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IntroductionCardiovascular disease (CVD) surveillance in Quebec and the rest of Canada is carried out using health administrative databases, which in Quebec includes the physician claims database. The presence of billing claims without diagnoses can lead to the number of CVD cases being underestimated. The purpose of this study is to estimate the proportion of CVD diagnoses and CVD cases that may be missing from these databases. MethodsThe study was conducted using a prospective cohort of 8781 participants living in the Québec City area. Access to health administrative databases was granted for the entire 28-year follow-up period. First, we performed frequency analyses to estimate the proportion of missing CVD diagnoses. Then we used validated algorithms to identify CVD cases and estimate the proportion of CVD cases that were potentially not captured over the 28-year period. ResultsAbout one-fifth (22.1%) of the diagnoses in the physician claims database were missing. The proportion of missing CVD cases was estimated at 12.7% for 1991–2018, although this varied with the period covered (1991–1996: 15.5%; 1997–2013: 10.7%; and 2014–2018: 16.3%). ConclusionApproximatively 1 in 10 CVD cases are not identified due to a missing diagnosis. This underestimation of CVD cases is a potential limitation that should be considered when using Quebec health administrative databases to identify CVD cases for surveillance work and epidemiological studies.

IntroductionLa surveillance des maladies cardiovasculaires (MCV) au Québec et dans le reste du Canada est effectuée à l’aide de fichiers médico-administratifs, parmi lesquels on retrouve, au Québec, le fichier des services médicaux rémunérés à l’acte. La présence d’actes facturés sans diagnostic peut entraîner une sous-estimation du nombre de cas de MCV. L’objectif de cette étude est d’estimer la proportion de diagnostics de MCV et de cas de MCV possiblement manquants dans ces fichiers. MéthodologieL’étude a été réalisée en utilisant une cohorte prospective comprenant 8 781 participants de la région de Québec. L'accès aux fichiers médico-administratifs a été obtenu pour l’ensemble des 28 années de suivi. Nous avons d’abord effectué des analyses de fréquence afin d’estimer la proportion de diagnostics de MCV manquants. Nous avons ensuite utilisé des algorithmes validés afin d’identifier les cas de MCV et d’estimer la proportion de cas de MCV possiblement manquants sur 28 ans. RésultatsEnviron un cinquième (22,1 %) des diagnostics du fichier des services médicaux rémunérés à l’acte était manquant. La proportion de cas de MCV manquants a été estimée à 12,7 % pour la période 1991-2018, avec des variations selon la période (1991-1996 : 15,5 %; 1997-2013 : 10,7 %; 2014-2018 : 16,3 %). ConclusionEnviron 1 cas de MCV sur 10 n’est pas identifié en raison des diagnostics manquants. Cette sous-estimation constitue une limite potentielle dont il faut tenir compte lors de l’utilisation des fichiers médico-administratifs québécois pour l’identification des cas de MCV dans un contexte de travaux de surveillance et d’études épidémiologiques.

ABSTRACT: In this study, the main objective was to assess if long luteal phases could have causes other than pregnancy loss. We enrolled Holstein dairy cows ≥50 DIM from a commercial herd in Brazil from October 2016 to August 2017. All cows received an estradiol-based synchronization protocol, and, on the day of insemination (d 0), were randomly assigned either an AI or a placebo insemination (PBO) in a 3:1 ratio. An ultrasound was used to assess the presence of a corpus luteum (CL) on d 17, 24, and 31, which, combined to the information from patches for the detection of estrus, was used to determine the length of the luteal phase following AI or PBO. Pregnancy was assessed by ultrasound on d 31 and cows that were pregnant were excluded from the analyses. The length of the estrous cycles was categorized as short (

Abstract Despite the importance of cellular senescence in human health, how damaged cells undergo senescence remains elusive. We have previously shown that promyelocytic leukemia nuclear body (PML-NBs) translocation of the ciliary FBF1 is essential for senescence induction in stressed cells. Here we discover that an early cellular event occurring in stressed cells is the transient assembly of stress-induced nucleus-to-cilium microtubule arrays (sinc-MTs). The sinc-MTs are distinguished by unusual polyglutamylation and unique polarity, with minus-ends nucleating near the nuclear envelope and plus-ends near the ciliary base. KIFC3, a minus-end-directed kinesin, is recruited to plus-ends of sinc-MTs and interacts with the centrosomal protein CENEXIN1. In damaged cells, CENEXIN1 co-translocates with FBF1 to PML-NBs. Deficiency of KIFC3 abolishes PML-NB translocation of FBF1 and CENEXIN1, as well as senescence initiation in damaged cells. Our study reveals that KIFC3-mediated nuclear transport of FBF1 along polyglutamylated sinc-MTs is a prerequisite for senescence induction in mammalian cells.

ABSTRACT: The objective of this cross-sectional study was to estimate the validity of laboratory culture, Petrifilm and Tri-Plate on-farm culture systems, as well as luminometry to correctly identify IMI at dry-off in dairy cows, considering all tests to be imperfect. From September 2020 until December 2021, we collected composite milk samples from cows before dry-off and divided them into 4 aliquots for luminometry, Petrifilm (aerobic count), Tri-Plate, and laboratory culture tests. We assessed multiple thresholds of relative light units (RLU) for luminometry, and we used thresholds of ≥100 cfu/mL for the laboratory culture, ≥50 cfu/mL for Petrifilm, and ≥1 cfu for Tri-Plate tests. We fitted Bayesian latent class analysis models to estimate the sensitivity (Se) and specificity (Sp) for each test to identify IMI, with 95% credibility interval (BCI). Using different prevalence measures (0.30, 0.50, and 0.70), we calculated the predictive values (PV) and misclassification cost terms (MCT) at different false negative-to-false-positive ratios (FN:FP). A total of 333 cows were enrolled in the study from one commercial Holstein herd. The validity of the luminometry was poor for all thresholds, with an Se of 0.51 (95% BCI = 0.43–0.59) and Sp of 0.38 (95% BCI = 0.26–0.50) when using a threshold of ≥150 RLU. The laboratory culture had an Se of 0.93 (95% BCI = 0.85–0.98) and Sp of 0.69 (95% BCI = 0.49–0.89); the Petrifilm had an Se of 0.91 (95% BCI = 0.80–0.98) and Sp of 0.71 (95% BCI = 0.51–0.90); and the Tri-Plate had an Se of 0.65 (95% BCI = 0.53–0.82) and Sp of 0.85 (95% BCI = 0.66–0.97). Bacteriological tests had good PV, with comparable positive PV for all 3 tests, but lower negative PV for the Tri-Plate compared with the laboratory culture and the Petrifilm. For a prevalence of IMI of 0.30, all 3 tests had similar MCT, but for prevalence of 0.50 and 0.70, the Tri-Plate had higher MCT in scenarios where leaving a cow with IMI untreated is considered to have greater detrimental effects than treating a healthy cow (i.e., FN:FP of 3:1). Our results showed that the bacteriological tests have adequate validity to diagnose IMI at dry-off, but luminometry does not. We concluded that although luminometry is not useful to identify IMI at dry-off, the Petrifilm and Tri-Plate tests performed similarly to laboratory culture, depending on the prevalence and importance of the FP and FN results.

PURPOSE: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy. EXPERIMENTAL DESIGN: We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia. RESULTS: Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL. CONCLUSIONS: Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.

Abstract Background The primary objective of this cross-sectional study, conducted in Québec and Bristish Columbia (Canada) between February 2021 and January 2022, was to measure the prevalence of viral RNA in oronasal and rectal swabs and serum antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) amongst cats living in households with at least one confirmed human case. Secondary objectives included a description of potential risk factors for the presence of SARS-CoV-2 antibodies and an estimation of the association between the presence of viral RNA in swabs as well as SARS-CoV-2 antibodies and clinical signs. Oronasal and rectal swabs and sera were collected from 55 cats from 40 households at most 15 days after a human case confirmation, and at up to two follow-up visits. A RT-qPCR assay and an ELISA were used to detect SARS-CoV-2 RNA in swabs and serum SARS-CoV-2 IgG antibodies, respectively. Prevalence and 95% Bayesian credibility intervals (BCI) were calculated, and associations were evaluated using prevalence ratio and 95% BCI obtained from Bayesian mixed log-binomial models. Results Nine (0.16; 95% BCI = 0.08–0.28) and 38 (0.69; 95% BCI = 0.56–0.80) cats had at least one positive RT-qPCR and at least one positive serological test result, respectively. No risk factor was associated with the prevalence of SARS-CoV-2 serum antibodies. The prevalence of clinical signs suggestive of COVID-19 in cats, mainly sneezing, was 2.12 (95% BCI = 1.03–3.98) times higher amongst cats with detectable viral RNA compared to those without. Conclusions We showed that cats develop antibodies to SARS-CoV-2 when exposed to recent human cases, but detection of viral RNA on swabs is rare, even when sampling occurs soon after confirmation of a human case. Moreover, cats with detectable levels of virus showed clinical signs more often than cats without signs, which can be useful for the management of such cases.

Abstract Cities concentrate problems that affect human well-being and biodiversity. Exploring the link between mental health and biodiversity can inform more holistic public health and urban planning. Here we examined associations between bird and tree species diversity estimates from eBird community science datasets and national forest inventories with self-rated mental health metrics from the Canadian Community Health Survey. We linked data across 36 Canadian Metropolitan Areas from 2007-2022 at a postal code level. After controlling for covariates, we found that bird and tree species diversity were significantly positively related to good self-reported mental health. Living in a postal code with bird diversity one standard deviation higher than the mean increased reporting of good mental health by 6.64%. Postal codes with tree species richness one standard deviation more than the mean increased reporting of good mental health by 5.36%. Our results suggest that supporting healthy urban ecosystems may also benefit human well-being.

Problem, research strategy, and findingsThe 1968 Fair Housing Act required local government recipients of federal money to take meaningful actions to affirmatively further fair housing (AFFH). Current fair housing analysis requirements are copious but do not request an assessment of how land use policies affect the potential for neighborhood integration. A recent California law requires local governments to include AFFH analysis in existing planning processes, and state guidelines encourage the measurement of the spatial distribution of planned sites for low-income housing with respect to opportunity. We propose and evaluate a fair housing land use score (FHLUS) that measures whether local governments’ land use policies promote inclusion across neighborhoods. We illustrate the FHLUS by examining zoning and housing plans for three municipalities in California that differ in terms of neighborhood variation in incomes. In all three cases, we found that municipal zoning and housing plans exacerbated patterns of segregation rather than reversed them. Our metric is more precise than existing approaches, but all measures of this phenomenon will be less useful in smaller, more homogenous jurisdictions. The analysis raises important questions about the geographic scale and outcome measures for AFFH analysis and expectations for municipalities of different sizes and levels of diversity. Takeaway for practiceOur metric is a useful tool for advocates and planners at all levels of government. We recommend the federal government consider incorporating it into the AFFH toolkit and practicing planners employ the measure to analyze local zoning and investment decisions. The Technical Appendix is a step-by-step guide, including an Excel formula.

BackgroundSurvivors of critical illness are at risk of developing physical dysfunction following intensive care unit (ICU) discharge. ICU-based rehabilitation interventions, such as early in-bed cycle ergometry, may improve patients’ short-term physical function. ObjectiveBefore unblinding and trial database lock, we describe a prespecified statistical analysis plan (SAP) for the CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) randomized controlled trial (RCT). MethodsCYCLE is a 360-patient, international, multicenter, open-label, parallel-group RCT (1:1 ratio) with blinded primary outcome assessment at 3 days post-ICU discharge. The principal investigator and statisticians of CYCLE prepared this SAP with approval from the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes (including adverse events) and describes the planned primary, secondary, and subgroup analyses. The primary outcome of the CYCLE trial is the Physical Function Intensive Care Unit Test-scored (PFIT-s) at 3 days post-ICU discharge. The PFIT-s is a reliable and valid performance-based measure. We plan to use a frequentist statistical framework for all analyses. We will conduct a linear regression to evaluate the primary outcome, incorporating randomization as an independent variable and adjusting for age (≥65 years versus

ABSTRACT Background Immune stressors, such as lipopolysaccharides (LPS), profoundly affect microbiota balance, leading to gut dysbiosis. This imbalance disrupts the metabolic phenotype and structural integrity of the gut, increasing intestinal permeability. During puberty, a critical surge in estrogen levels is crucial for mammary gland development. However, inflammation originating from the gut in this period may interfere with this development, potentially heightening breast cancer risk later. The long‐term effects of pubertal inflammation on mammary development and breast cancer risk are underexplored. Such episodes can dysregulate cytokine levels and microRNA expression, altering mammary cell gene expression, and predisposing them to tumorigenesis. Methods This study hypothesizes that prebiotics, specifically Lentinula edodes Cultured Extract (AHCC), can counteract LPS's adverse effects. Using BALB/c mice, an acute LPS dose was administered at puberty, and breast cancer predisposition was assessed at 13 weeks. Cytokine and tumor‐related microRNA levels, tumor development, and cancer stem cells were explored through immunoassays and qRT‐PCR. Results Results show that LPS induces lasting effects on cytokine and microRNA expression in mammary glands and tumors. AHCC modulates cytokine expression, including IL‐1β, IL‐17A/F, and IL‐23, and mitigates LPS‐induced IL‐6 in mammary glands. It also regulates microRNA expression linked to tumor progression and suppression, particularly counteracting the upregulation of oncogenic miR‐21, miR‐92, and miR‐155. Although AHCC slightly alters some tumor‐suppressive microRNAs, these changes are modest, highlighting a complex regulatory role that warrants further study. Conclusion These findings underscore the potential of dietary interventions like AHCC to mitigate pubertal LPS‐induced inflammation on mammary gland development and tumor formation, suggesting a preventive strategy against breast cancer.

The objectives of this herd-level prospective observational cohort study were to describe the proportion of cows with elevated prepartum nonesterified fatty acid concentrations (PropElevNEFA) in dairy herds and to assess the herd-level associations between PropElevNEFA and postpartum diseases, reproductive performance, and culling. From November 2018 to December 2020, a convenience sample of 49 herds was enrolled in this study. Blood sampling (16 to 29 cows per herd) was performed during the week before and during the 2 wk following calving to quantify the concentration of nonesterified fatty acids (NEFA) and β-hydroxybutyrate acids (BHBA), respectively. Elevated NEFA was defined as ≥280 µmol/L and hyperketonemia as BHBA ≥1.4 mmol/L. Retained placenta, metritis, purulent vaginal discharge, endometritis, and mastitis were diagnosed on-farm following standardized definitions, and success at first artificial insemination (AI) and culling events were recorded. The associations between PropElevNEFA and each individual disease, success at first AI, and culling were evaluated using Bayesian aggregated binomial regression models with weakly informative priors, from the which odds ratio (OR) and the 95% credible intervals (BCI) were obtained. A total of 981 cows were included in the statistical analyses representing 16 to 29 (median = 19) cows per herd. Cows were enrolled in the prepartum period of their first to tenth (median = third) lactation, and 41% of them had an elevated prepartum NEFA concentration. At the herd level, PropElevNEFA varied between 11% and 78% (median = 39%). The odds of metritis (OR = 1.37, 95% BCI = 1.13–1.67) increased for every 10-point increase in PropElevNEFA, whereas the odds of success at first AI decreased (OR = 0.69, 95% BCI = 0.59–0.80). The PropElevNEFA was not associated with the other tested diseases or culling. Our results suggest that the herd-level proportion of cows having elevated prepartum NEFA concentrations is associated with metritis and poor success at first AI in dairy herds.

A recent measure was developed to assess the Quality of Life (QoL) of young people with advanced cancer and is available for parents and professionals (Advance QoL). The present study aimed to elaborate self-reported versions for children and adolescents with advanced cancer. We adopted a four-phase research plan: (1) to elaborate the Advance QoL questionnaire for youth (8–12 and 13–18 years old) with a team of young research partners; (2) to evaluate the understandability of these versions in a sample of 12 young patients from the target population using cognitive interviews; (3) to assess social validity in the same group using a questionnaire and the content validity index (CVI); and (4) to refine the questionnaires according to these results. Four major themes were identified: (1) issues affecting the understanding of the tool; (2) issues that did not affect the understanding of the tool; (3) modifications to improve the tool; and (4) positive features of the tool. Advance QoL was well received, and feedback was positive. Adjustments were made according to young people’s comments and two self-reported versions are now available. It is essential to measure the key domains of QoL in advanced cancer. Advance QoL self-report versions will help target the specific needs of young people with this condition and their families.

Abstract Background With increased attention to the importance of integrating the One Health approach into zoonotic disease surveillance and response, a greater understanding of the mechanisms to support effective communication and information sharing across animal and human health sectors is needed. The objectives of this qualitative case study were to describe the communication channels used between human and animal health stakeholders and to identify the elements that have enabled the integration of the One Health approach. Methods We combined documentary research with interviews with fifteen stakeholders to map the communication channels used in human and swine influenza surveillance in Alberta, Canada, as well as in the response to a human case of H1N2v in 2020. A thematic analysis of the interviews was also used to identify the barriers and facilitators to communication among stakeholders from the animal and human health sectors. Results When a human case of swine influenza emerged, the response led by the provincial Chief Medical Officer of Health involved players at various levels of government and in the human and animal health sectors. The collaboration of public and animal health laboratories and of the swine sector, in addition to the information available through the surveillance systems in place, was swift and effective. Elements identified as enabling smooth communication between the human and animal health systems included preexisting relationships between the various stakeholders, a relationship of trust between them (e.g., the swine sector and their perception of government structures), the presence of stakeholders acting as permanent liaisons between the ministries of health and agriculture, and stakeholders' understanding of the importance of the One Health approach. Conclusions Information flows through formal and informal channels and both structural and relational features that can support rapid and effective communication in infectious disease surveillance and outbreak response.

Abstract Introduction Despite older adults being more vulnerable to sepsis, most preclinical research on sepsis has been conducted using young animals. This results in decreased scientific validity since age is an independent predictor of poor outcome. In this study, we explored the impact of aging on the host response to sepsis using the fecal-induced peritonitis (FIP) model developed by the National Preclinical Sepsis Platform (NPSP). Methods C57BL/6 mice (3 or 12 months old) were injected intraperitoneally with rat fecal slurry (0.75 mg/g) or a control vehicle. To investigate the early stage of sepsis, mice were culled at 4 h, 8 h, or 12 h to investigate disease severity, immunothrombosis biomarkers, and organ injury. Mice received buprenorphine at 4 h post-FIP. A separate cohort of FIP mice were studied for 72 h (with buprenorphine given at 4 h, 12 h, and then every 12 h post-FIP and antibiotics/fluids starting at 12 h post-FIP). Organs were harvested, plasma levels of Interleukin (IL)-6, IL-10, monocyte chemoattract protein (MCP-1)/CCL2, thrombin-antithrombin (TAT) complexes, cell-free DNA (CFDNA), and ADAMTS13 activity were quantified, and bacterial loads were measured. Results In the 12 h time course study, aged FIP mice demonstrated increased inflammation and injury to the lungs compared to young FIP mice. In the 72 h study, aged FIP mice exhibited a higher mortality rate (89%) compared to young FIP mice (42%) (p