer la politique et la gestion de l'utilisation des antimicrobiens.(Traduit par Dr Serge Messier).

Comparison of postweaning bovine respiratory disease treatment rates between non-vaccinated control beef calves and calves variably primed and boosted using commercially available bovine coronavirus vaccines.

Objective: Bovine respiratory disease (BRD) and overall postweaning treatment rates were compared among 3 groups of calves either differentially primed and boosted with commercially available bovine coronavirus (BCoV) vaccine or not vaccinated against BCoV. Animals: Commercial heifer and steer beef calves born in April and May 2022. Procedure: In June 2022, calves were randomly enrolled into 3 treatment groups. Those in 2 groups [V1 (n = 160) and V2 (n = 160)] were administered a mucosal priming dose of 1 of 2 commercial BCoV vaccines; those in the 3rd group [CTL (n = 151)] were unvaccinated against BCoV. The V1 and V2 groups were boosted by intramuscular injection pre-weaning with the same vaccine used for priming. Weaning occurred 3 wk after the last preweaning processing day. Ranch staff used a BRD case definition provided by their herd veterinarian to identify, treat, and record treatments for 45 d post-weaning. Results: Postweaning BRD treatment rates for V1, V2, and CTL were 7%, 9%, and 14%, respectively. The CTL calves had 2.2× greater odds of receiving treatment for BRD than V1 calves. There were no differences in odds of treatment between CTL and V2 calves or V1 and V2 calves. Conclusion: In a herd with previously diagnosed BCoV BRD cases, prime-boost vaccination of calves is associated with a difference in odds of BRD treatment post-weaning compared to not vaccinating calves against BCoV. Clinical relevance: Prime-boost vaccination with commercial BCoV vaccine may be an important management tool for herds with known BCoV BRD outbreaks.

Comparaison des taux de traitement des maladies respiratoires bovines après le sevrage entre des veaux de boucherie témoins non vaccinés et des veaux vaccinés amorce-rappel de manière variable à l'aide de vaccins contre le coronavirus bovin commercialement disponibles. Objectif: La maladie respiratoire bovine (BRD) et les taux globaux de traitement post-sevrage ont été comparés parmi 3 groupes de veaux soit vaccinés de manière différentielle et avec un rappel avec le vaccin contre le coronavirus bovin (BCoV) disponible commercialement, soit non vaccinés contre le BCoV. Animaux: Génisses et veaux de boucherie commerciaux nés en avril et mai 2022. Procédure: En juin 2022, les veaux ont été randomisés lors du recrutement dans 3 groupes de traitement. Ceux des 2 groupes [V1 (n = 160) et V2 (n = 160)] ont reçu une dose d'amorce par voie muqueuse de l'un des deux vaccins commerciaux BCoV; ceux du 3ème groupe [CTL (n = 151)] n'étaient pas vaccinés contre le BCoV. Les groupes V1 et V2 ont eu un rappel par injection intramusculaire avant le sevrage avec le même vaccin que celui utilisé pour l'amorçage. Le sevrage a eu lieu 3 semaines après le dernier jour de conditionnement pré-sevrage. Le personnel du ranch a utilisé une définition de cas de BRD fournie par le vétérinaire de leur troupeau pour identifier, traiter et enregistrer les traitements pendant 45 jours après le sevrage. Résultats: Les taux de traitement BRD post-sevrage pour V1, V2 et CTL étaient respectivement de 7 %, 9 % et 14 %. Les veaux CTL avaient 2,2 fois plus de chances de recevoir un traitement contre la BRD que les veaux V1. Il n'y avait aucune différence dans les probabilités de traitement entre les veaux CTL et V2 ou entre les veaux V1 et V2. Conclusion: Dans un troupeau avec des cas de BRD causés par le BCoV déjà diagnostiqués, la vaccination amorce-rappel des veaux est associée à une différence de probabilité de traitement par le BRD après le sevrage par rapport à la nonvaccination des veaux contre le BCoV. Pertinence clinique: La vaccination amorce-rappel avec le vaccin commercial BCoV peut être un outil de gestion important pour les troupeaux présentant des foyers connus de BCoV BRD.(Traduit par Dr Serge Messier).

IL-6 and TGF-ß-Secreting Adoptively-Transferred Murine Mesenchymal Stromal Cells Accelerate Healing of Psoriasis-like Skin Inflammation and Upregulate IL-17A and TGF-ß.

Mesenchymal stromal cells (MSC) show promise as cellular therapeutics. Psoriasis is a chronic inflammatory disease affecting the skin and the joints. Injury, trauma, infection and medications can trigger psoriasis by disrupting epidermal keratinocyte proliferation and differentiation, which activates the innate immune system. Pro-inflammatory cytokine secretion drives a T helper 17 response and an imbalance of regulatory T cells. We hypothesized that MSC adoptive cellular therapy could immunomodulate and suppress the effector T cell hyperactivation that underlies the disease. We used the imiquimod-induced psoriasis-like skin inflammation model to study the therapeutic potential of bone marrow and adipose tissue-derived MSC in vivo. We compared the secretome and the in vivo therapeutic potential of MSC with and without cytokine pre-challenge ("licensing"). The infusion of both unlicensed and licensed MSC accelerated the healing of psoriatic lesions, and reduced epidermal thickness and CD3+ T cell infiltration while promoting the upregulation of IL-17A and TGF-ß. Concomitantly, the expression of keratinocyte differentiation markers in the skin was decreased. However, unlicensed MSC promoted the resolution of skin inflammation more efficiently. We show that MSC adoptive therapy upregulates the transcription and secretion of pro-regenerative and immunomodulatory molecules in the psoriatic lesion. Accelerated healing is associated with the secretion of TGF-ß and IL-6 in the skin and MSC drives the production of IL-17A and restrains T-cell-mediated pathology.

Producer attitudes regarding antimicrobial use and resistance in Canadian cow-calf herds.

Objective: To describe producer attitudes toward antimicrobial use (AMU) and antimicrobial resistance (AMR), identify factors associated with attitudes, and inform stewardship initiatives. Animal: Beef cattle, cow-calf. Procedure: Cow-calf producers from the Canadian Cow-Calf Surveillance Network (C3SN) completed a survey (n = 146) on producers' attitudes toward AMU, AMR, and impacts of recent regulatory changes requiring a prescription for the purchase of medically important antimicrobials (MIA). Results: Most producers (78%, 114/146) reported being aware of initiatives to improve antimicrobial stewardship within the beef industry and 67% (97/146) indicated that AMR was a highly important issue to the industry and producers personally. Almost half of producers reported concerns that AMR development has impacted AMU decisions on their operations. Overall, veterinarians were producers' primary source of information regarding AMU, including treatment protocols, stewardship programs, and regulatory changes. Following introduction of the 2018 prescription-only regulations, 95% (138/146) of producers reported no change in AMU on their operations. Similarly, 77% (112/146) of producers reported no change in antimicrobial product access, whereas 63% (91/146) reported no change in cost. Conclusion: Most producers reported little change in access to antimicrobials and in AMU following the introduction of regulations requiring a prescription for MIA. Clinical relevance: Producers rely on veterinarians as their primary source of information regarding antimicrobial regulations and AMU. It is therefore important for veterinarians to understand their role as educators for beef cow-calf producers. Ultimately, veterinarians and producers need to work together to ensure that the health and welfare of animals are protected while using antimicrobials in a responsible manner.

Attitudes des producteurs à l'égard de l'utilisation des antimicrobiens et de la résistance dans les troupeaux vache-veau canadiens. Objectif: Décrire les attitudes des producteurs à l'égard de l'utilisation des antimicrobiens (AMU) et de la résistance aux antimicrobiens (RAM), identifier les facteurs associés à ces attitudes et les informations sur les initiatives de gouvernance. Animal: Bovins de boucherie, vache-veau. Procédure: Les producteurs naisseurs du Réseau canadien de surveillance vache-veau (C3SN) ont répondu à une enquête (n = 146) sur les attitudes des producteurs à l'égard de l'AMU, de la RAM et des impacts des récents changements réglementaires exigeant une ordonnance pour l'achat d'antimicrobiens médicalement importants (MIA). Résultats: La plupart des producteurs (78 %, 114/146) ont déclaré être au courant des initiatives visant à améliorer la gouvernance des antimicrobiens au sein de l'industrie du bœuf et 67 % (97/146) ont indiqué que la RAM était un problème très important pour l'industrie et les producteurs personnellement. Près de la moitié des producteurs ont fait part de leurs inquiétudes quant au fait que le développement de la RAM ait un impact sur les décisions d'AMU sur leurs opérations. Dans l'ensemble, les médecins vétérinaires étaient la principale source d'information des producteurs concernant l'AMU, y compris les protocoles de traitement, les programmes de gouvernance et les changements réglementaires. À la suite de l'introduction de la réglementation sur prescription uniquement en 2018, 95 % (138/146) des producteurs n'ont signalé aucun changement dans l'AMU de leurs opérations. De même, 77 % (112/146) des producteurs n'ont signalé aucun changement dans l'accès aux produits antimicrobiens, tandis que 63 % (91/146) n'ont signalé aucun changement dans le coût. Conclusion: La plupart des producteurs ont signalé peu de changements dans l'accès aux antimicrobiens et dans l'AMU par suite de l'introduction de réglementations exigeant une prescription pour le MIA. Pertinence clinique: Les producteurs comptent sur les médecins vétérinaires comme principale source d'information concernant la réglementation antimicrobienne et l'AMU. Il est donc important que les médecins vétérinaires comprennent leur rôle d'éducateurs auprès des producteurs de vaches-veaux de boucherie. En fin de compte, les médecins vétérinaires et les producteurs doivent travailler ensemble pour garantir la protection de la santé et du bien-être des animaux tout en utilisant les antimicrobiens de manière responsable.(Traduit par Dr Serge Messier).

Effects of naturally acquired gastrointestinal nematode infection on bovine viral diarrhea virus vaccine-directed antibody response in western Canadian feedlot cattle.

Objective: To determine how gastrointestinal nematode (GIN) infection, reflected by fecal egg counts and Ostertagia ostertagi serum antibody titers, is associated with the antibody response to bovine viral diarrhea virus type 1 (BVDV-1) vaccine antigen in fall-weaned feedlot cattle from western Canada. Animals: Cross-sectional study with 240 steer calves derived from an auction market. Procedure: At feedlot arrival, calves were given a commercial vaccine containing modified live BVDV-1. Serum neutralization antibody titers against BVDV-1 antigens were determined in individual blood samples collected pre-vaccination and 21 d after vaccination. A modified Wisconsin sugar floatation method was used to obtain individual calf GIN egg counts in fecal samples on arrival. Antibody titers against O. ostertagi were determined using an enzyme-linked immunosorbent assay in on-arrival blood samples. Results: Fecal egg counts and O. ostertagi titers were not associated with vaccine antibody-fold changes. Similarly, fecal egg counts and O. ostertagi titers were not associated with vaccine-induced seroconversion. Conclusions: The relatively low GIN burdens, reflected by the overall low fecal egg counts in these fall-weaned feedlot calves, did not have measurable adverse effects on the humoral immune response to BVDV-1 vaccine antigens. Clinical relevance: An adequate response to vaccination is important for cattle welfare and productivity. Conditions that negatively affect this response may vary regionally, such as GIN infection. Understanding this is essential. Although subclinical intestinal parasitism did not noticeably affect the antibody response in these steers, higher GIN burdens and actual immune protection from clinical disease remain to be investigated.

Effets d'une infection par des nématodes gastro-intestinaux d'origine naturelle sur la réponse en anticorps dirigés par le vaccin contre le virus de la diarrhée virale bovine chez les bovins des parcs d'engraissement de l'Ouest canadien. Objectif: Déterminer comment l'infection par les nématodes gastro-intestinaux (GIN), reflétée par le nombre d'oeufs fécaux et les titres d'anticorps sériques d'Ostertagia ostertagi, est associée à la réponse en anticorps à l'antigène du vaccin contre le virus de la diarrhée virale bovine de type 1 (BVDV-1) chez les bovins en parc d'engraissement sevrés à l'automne de l'Ouest canadien. Animaux: Étude transversale auprès de 240 veaux bouvillons issus d'un marché aux enchères. Procédure: À leur arrivée au parc d'engraissement, les veaux ont reçu un vaccin commercial contenant du BVDV-1 vivant modifié. Les titres d'anticorps sériques neutralisants contre les antigènes BVDV-1 ont été déterminés dans des échantillons de sang individuels prélevés avant la vaccination et 21 jours après la vaccination. Une méthode de Wisconsin modifiée de flottation au sucre a été utilisée pour obtenir le nombre d'oeufs GIN de chaque veau dans les échantillons fécaux à l'arrivée. Les titres d'anticorps dirigés contre O. ostertagi ont été déterminés à l'aide d'un dosage immuno-enzymatique dans des échantillons de sang à l'arrivée. Résultats: Le nombre d'oeufs fécaux et les titres d'O. ostertagi n'étaient pas associés aux modifications du titre d'anticorps vaccinaux. De même, le nombre d'oeufs fécaux et les titres d'O. ostertagi n'étaient pas associés à la séroconversion induite par le vaccin. Conclusion: Les charges relativement faibles de GIN, reflétées par le faible nombre global d'oeufs fécaux chez ces veaux d'engraissement sevrés à l'automne, n'ont pas eu d'effets indésirables mesurables sur la réponse immunitaire humorale aux antigènes du vaccin BVDV-1. Pertinence clinique: Une réponse adéquate à la vaccination est importante pour le bien-être et la productivité des bovins. Les conditions qui affectent négativement cette réponse peuvent varier selon les régions, telles que l'infection par les GIN. Comprendre cela est essentiel. Bien que le parasitisme intestinal subclinique n'ait pas sensiblement affecté la réponse en anticorps chez ces bouvillons, des charges de GIN plus élevées et une protection immunitaire réelle contre la maladie clinique restent à étudier.(Traduit par Dr Serge Messier).

A Variational Synthesis of Evolutionary and Developmental Dynamics.

This paper introduces a variational formulation of natural selection, paying special attention to the nature of 'things' and the way that different 'kinds' of 'things' are individuated from-and influence-each other. We use the Bayesian mechanics of particular partitions to understand how slow phylogenetic processes constrain-and are constrained by-fast, phenotypic processes. The main result is a formulation of adaptive fitness as a path integral of phenotypic fitness. Paths of least action, at the phenotypic and phylogenetic scales, can then be read as inference and learning processes, respectively. In this view, a phenotype actively infers the state of its econiche under a generative model, whose parameters are learned via natural (Bayesian model) selection. The ensuing variational synthesis features some unexpected aspects. Perhaps the most notable is that it is not possible to describe or model a population of conspecifics per se. Rather, it is necessary to consider populations of distinct natural kinds that influence each other. This paper is limited to a description of the mathematical apparatus and accompanying ideas. Subsequent work will use these methods for simulations and numerical analyses-and identify points of contact with related mathematical formulations of evolution.

Recruitment and retention of staff in rural dispensing practice.

INTRODUCTION: Rural General Practice (GP) surgeries often struggle to employ and retain multidisciplinary team members. Existing research into rural recruitment and retention issues is limited, and usually focussed on doctors. Rural practices often rely on income from dispensing medications; little is known about how maintaining dispensing services contributes to the recruitment and retention of staff. This study aimed to understand the barriers and facilitators to working and remaining in rural dispensing practices, and to explore how the primary care team value dispensing services. METHODS: We undertook semi-structured interviews with multidisciplinary team members of rural dispensing practices across England. Interviews were audio-recorded, transcribed and anonymised. Framework analysis was conducted using Nvivo 12. RESULTS: Seventeen staff members (including GPs, practice nurses, practice managers, dispensers and administrative staff) from 12 rural dispensing practices across England were interviewed. Personal and professional reasons for taking up a role in a rural dispensing practice included perceived career autonomy and development opportunities, and preference for working and living in a rural setting. Key factors impacting retention of staff included revenue generated by dispensing, opportunities for staff development, job satisfaction and the positive work environment. Perceived challenges to retention were the balancing of the required skillset of dispensing with the wages available for the role, lack of skilled job applicants, travel difficulties and negative perceptions of rural primary care practice. DISCUSSION: These findings will inform national policy and practice with the aim of providing further understanding of the drivers and challenges of working in rural dispensing primary care in England.

Comments on the articles dealing with individual performance criteria that are included in this special issue of Military Psychology.

Individual performance criterion measurement is central to effective personnel management in the military services, and to all other organizations as well. The articles in this special issue summarize the state of the art in all major phases of performance criterion development and assessment. The overall record, while it varies in terms of current progress across the major parts, is admirable. What's next is an equally thorough examination of the utility of validity.