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Background: There exist few maximal oxygen uptake (VO2max) non-exercise-based prediction equations, fewer using machine learning (ML), and none specifically for older adults. Since direct measurement of VO2max is infeasible in large epidemiologic cohort studies, we sought to develop, validate, compare, and assess the transportability of several ML VO2max prediction algorithms. Methods: The Baltimore Longitudinal Study of Aging (BLSA) participants with valid VO2max tests were included (n = 1080). Least absolute shrinkage and selection operator, linear- and tree-boosted extreme gradient boosting, random forest, and support vector machine (SVM) algorithms were trained to predict VO2max values. We developed these algorithms for: (a) the overall BLSA, (b) by sex, (c) using all BLSA variables, and (d) variables common in aging cohorts. Finally, we quantified the associations between measured and predicted VO2max and mortality. Results: The age was 69.0 ± 10.4 years (mean ± SD) and the measured VO2max was 21.6 ± 5.9 mL/kg/min. Least absolute shrinkage and selection operator, linear- and tree-boosted extreme gradient boosting, random forest, and support vector machine yielded root mean squared errors of 3.4 mL/kg/min, 3.6 mL/kg/min, 3.4 mL/kg/min, 3.6 mL/kg/min, and 3.5 mL/kg/min, respectively. Incremental quartiles of measured VO2max showed an inverse gradient in mortality risk. Predicted VO2max variables yielded similar effect estimates but were not robust to adjustment. Conclusion: Measured VO2max is a strong predictor of mortality. Using ML can improve the accuracy of prediction as compared to simpler approaches but estimates of association with mortality remain sensitive to adjustment. Future studies should seek to reproduce these results so that VO2max, an important vital sign, can be more broadly studied as a modifiable target for promoting functional resiliency and healthy aging.

Zebrafish (Danio rerio) are a good model for cancer research including studies on chemotherapy treatments. We treated wild-type and miR-34a deletion mutant zebrafish embryos at 24 h post-fertilization with 1 µM of the topoisomerase I inhibitor, camptothecin (CPT), for 4 h to catalogue gene expression changes induced by this DNA damage treatment and to understand if these changes are influenced by loss of miR-34a. The 4 sample groups of 3 independent biological samples consisting of 30 embryos each were analyzed by RNA-sequencing using the recently updated zebrafish transcriptome annotation based on GRCz11, which enabled a more complete and sensitive read mapping and gene assignment than standard annotations. Using this gene expression estimates dataset as the primary resource, we performed a differentially expressed gene (DEG) analysis based on treatment as loss of miR-34a had minimal effects on CPT-induced expression changes. The DEGs were analyzed for Gene Ontology and KEGG pathway terms. Enriched terms and pathways among up-regulated genes were mostly related to stress, cell death, cell cycle regulation, transcriptional regulation, cell signalling, developmental processes and synthesis of retinol and steroid hormones. By contrast, down-regulated genes were most strongly associated with genes involved in key developmental processes, adhesion molecules, as well as some transport and metabolic pathways, together suggesting a “developmental shutdown”. We also identified interferon-regulated genes and p53 target genes activated or inhibited by DNA damage due to topoisomerase I inhibition, suggesting that they are important components of the response to this type of DNA damage in zebrafish embryos.

The aim of this study was to identify the impact of staging on a six-months transition in Ultra-High Risk (UHR) youth.Subjects were enrolled at assessment; evolution was monitored for six months. Clinical determinants (unusual thought content, perceptual abnormalities, cognitive complaint, etc.) were collected.37 non-psychotic and 39 UHR subjects were included. 13 UHR (35.2 %) experienced psychotic transition, while none of non-psychotic subjects did log-rank p

Objective: The American Heart Association’s Life’s Essential 8 (LE8) metric includes self-reported physical activity as one of the metrics for assessing cardiovascular health. Self-reported physical activity is prone to misclassification, whereas accelerometer measures are less biased. We examined associations of LE8 and incident cardiovascular disease (CVD) using self-reported and accelerometer-measured physical activity. Methods: Participants in the Women’s Health Initiative (WHI) Objective Physical Activity and Cardiovascular Health Study (n = 4,243; mean age = 79 ± 7 years) with no CVD history completed the WHI physical activity questionnaire and the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire prior to wearing a hip-worn accelerometer for up to seven days in 2012–2014. LE8 components (physical activity, diet, sleep, body mass index, smoking, blood pressure, non-HDL cholesterol, and glucose) were scored according to guidelines. Scores were created using five physical activity measures: WHI questionnaire (LE8WHI), CHAMPS (LE8CHAMPS), accelerometer-measured physical activity (LE8A), and sample quantiles of accelerometer-measured physical activity (LE8AQ) and daily steps (LE8STEPS). Hazard ratios (HR) for physician-adjudicated CVD were estimated using Cox regression. Results: 707 incident CVD events occurred over an average 7.5 years. Multivariable HRs (95 % CI) comparing women in the highest vs. lowest quartiles of LE8 scores were: LE8WHI = 0.53 (0.43–0.67), LE8CHAMPS = 0.47 (0.38–0.60), LE8A = 0.44 (0.36–0.56), LE8AQ = 0.44 (0.35–0.55), and LE8STEPS = 0.45 (0.35–0.57). Conclusions: The LE8-incident CVD association varies by physical activity measurement, however all methods showed reduced risk. Device-measures of physical activity may be more accurate in the LE8, but when impractical to implement, also support use of self-reported measures.

Background: Alcohol use disorders (AUDs) are complex pathologies with a myriad of molecular actors involved in both disease progression and remission. Brain-derived neurotrophic factor (BDNF) is suspected to be one such actor due to its neurotrophic effects. The BDNF precursor, pro-BDNF, has different effects, as it mainly promotes neuronal apoptosis. Both forms also play a role in depression and depressive episodes (DE). The aim of this exploratory study was to compare serum BDNF and pro-BDNF levels in patients with AUDs after withdrawal and according to DE status with those of controls without AUDs or DE. Materials and methods: Ninety-nine AUD patients and 40 controls were included. Questionnaires were used to assess both alcohol and psychiatric domains: the severity of hazardous alcohol consumption was assessed using Alcohol Use Disorders Identification Test (AUDIT), craving was assessed using Obsessive and Compulsive Drinking Scale (OCDS), anxiety was assessed with Hamilton Anxiety Rating Scale (HAM-A) and depression with Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected during two visits: at the time of alcohol withdrawal (M0) and two months later (M2). ELISAs to measure serum BDNF and pro-BDNF levels were performed. AUD patients were categorized according to depression status at M2. Forty-five patients remained abstinent whereas 54 relapsed. BDNF serum levels rose after alcohol withdrawal, but pro-BDNF levels did not vary between M0 and M2. Results: AUD subjects without DE at M2 had higher BDNF levels at both M0 and M2 than AUD subjects with DE at M2. AUD subjects showed lower MADRS and OCD scores at M2 than at M0. AUD subjects without DE had lower BDNF levels at M0 than controls but not at M2, regardless of abstinence maintenance. Conclusion: BDNF serum levels were reduced in AUD patients compared to controls and were further reduced in patients with both AUDs and DE. Alcohol withdrawal treatment was sufficient to induce an increase in serum BDNF levels after 2 months, regardless of whether abstinence was maintained during this time period.

Background: The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has become one of the biggest health problems due to the lack of knowledge about effective therapy. Purpose: Some scientific studies have shown that essential oils (EOs) have anti-inflammatory, immunomodulatory, and antiviral properties. Study design: This study demonstrated the potential antiviral activity of EOs in emulsion and in vapor forms to reduce the replication of MHV-A59, a murine surrogate of SARS-CoV-2. Methods: In the present study, 32 EOs were screened in vitro against MHV-A59 on DBT cells using plaque assay. EOs in emulsions were applied at their maximum noncytotoxic concentrations to MHV-A59 after penetration of the viruses into the host cells for 1 h during intracellular virus replication. Results: Monarda didyma at 5000 µg/ml showed a reduction of 100% of viral plaque. Tanacetum annuum at 10000 µg/ml inhibited 5.03-log MHV-A59. Beyond 4-log, the drug can be qualified as an antiviral according to the guidelines of ICH. In vapor form, none of the EOs showed potential inhibitory effects against MHV-A59. Conclusion: Results demonstrated that all 32 undiluted EOs, incubated with MHV-A59 for 30 min, had a ≤1.09-log inactivation compared to an untreated virus. The findings of this study may provide proof-of-concept and insight into related trials.

Objective: To evaluate the association between shift-level organizational data (unit occupancy, nursing overtime ratios [OTRs], and nursing provision ratios [NPRs]) with nosocomial infection (NI) among infants born very preterm in the neonatal intensive care unit (NICU). Study design: This was a multicenter, retrospective cohort study, including 1921 infants 230/7-326/7 weeks of gestation admitted to 3 tertiary-level NICUs in Quebec between 2014 and 2018. Patient characteristics and outcomes (NIs) were obtained from the Canadian Neonatal Network database and linked to administrative data. For each shift, unit occupancy (occupied/total beds), OTR (nursing overtime hours/total nursing hours), and NPR (number of actual/number of recommended nurses) were calculated. Mixed-effect logistic regression models were used to calculate aOR for the association of organizational factors (mean over 3 days) with the risk of NI on the following day for each infant. Results: Rate of NI was 11.5% (220/1921). Overall, median occupancy was 88.7% [IQR 81.0-94.6], OTR 4.4% [IQR 1.5-7.6], and NPR 101.1% [IQR 85.5-125.1]. A greater 3-day mean OTR was associated with greater odds of NI (aOR 1.08, 95% CI 1.02-1.15), a greater 3-day mean NPR was associated lower odds of NI (aOR 0.96, 95% CI 0.95-0.98), and occupancy was not associated with NI (aOR, 0.99, 95% CI 0.96-1.02). These findings were consistent across multiple sensitivity analyses. Conclusions: Nursing overtime and nursing provision are associated with the adjusted odds of NI among infants born very preterm in the NICU. Further interventional research is needed to infer causality.

Selecting and raising dairy animals that are more likely to reach their potential is a strategy to increase milk production efficiency and overall profitability. However, indicators are necessary for the early identification of animals that are less likely to perform well, allowing for their early culling and ensuring that resources are allocated to those with the highest potential. The objective of this study was to analyze the association between early-life animal health and performance with longevity, production, and profitability. After data cleaning, the following early-life measures (i.e., predictors) were available for 363 female calves born between June 2014 and November 2015 in eight dairy herds from New Brunswick, Canada (average: 45 calves/farm; SD: 26.1 calves/farm; median: 42 calves/farm; range: 15–95 calves/farm): birth weight, weaning weight, weaning age, weaning average daily gain (weaning ADG), immunoglobulin G (IgG) serum concentration, the occurrence of navel infection, diarrhea, and pneumonia, and if animals received antibiotic treatment between birth and weaning. Their subsequent length of life (LL), length of productive life (LPL), lifetime cumulative energy-corrected milk (ECM), and lifetime cumulative milk value (i.e., response variables) were provided by the Canadian dairy herd improvement agency. Bayesian Additive Regression Tree models were trained for each response variable using 5-fold cross-validation. Models were evaluated using the RMSE and R2. The three most important predictors were identified using permutation, and the relationship between response variables and important predictors was assessed using accumulated local effect plots. The RMSE for LL, LPL, ECM, and milk value were 1.43 years, 1.37 years, 16 314.94 kg, and $CAD 11 525.68, respectively, whereas the R2 values were 0.30, 0.25, 0.29, and 0.29, respectively, indicating a moderate relationship between predictors and response variables. Non-linear relationships were found between the response variables and important predictors. Animals born with low or high birth weights were associated with decreased LL, LPL, ECM, and milk value. The highest LL, LPL, and milk value was observed for calves weaned between 1.9 and 2.0 months old, followed by a decline for calves weaned at older ages. The lowest LL and ECM were associated with weaning ADG of 0.786 kg/day, while 0.787 kg/day was associated with the lowest LPL. Lastly, both ECM and milk value were highest when serum IgG values were 1 659 mg/dL. These findings provide valuable insights for optimizing early culling decisions and enhancing the productivity and profitability of dairy farms.

Objective: To evaluate the rate of loss to follow-up in a cochlear implant program from the public health system in Southern Brazil as well as the characteristics of hearing loss, sociodemographic, sociocultural and the development of oral language in children with prelingual deafness. Methods: Retrospective cohort study with children who underwent CI surgery between 2010 and 2020. Data was collected through of interviews and review of medical records. The language development assessment was performed using the MUSS, MAIS and IT-MAIS scales. For the classification of language development, we used as parameters the values (mean ± SD) found in a previous national study. From those values, the Z-score for each patient at each hearing age (time of experience with the cochlear implant) was calculated. Results: Of the 225 children implanted between 2010–2020, 129 were included in this study. The rate of loss to follow-up in the program was 42.6%. The mean age at first surgery was 40.5 (±16.9) months, with 77.5% of patients having received a unilateral implant. Language results below the expected for hearing age (

Background: Traditionally, transforaminal steroid injection is performed in the management of cervical radiculopathy in medical failure treatment but carried a true risk of catastrophic complication. Another approach currently used is to perform intra-articular facet steroid injection to reach the epidural space. Purpose: The aim of this study was to describe the evolution of symptoms following intra-articular facet steroid injection in cervical radiculopathy. Material and methods: We conducted a retrospective study. We assessed all patients who had a CT-guided intra-articular facet steroid injection in our center (xx, xx, xx) from December 2015 to February 2021. Cervical MR pretherapeutic images were analyzed and classified according to cervical pain etiology: uncodiscarthrosis, disk herniation or congestive cervical posterior osteo-arthritis. All patients had clinical initial evaluation and then follow-up at 1 and 6 months. Pain severity was rated on a visual analog scale and expressed as a percentage of improvement. Results: Ninety-three patients were included. There were 56 patients with uncodiscarthrosis, 29 with a disk herniation and 8 with a cervical posterior congestive osteoarthritis. A significant improvement of the visual analog scale percentage was found for all patient at 1 and 6 months (p < 0.01). Visual analog scale percentage improvement was about 50 % for all etiologies. For all patients, no severe complications were reported. Conclusion: Intra-articular facet steroid injection may be considered for the treatment of cervical radiculopathy when other medical treatments have failed.

Summary: Background: Circadian rhythms regulate cellular physiology and could influence the efficacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271). Methods: 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00–11:59 (morning), 12:00–17:59 (afternoon), 18:00–23:59 (evening), or 24:00–05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial and the results of this observational study are reported here. Findings: ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n = 465, 54.4%) or afternoon (n = 45, 5.4%) ET intake were older than those declaring evening (n = 339, 39.6%) or nighttime (n = 5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n = 30) or metastasis relapse (n = 84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR = 0.77, 95% CI [0.53–1.12]). The association between ET intake timing and DFS according to the stratification factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR = 0.43, 95% CI [0.22–0.85]), while no association was found for AI intake (HR = 1.07, 95% CI [0.68–1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR = 0.38 [0.16–0.91]). Interpretation: Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies. Funding: UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis.

Breast cancer is the most common female cancer in the world. Numerous studies have shown that the risk of metastatic disease increases with tumor volume. In this context, it is useful to assess whether the regular practice of formal breast self-examination (BSE) as opposed to breast awareness has an impact on the number of cancers diagnosed, their stage, the treatments used and mortality. Design: The Commission of Senology (CS) of the Collège National de Gynécologie et Obstétrique Français (CNGOF) respected and followed the Grading of Recommendations Assessment, Development and Evaluation method to assess the quality of the evidence on which the recommendations were based. Methods: The CS studied 16 questions individualizing four groups of women (general population, women aged over 75, high-risk women, and women previously treated for breast cancer). For each situation, it was determined whether the practice of BSE versus abstention from this examination led to detection of more breast cancers and/or recurrences and/or reduced treatment and/or increased survival. Results: BSE should not be recommended for women in the general population, who otherwise benefit from clinical breast examination by practitioners from the age of 25, and from organized screening from 50 to 74 (strong recommendation). In the absence of data on the benefits of BSE in patients aged over 75, for those at high risk and those previously treated for breast cancer, the CS was unable to issue recommendations. Thus, if women in these categories wish to undergo BSE, information on the benefits and risks observed in the general population must be given, notably that BSE is associated with a higher number of referrals, biopsies, and a reduced quality of life.

Objective: This study aimed to determine whether or not transfusion of fresh red blood cells (RBCs) reduced the incidence of new or progressive multiple organ dysfunction syndrome compared with standard-issue RBCs in pediatric patients undergoing cardiac surgery. Methods: Preplanned secondary analysis of the Age of Blood in Children in Pediatric Intensive Care Unit study, an international randomized controlled trial. This study included children enrolled in the Age of Blood in Children in Pediatric Intensive Care Unit trial and admitted to a pediatric intensive care unit after cardiac surgery with cardiopulmonary bypass. Patients were randomized to receive either fresh (stored ≤7 days) or standard-issue RBCs. The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured up to 28 days postrandomization or at pediatric intensive care unit discharge, or death. Results: One hundred seventy-eight patients (median age, 0.6 years; interquartile range, 0.3-2.6 years) were included with 89 patients randomized to the fresh RBCs group (median length of storage, 5 days; interquartile range, 4-6 days) and 89 to the standard-issue RBCs group (median length of storage, 18 days; interquartile range, 13-22 days). There were no statistically significant differences in new or progressive multiple organ dysfunction syndrome between fresh (43 out of 89 [48.3%]) and standard-issue RBCs groups (38 out of 88 [43.2%]), with a relative risk of 1.12 (95% CI, 0.81 to 1.54; P = .49) and an unadjusted absolute risk difference of 5.1% (95% CI, −9.5% to 19.8%; P = .49). Conclusions: In neonates and children undergoing cardiac surgery with cardiopulmonary bypass, the use of fresh RBCs did not reduce the incidence of new or progressive multiple organ dysfunction syndrome compared with the standard-issue RBCs. A larger trial is needed to confirm these results.

Summary: PIEZO channels sense mechanical forces through conformational rearrangements of a mechanosensory domain called blade. To probe these rearrangements in real time, we have inserted conformational-sensitive cyclic-permuted GFP into several positions of PIEZO1’s blade. Here, we describe the step-by-step experimental procedure we developed to simultaneously measure flow-activated ionic currents and fluorometric signals in cells expressing these engineered constructs. We describe steps for performing transfection, seeding cells on coverslips, setting up a perfusion-based fluid shear application system, and performing voltage-clamp fluorometry.For complete details on the use and execution of this protocol, please refer to Ozkan et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: Mechanical forces are thought to activate mechanosensitive PIEZO channels by changing the conformation of a large transmembrane blade domain. Yet, whether different stimuli induce identical conformational changes in this domain remains unclear. Here, we repurpose a cyclic permuted green fluorescent protein as a conformation-sensitive probe to track local rearrangements along the PIEZO1 blade. Two independent probes, one inserted in an extracellular site distal to the pore and the other in a distant intracellular proximal position, elicit sizable fluorescence signals when the tagged channels activate in response to fluid shear stress of low intensity. Neither cellular indentations nor osmotic swelling of the cell elicit detectable fluorescence signals from either probe, despite the ability of these stimuli to activate the tagged channels. High-intensity flow stimuli are ineffective at eliciting fluorescence signals from either probe. Together, these findings suggest that low-intensity fluid shear stress causes a distinct form of mechanical stress to the cell.

The artemin-GFRα3 signaling pathway has been implicated in various painful conditions including migraine, cold allodynia, hyperalgesia, inflammatory bone pain, and mouse knees contain GFRα3-immunoreactive nerve endings. We developed high affinity mouse (REGN1967) and human (REGN5069) GFRα3-blocking monoclonal antibodies and, following in vivo evaluations in mouse models of chronic joint pain (osteoarthritic-like and inflammatory), conducted a first-in-human phase 1 pharmacokinetics (PK) and safety trial of REGN5069 (NCT03645746) in healthy volunteers, and a phase 2 randomized placebo-controlled efficacy and safety trial of REGN5069 (NCT03956550) in patients with knee osteoarthritis (OA) pain. In three commonly used mouse models of chronic joint pain (destabilization of the medial meniscus, intra-articular monoiodoacetate, or Complete Freund’s Adjuvant), REGN1967 and REGN5069 attenuated evoked behaviors including tactile allodynia and thermal hyperalgesia without discernably impacting joint pathology or inflammation, prompting us to further evaluate REGN5069 in humans. In the phase 1 study in healthy subjects, the safety profiles of single doses of REGN5069 up to 3000 mg (intravenous) or 600 mg (subcutaneous) were comparable to placebo; PK were consistent with a monoclonal antibody exhibiting target-mediated disposition. In the phase 2 study in patients with OA knee pain, two doses of REGN5069 (100 mg or 1000 mg intravenous every 4 weeks) for 8 weeks failed to achieve the 12-week primary and secondary efficacy endpoints relative to placebo. In addition to possible differences in GFRα3 biology between mice and humans, we highlight here differences in experimental parameters that could have contributed to a different profile of efficacy in mouse models versus human OA pain. Additional research is required to more fully evaluate any potential role of GFRα3 in human pain.

Purpose/Objective(s): To analyze the long term efficacy and safety of an ultra-hypofractionated (UHF) radiation therapy prostate treatment regimen with HDR brachytherapy boost (BB) and compare it to moderate-hypofractionated regimens (MHF). Materials/Methods: In this single arm, prospective monocentric study, 28 patients with intermediate risk prostate cancer were recruited in an experimental treatment arm of 25 Gy in 5 fractions plus a 15 Gy HDR BB. They were then compared to two historical control groups, treated with either 36 Gy in 12 fractions or 37.5 Gy in 15 fractions with a similar HDR BB. The control groups included 151 and 311 patients respectively. Patient outcomes were reported using the International Prostate Symptom Score (IPSS) and Expanded Prostate Index Composite (EPIC-26) questionnaires at baseline and at each follow-up visit. Results: Median follow-up for the experimental arm was 48.5 months compared to 47 months and 60 months compared to the 36/12 and 37,5/15 groups respectively. The IPSS and EPIC scores did not demonstrate any significant differences in the gastrointestinal or genitourinary domains between the three groups over time. No biochemical recurrence occurred in the UHF arm as defined by the Phoenix criterion. Conclusion: The UHF treatment scheme with HDR BB seems equivalent to standard treatment arms in terms of toxicities and local control. Randomized control trials with larger cohorts are ongoing and needed to further confirm our findings.

In a previous study, we have shown that parabiotic coupling of a knock-in mouse model (zQ175) of Huntington's disease (HD) to wild-type (WT) littermates resulted in a worsening of the normal phenotype as seen by detection of mutant huntingtin protein (mHTT) aggregates within peripheral organs and the cerebral cortex as well as vascular abnormalities in WT mice. In contrast, parabiosis improved disease features in the zQ175 mice such as reduction of mHTT aggregate number in the liver and cortex, decrease in blood-brain barrier (BBB) permeability and attenuation of mitochondrial impairments. While the shared circulation mediated these effects, no specific factor was identified. To better understand which blood elements were involved in the aforementioned changes, WT and zQ175 mice underwent parabiotic surgery prior to exposing one of the paired animals to irradiation. The irradiation procedure successfully eliminated the hematopoietic niche followed by repopulation with cells originating from the non-irradiated parabiont, as measured by the quantification of mHTT levels in peripheral blood mononuclear cells. Although irradiation of the WT parabiont, causing the loss of healthy hematopoietic cells, did lead to a few alterations in mitochondrial function in the muscle (TOM40 levels), and increased neuroinflammation in the striatum (GFAP levels), most of the changes observed were likely attributable to the irradiation procedure itself (e.g. mHTT aggregates in cortex and liver; cellular stress in peripheral organs). However, factors such as mHTT aggregation in the brain and periphery, and BBB leakage, which were improved in zQ175 mice when paired to WT littermates in the previous parabiosis experiment, were unaffected by perturbation of the hematopoietic niche. It would therefore appear that cells of the hematopoietic stem cell niche are largely uninvolved in the beneficial effects of parabiosis.

Discovery of therapeutics for neurological diseases is hampered by the lack of predictive in vitro and in vivo models. Traditionally, in vitro assays rely on engineered cell lines grown two-dimensionally (2D) outside a physiological tissue context, which makes them very amenable for large scale drug screening but reduces their relevance to in vivo neurophysiology. In recent years, three-dimensional (3D) neural cell culture models derived from human induced pluripotent stem cells (iPSCs) have been developed as an in vitro assay platform to investigate brain development, neurological diseases, and for drug screening. iPSC-derived neural spheroids or organoids can be developed to include complex neuronal and glial cell populations and display spontaneous, synchronous activity, which is a hallmark of in vivo neural communication. In this report we present a proof-of-concept study evaluating 3D iPSC-derived cortical neural spheroids as a physiologically- and pharmacologically-relevant high-throughput screening (HTS) platform and investigate their potential for use for therapeutic development. To this end, a library of 687 neuroactive compounds were tested in a phenotypic screening paradigm which measured calcium activity as a functional biomarker for neural modulation through fluctuations in calcium fluorescence. Pharmacological responses of cortical neural spheroids were analyzed using a multi-parametric approach, whereby seven peak characteristics from the calcium activity in each well were quantified and incorporated into principal component analysis and Sammon mapping to measure compound response. Here, we describe the implementation of the 687-compound library screen and data analysis demonstrating that iPSC-derived cortical spheroids are a robust and information-rich assay platform for HTS.

Background: Pasteurella spp. can lead to fatal infections in humans. Objective: To assess prognostic factors of invasive pasteurellosis. Methods: We conducted a single retrospective cohort study of local versus invasive Pasteurella infections from January 1, 2005, to December 31, 2018, in the Amiens-Picardie University Hospital, France. Results: Forty-five (20.9%) invasive pasteurellosis and 22 (10.2%) complicated local infections were reported among a total of 215 Pasteurella infections. The mortality rate among invasive infections was 22.2% (10/ 45) whereas no death was recorded in local infections group. Non–drug-induced prothrombin time test

Balloon type cross laminated timber (CLT) rocking shear walls are a novel seismic force resisting system. In this paper, the seismic performance of four 12-story balloon type CLT rocking shear walls, designed by a structural engineering firm located in Vancouver (Canada) using the performance-based design procedure outlined in the technical guideline published by the Canadian Construction Materials center (CCMC)/National Research Council Canada (NRC), is assessed. The seismic performance of the prototype CLT rocking shear walls was investigated using nonlinear time history analyses. Robust nonlinear finite element models were developed using OpenSees and the nonlinear behavior of the displacement-controlled components was calibrated using available experimental data. A detailed site-specific hazard analysis was conducted and sets of ground motions suitable for the prototype buildings were selected. The ground motions were used in a series of incremental dynamic analyses (IDAs) to quantify the adjustable collapse margin ratio (ACMR) of the prototype balloon type CLT rocking shear walls. The results show that the prototype balloon type CLT rocking shear walls designed using the performance-based design procedure outlined in the CCMC/NRC technical guideline have sufficient ACMR when compared to the acceptable limits recommended by FEMA P695.

ABSTRACT: Studies of dairy cow longevity usually focus on the animal life after first calving, with few studies considering early life conditions and their effects on longevity. The objective was to evaluate the effect of birth conditions routinely collected by Dairy Herd Improvement agencies on offspring longevity measured as length of life and length of productive life. Lactanet provided 712,890 records on offspring born in 5,425 Quebec dairy herds between January 1999 and November 2015 for length of life, and 506,066 records on offspring born in 5,089 Quebec dairy herds between January 1999 and December 2013 for length of productive life. Offspring birth conditions used in this study were calving ease (unassisted, pull, surgery, or malpresentation), calf size (small, medium, or large), and twinning (yes or no). Observations were considered censored if the culling reason was “exported,” “sold for dairy production,” or “rented out” as well as if the animals were not yet culled at the time of data extraction. If offspring were not yet culled when the data were extracted, the last test-day date was considered the censoring date. Conditional inference survival trees were used in this study to analyze the effect of offspring birth conditions on offspring longevity. The hazard ratio of culling between the groups of offspring identified by the survival trees was estimated using a Cox proportional hazard model with herd-year-season as a frailty term. Five offspring groups were identified with different length of life based on their birth condition. Offspring with the highest length of life [median = 3.61 year; median absolute deviation (MAD) = 1.86] were those classified as large or medium birth size and were also the result of an unassisted calving. Small offspring as a result of a twin birth had the lowest length of life (median = 2.20 year; MAD = 1.69) and were 1.52 times more likely to be culled early in life. Six groups were identified with different length of productive life. Offspring that resulted from an unassisted or surgery calving and classified as large or medium when they were born were in the group with the highest length of productive life (median = 2.03 year; MAD = 1.63). Offspring resulting from a malpresentation or pull in a twin birth were in the group with the lowest length of productive life (median = 1.15 year; MAD = 1.11) and were 1.70 times more likely to be culled early in life. In conclusion, birth conditions of calving ease, calf size, and twinning greatly affected offspring longevity, and such information could be used for early selection of replacement candidates.

Due to the restrictions of its use, Bisphenol A (BPA) has been replaced by many structurally related bisphenols (BPs) in consumer products. The endocrine disrupting potential similar to that of BPA has been described for several bisphenols, there is therefore an urgent need of toxicokinetic (TK) data for these emerging BPs in order to evaluate if their internal exposure could increase the risk of endocrine disruption. We investigated TK behaviors of eleven BPA substitutes (BPS, BPAF, BPB, BPF, BPM, BPZ, 3-3BPA, BP4-4, BPAP, BPP, and BPFL) by intravenous and oral administrations of mixtures of them to piglets and serial collection of blood over 72 h and urine over 24 h, to evaluate their disposition. Data were analyzed using nonlinear mixed-effects modeling and a comparison was made with TK predicted by the generic model HTTK package. The low urinary excretion of some BPs, in particular BPM, BPP and BPFL, is an important aspect to consider in predicting human exposure based on urine biomonitoring. Despite their structural similarities, for the same oral dose, all BPA analogues investigated showed a higher systemic exposure (area under the plasma concentration-time curve (AUC) of the unconjugated Bisphenol) than BPA (2 to 4 fold for 3-3BPA, BPAF, BPB and BPZ, 7–20 fold for BP4-4, BPAP, BPP, BPFL, BPF and BPM and 150 fold for BPS) due mainly to a considerable variation of oral bioavailability (proportion of BP administered by oral route that attains the systemic circulation unchanged). Given similarities in the digestive tract between pigs and humans, our TK data suggest that replacing BPA with some of its alternatives, particularly BPS, will likely lead to higher internal exposure to potential endocrine disruptive compounds. These findings are crucial for evaluating the risk of human exposure to these emerging BPs.

Measuring the thermoelectric transport properties of a material is a prerequisite to determining its usefulness for application in waste heat recovery or cooling and the basis for devising improvement strategies. While well-established characterization methods exist for bulk samples, characterization of microscale samples remains challenging. This usually results in incomplete characterization such as restriction to study of the thermal transport properties, which can be misleading. While elaborate microdevices for complete thermoelectric characterization have been fabricated, a demanding transfer of the samples onto these devices is generally required and establishing sufficient electrical contact can be challenging in this case. Therefore a complete and transfer free in-plane characterization method for samples obtained by deposition processes was developed. The approach is based on expanding a well-established self-heating technique for the measurement of electrical and thermal conductivity to allow, in addition, for the measurement of the Seebeck coefficient. The fabrication exclusively involves photolithography and wet etching, with no need for other steps like electron-beam lithography and a lift-off process. The accuracy of the method is verified by numerical studies closely mimicking the actual measurement process, comparison to measurements on simultaneously deposited reference samples and results from literature.

In this article, we tested the respective importance of low spatial frequencies (LSF) and high spatial frequencies (HSF) for conscious visual recognition of emotional stimuli by using an attentional blink paradigm. Thirty-eight participants were asked to identify and report two targets (happy faces) embedded in a rapid serial visual presentation of distractors (angry faces). During attentional blink, conscious perception of the second target (T2) is usually altered when the lag between the two targets is short (200–500 ms) but is restored at longer lags. The distractors between T1 and T2 were either non-filtered (broad spatial frequencies, BSF), low-pass filtered (LSF), or high-pass filtered (HSF). Assuming that prediction abilities could be at the root of conscious visual recognition, we expected that LSF distractors could result in a greater disturbance of T2 reporting than HSF distractors. Results showed that both LSF and HSF play a role in the emergence of exogenous consciousness in the visual system. Furthermore, HSF distractors strongly affected T1 and T2 reporting irrespective of the lag between targets, suggesting their role for facial emotion processing. We discuss these results with regards to other models of visual recognition. .

Multiscale molecular dynamics simulations using Martini coarse-grained (CG) and all-atom (AA) force fields are commonly used in membrane protein studies. In particular, reverse mapping an equilibrated CG model to an AA model offers an efficient way for preparing large membrane protein systems with complex protein shapes and lipid compositions. Here, we report that this hybrid CG-equilibrium-AA-production protocol may artificially increase lipid density and decrease hydration in ion channel pores walled with transmembrane gaps. To understand the origin of this conundrum, we conducted replicas of CG, AA, and CG reverse-mapped AA simulations of the pore domain of the mechanosensitive Piezo1 channel in a nonconducting conformation. Lipid/water density analysis and free energy calculations reveal that the lack of initial pore hydration allows excessive lipids to enter the upper pore lumen through gaps between pore helices during CG simulation. Due to the mismatch between CG and AA lipid kinetics, these pore lipids remain trapped in the subsequent AA simulations, despite unfavorable binding free energy. We tested several CG equilibrium protocols and found that a protocol restraining the whole lipid produces pore hydration consistent with AA results, thus eliminating this artifact for further studies of lipid gating and protein-lipid interactions.

Fragile-X syndrome (FXS) and Neurofibromatosis of type 1 (NF-1) are two monogenic disorders sharing neurobehavioral symptoms and pathophysiological mechanisms. Namely, preclinical models of both conditions show overactivity of the mTOR signaling pathway as well as GABAergic alterations. However, despite its potential clinical relevance for these disorders, the GABAergic system has not been systematically studied in humans. In the present study, we used an extensive transcranial magnetic stimulation (TMS) assessment battery in combination with magnetic resonance spectroscopy (MRS) to provide a comprehensive picture of the main inhibitory neurotransmitter system in patients with FXS and NF1. Forty-three participants took part in the TMS session (15 FXS, 10 NF1, 18 controls) and 36 in the MRS session (11 FXS, 14 NF1, 11 controls). Results show that, in comparison to healthy control participants, individuals with FXS and NF1 display lower GABA concentration levels as measured with MRS. TMS result show that FXS patients present increased GABAB-mediated inhibition compared to controls and NF1 patients, and that GABAA-mediated intracortical inhibition was associated with increased excitability specifically in the FXS groups. In line with previous reports, correlational analyses between MRS and TMS measures did not show significant relationships between GABA-related metrics, but several TMS measures correlated with glutamate+glutamine (Glx) levels assessed with MRS. Overall, these results suggest a partial overlap in neurophysiological alterations involving the GABA system in NF1 and FXS, and support the hypothesis that MRS and TMS assess different aspects of the neurotransmitter systems.

The built environment can influence physical activity behavior. Walk Score is a widely used measure of the neighborhood built environment to support walking. However, studies of the association between Walk Score and accelerometer-measured physical activity are equivocal and no studies have examined this relationship among older adults. We analyzed data from a large, diverse sample of women (n = 5650) with a mean age of 79.5 (SD = 6.7) at time of accelerometry wear in the Women’s Health Initiative Objective Physical Activity Cardiovascular Health Study in the United States to examine associations between neighborhood Street Smart Walk Score (SSWS) and accelerometer-measured physical activity. Participants wore triaxial accelerometers for seven days and SSWS was determined from home addresses. 67 % of the sample lived in “car-dependent” locations (SSWS 0–49 out of 100); only 3 % lived in “walker’s paradise” locations (SSWS 90–100). The multivariable model indicated an association between SSWS and accelerometer-measured physical activity (steps/day) in the total sample. The association varied by neighborhood socioeconomic status; in high socioeconomic status neighborhoods, higher SWSS was associated with greater steps per day, while no significant association between SWSS and physical activity was observed in low socioeconomic neighborhoods. This study should catalyze furtherresearch regarding the utility of SSWS in determining neighborhood walkability for older women across different neighborhood settings and suggests other built environment factors must be considered when determining walkability. Future studies should examine what factors influence walkability and develop age-relevant methods to assess and characterize neighborhood walkability.

Increasing the productive lifespan of dairy cows is important to achieve a sustainable dairy industry, but making strategic culling decisions based on cow profitability is challenging for farmers. The objective of this study was to carry out a lifetime cost-benefit analysis based on production and health records and to explore different culling decisions among farmers. The cost-benefit analysis was conducted for 22 747 dairy cows across 114 herds in Quebec, Canada for which feed costs and the occurrence of diseases were reported. Costs and revenues related to productive lifespan were compared among cohorts of cows that left their respective herd at the end of their last completed lactation or stayed for a complete additional lactation. Hierarchical clustering analysis was carried out based on costs and revenues to explore different culling decisions among farmers. Our results showed that the knowledge of lifetime cumulative costs and revenues was of great importance to identify low-profitable cows at an earlier lactation, while only focusing on current lactation costs and revenues can lead to an erroneous assessment of profitability. While culling decisions were mostly based on current lactation costs and revenues and disregarded the occurrence of costly events on previous lactations, there was variation among farmers as we identified three different culling decision clusters. Monitoring cumulative costs and revenues would help farmers to identify low-profitable cows at an earlier lactation and make the decision to increase herd productive lifespan and farm profitability by keeping the most profitable cows.

Objective: To describe variables used by Saudi pediatric intensivists to make antibiotic-related decisions for children with suspected severe bacterial infections. Methods: We conducted a cross-sectional survey, which was developed using a multi-step methodological approach. The survey included 4 clinical scenarios of the most relevant bacterial infections in pediatric critical care (pneumonia, sepsis, meningitis and intra-abdominal infection). The potential determinants of antibiotic treatment duration addressed in all scenarios included clinical variables (patient characteristics, disease severity), laboratory infection markers, radiologic findings, and pathogens. Results: The response rate was 65% (55/85). Eight variables (immunodeficiency, 3 months of age, 2 or more organ dysfunctions, Pediatric Risk of Mortality III score >10, leukocytosis, elevated C-reactive protein [CRP], elevated erythrocyte sedimentation rate [ESR], and elevated procalcitonin [PCT]) were associated with prolonging antibiotic treatment duration for all 4 clinical scenarios, with a median increase ranging from 3.0 days (95% confidence interval [CI] 0.5, 3.5, leukocytosis) to 8.8 days (95% CI 5.5, 10.5, immunodeficiency). There were no variables that were consistently associated with shortening antibiotic duration across all scenarios. Lastly, the proportion of physicians who would continue antibiotics for ≥5 days despite a positive viral polymerase chain reaction test result was 67% for pneumonia, 85% for sepsis, 63% for meningitis, and 95% for intra-abdominal infections. Conclusion: Antibiotic-related decisions for critically ill patients are complex and depend on several factors. Saudi pediatric intensivists will use prolonged courses of antibiotics for younger patients, patients with severe clinical picture, and patients with persistently elevated laboratory markers and hospital acquired infections, even when current literature and guidelines do not suggest such practices. Antimicrobial stewardship programs should include interventions to address these misconceptions to ensure the rational use of antibiotics in pediatric intensive care units.

Background: The effectiveness of screening strategies targeting pregnancies at higher risk of congenital heart disease (CHD) is reduced by the low prevalence of severe CHD, the increase in CHD detection rates by second-trimester ultrasound (U/S), and the high proportion of severe CHD in low-risk pregnancies. We aimed to determine situations in which additional screening by fetal echocardiography (FE) would result in a significant increase in sensitivity and a sizable decrease in the false-negative rate of detection of severe CHD. Methods: We simulated the change in the numbers of detected severe CHD cases when FE is offered to women with a normal second-trimester U/S who have a higher risk of bearing a child with CHD, compared to U/S alone. The primary outcome was the increase in sensitivity. Secondary outcomes were the number needed to screen and the reduction in the rate of missed cases. Results: For an U/S sensitivity of 60%, the addition of FE in pregnancies at high risk of CHD (risk ratio 3.5; range: 2 to 5) increased sensitivity by 2.4 percentage points (1.1 to 7.9). The number needed to screen to detect one additional case of severe CHD was 436 (156 to 952). The rate of additional severe CHD cases detected by FE was 4 per 100,000 pregnancies (2 to 32). Conclusions: The addition of FE to U/S for severe CHD prenatal screening in pregnancies at high risk of CHD yielded marginal benefits in terms of increased sensitivity and decreased rates of false negatives, at the expense of significant resource utilization. Résumé: Contexte: L'efficacité des stratégies de dépistage ciblant les grossesses à haut risque de cardiopathie congénitale (CC) se trouve réduite par la faible prévalence des CC sévères, par l'augmentation des taux de détection des CC par l'échographie (E/G) du deuxième trimestre, et par la proportion élevée de CC sévères dans les grossesses à faible risque. Dans le cadre de la détection prénatale des CC sévères, nous avons cherché à identifier les situations pour lesquelles un dépistage supplémentaire par échocardiographie fœtale (EF) entraînerait une augmentation significative de la sensibilité et une diminution notable du taux de faux négatifs. Méthodes: Nous avons simulé le changement du nombre de cas de CC sévère détectées lorsque l'EF est proposée aux femmes dont l'E/G du deuxième trimestre est normal et qui présentent un risque plus élevé de porter un enfant atteint de CC, par rapport à l'examen du deuxième trimestre seul. L'issue primaire était l'augmentation de la sensibilité. Les issues secondaires étaient le nombre de dépistages nécessaires et la réduction du taux de cas manqués. Résultats: Pour une sensibilité de l'E/G de 60 %, l'ajout de l'EF pour les grossesses à haut risque de CC (rapport de risque de 3,5; intervalle: 2 à 5) a accru la sensibilité de 2,4 points de pourcentage (1,1 à 7,9). Le nombre de dépistages nécessaires pour détecter un cas supplémentaire de CC sévères était de 436 (156 à 952). La proportion de cas supplémentaires de CC sévères détectées par EF était de 4 pour 100 000 grossesses (2 à 32). Conclusions: L'ajout de l'EF à l'E/G pour le dépistage prénatal des CC sévères pour les grossesses à risque élevé de CC n'a apporté que des avantages marginaux en termes d'augmentation de la sensibilité et de diminution des taux de faux négatifs, cela au prix d'une utilisation importante des ressources.

Heparin-free hemodialysis is often warranted in postoperative states, bleeding diathesis, and critically ill patients. Conventionally, this is achieved through normal saline flushes or regional citrate anticoagulation. An 87-year-old white man with end-stage renal disease and atrial fibrillation, who was taking warfarin and using maintenance home hemodialysis (HHD) with an NxStage machine, underwent laparoscopic appendicectomy. The procedure was complicated by intra-abdominal abscess, sepsis, and tamponade from a bloody pericardial effusion. He needed emergent therapeutic pericardiocentesis. Warfarin was promptly discontinued. He was discharged home with heparin-free HHD. Prior heparin anticoagulation for HHD was an initial bolus of 4000 units of heparin. He continued to clot his extracorporeal system with resultant very high venous pressures and compromised HHD. Heparin anticoagulation was still contraindicated. Flushes with 250-500 mL normal saline, delivered in aliquots every 15-30 minutes, failed to prevent the frequent clotting. The first author, our HD Senior Technician, had astutely observed that the horizontally placed hemodialysis filter exhibited early “clot” formation at the 12-o’clock position, despite the saline flushes. Through trial and error, he discovered that rotating the horizontally placed hemodialysis filter along its long axis, 60 degrees clockwise for 15 minutes, return to the neutral position for 15 minutes, rotating the filter another 60 degrees counterclockwise for 15 minutes, with this repeated cycle of rotations “did the trick.” It promptly and consistently resolved the clotting problem. The lines stopped clotting, and he has not needed saline flushes for smooth heparin-free HHD for more than 7 months. To our knowledge, this is the first such report. Further study is justified. We have hypothesized a mechanism and have named this the “Locke-Onuigbo Maneuver.”

Summary: Background: Severe COVID-19 is associated with a high circulating level of calprotectin, the S100A8/S100A9 alarmin heterodimer. Baseline calprotectin amount measured in peripheral blood at diagnosis correlates with disease severity. The optimal use of this biomarker along COVID-19 course remains to be delineated. Methods: We focused on patients with a WHO-defined moderate COVID-19 requiring hospitalization in a medical ward. We collected plasma and serum from three independent cohorts (N = 626 patients) and measured calprotectin amount at admission. We performed longitudinal measures of calprotectin in 457 of these patients (1461 samples) and used a joint latent class mixture model in which classes were defined by age, body mass index and comorbidities to identify calprotectin trajectories predicting the risk of transfer into an intensive care unit or death. Findings: After adjustment for age, sex, body mass index and comorbidities, the predictive value of baseline calprotectin in patients with moderate COVID19 could be refined by serial monitoring of the biomarker. We discriminated three calprotectin trajectories associated with low, moderate, and high risk of poor outcome, and we designed an algorithm available as online software (https://calpla.gustaveroussy.fr:8443/) to monitor the probability of a poor outcome in individual patients with moderate COVID-19. Interpretation: These results emphasize the clinical interest of serial monitoring of calprotectin amount in the peripheral blood to anticipate the risk of poor outcomes in patients with moderate COVID-19 hospitalized in a standard care unit. Funding: The study received support (research grants) from ThermoFisher immunodiagnostics (France) and Gustave Roussy Foundation.

Background: The TP53 gene is one of the most commonly inactivated tumor suppressors in human cancers. p53 functions during cancer progression have been linked to a variety of transcriptional and non-transcriptional activities that lead to the tight control of cell proliferation, senescence, DNA repair, and cell death. However, converging evidence indicates that p53 also plays a major role in metabolism in both normal and cancer cells. Scope of review: We provide an overview of the current knowledge on the metabolic activities of wild type (WT) p53 and highlight some of the mechanisms by which p53 contributes to whole body energy homeostasis. We will also pinpoint some evidences suggesting that deregulation of p53-associated metabolic activities leads to human pathologies beyond cancer, including obesity, diabetes, liver, and cardiovascular diseases. Major conclusions: p53 is activated when cells are metabolically challenged but the origin, duration, and intensity of these stresses will dictate the outcome of the p53 response. p53 plays pivotal roles both upstream and downstream of several key metabolic regulators and is involved in multiple feedback-loops that ensure proper cellular homeostasis. The physiological roles of p53 in metabolism involve complex mechanisms of regulation implicating both cell autonomous effects as well as autocrine loops. However, the mechanisms by which p53 coordinates metabolism at the organismal level remain poorly understood. Perturbations of p53-regulated metabolic activities contribute to various metabolic disorders and are pivotal during cancer progression. Keywords: p53, Metabolism, Normal tissue homeostasis, Cancer

The gut microbiota is a unique ecosystem of microorganisms interacting with the host through several biochemical mechanisms. The endocannabinoidome (eCBome), a complex signaling system including the endocannabinoid system, approximately 50 receptors and metabolic enzymes, and more than 20 lipid mediators with important physiopathologic functions, modulates gastrointestinal tract function and may mediate host cell-microbe communications there. Germ-free (GF) mice, which lack an intestinal microbiome and so differ drastically from conventionally raised (CR) mice, offer a unique opportunity to explore the eCBome in a microbe-free model and in the presence of a reintroduced functional gut microbiome through fecal microbiota transplant (FMT). We aimed to gain direct evidence for a link between the microbiome and eCBome systems by investigating eCBome alterations in the gut in GF mice before and after FMT. Basal eCBome gene expression and lipid profiles were measured in various segments of the intestine of GF and CR mice at juvenile and adult ages using targeted quantitative PCR transcriptomics and LC-MS/MS lipidomics. GF mice exhibited age-dependent modifications in intestinal eCBome gene expression and lipid mediator levels. FMT from CR donor mice to age-matched GF male mice reversed several of these alterations, particularly in the ileum and jejunum, after only 1 week, demonstrating that the gut microbiome directly impacts the host eCBome and providing a cause-effect relationship between the presence or absence of intestinal microbes and eCBome signaling. These results open the way to new studies investigating the mechanisms through which intestinal microorganisms exploit eCBome signaling to exert some of their physiopathologic functions.

This article presents a meta-analysis of the studies related to teachers’ attitudes towards inclusive education for students with disabilities. It covers a total sample of 40512 in-service or pre-service teachers from 55 different countries. Globally, the teachers’ attitude is positive. A meta-regression analysis shows that the attitude has notably progressed from 2000 to 2020. In addition, teachers’ attitude is more favourable when the country's Human Development Index (HDI) is higher and special education teachers are more favourable to inclusive education than ordinary ones.

Bisphenol A (BPA), an endocrine disruptor, has been replaced by structural analogues including bisphenol S (BPS). BPA and BPS exhibited similar effects regarding reproductive functions. Moreover, metabolic status and lipid metabolism are related to female fertility and could worsen BPS effects. The objective was to determine BPS in vivo effects on folliculogenesis and embryo production after chronic exposure through diet, and the influence of metabolic status in adult ewes. Sixty primiparous 2.5 year-old ewes, undergoing a restricted or well fed diet, were exposed to BPS (0, 4 or 50 µg/kg/day) for at least three months. After hormonal oestrus synchronisation and ovarian stimulation, ewes were subjected to ovum pick-up (OPU) procedures to collect immature oocytes, that underwent in vitro maturation, fertilisation and embryo production. Body weight, body condition score and plasma glucose were higher in well-fed compared to restricted ewes, while plasma NEFA was lower during the 4–5 months after the beginning of the diets. Plasma progesterone levels increased on day 5 before OPU session in well-fed compared to restricted ewes. No effect of BPS dose was observed on follicle population, plasma AMH levels and embryo production numbers and rates. However, a significant diet x BPS dose interaction was reported for cleaved embryos, > 4-cell embryos, blastocyst and early blastocyst numbers, and plasma triiodothyronine levels. Our study showed that a contrasted diet did not affect follicle population nor embryo production in adult ewes but could affect the quality and progesterone secretion of the corpus luteum. Chronic low BPS exposure had no effect on follicular population and oocyte competence. Nevertheless, the significant diet x dose interactions observed on embryo production suggest that BPS effect is modulated by metabolic status. Further studies are required to assess the risk of BPS exposure for public reproductive health.

Background: Bipolar disorder (BP) and schizophrenia (SZ) are both psychiatric conditions characterized by deficits in cognitive control (executive function and attention) and emotion regulation. The emotional Stroop task makes it possible to measure such deficits and to study the impact of emotions on cognitive control. The objective of the present study was thus to explore this impact in people with BP or SZ. Methods: Participants were 21 individuals with BP, 23 participants with SZ, and 42 control participants (HC). Results: Participants with SZ had greater cognitive impairments than participants with BP, who had greater cognitive impairments than HC. The BP group had longer reaction times than the HC group for the negative valence, and the SZ group had longer reaction times than the HC group for all three valences (i.e., positive, negative, and neutral). We did not observe an effect of emotional valence within any of the three groups. Conclusions: The SZ and BP groups had difficulty inhibiting irrelevant emotional stimuli during a cognitive task, reflecting deficits in the engagement of cognitive control during emotion regulation in both pathologies.

Objective: Reduced functional capacity is a hallmark of early pre-clinical stages of heart failure (HF). The Short Physical Performance Battery (SPPB) is a valid measure of lower extremity physical function, has relatively low implementation burden, and is associated with cardiovascular disease and mortality. However, the SPPB-HF association is understudied in older women among whom HF burden is high. Methods: Women (n = 5325; mean age 79 ± 7 years; 34% Black, 18% Hispanic, and 49% White) without prior HF completed the SPPB consisting of standing balance, strength, and walking tests that were summarized as a composite score from 0 (lowest) to 12 (highest), categorized as very low (0–3), low (4–6), medium (7–9), or high (10–12). Participants were followed for up to 8 years for incident HF (306 cases identified). Cox proportional hazards regression estimated hazard ratios (HR) adjusting for age, race/ethnicity, education, smoking, alcohol, diabetes, hypertension, COPD, osteoarthritis, depression, BMI, systolic blood pressure, lipids, glucose, and accelerometer-measured moderate-vigorous physical activity (MVPA) and sedentary time. Results: Incident HF cases (crude rate per 1000 person-years) in the four SPPB categories (very low to high) were 34 (26.0), 79 (14.5), 128 (9.3), and 65 (5.6). Corresponding multivariable-adjusted HRs (95% CIs) were 2.22 (1.34–3.66), 1.63 (1.11–2.38), 1.39 (1.00–1.94), and 1.00 (referent; P-trend0.10. Conclusion: Lower SPPB scores were associated with greater risk of incident HF in older women even after accounting for differences in HF risk factors and objectively measured PA. Implementing the SPPB in clinical settings could potentially enhance individual-level HF risk assessment, which should be further explored.

Introduction: Cervical myomectomy can compromise cervical integrity and the risk of subsequent cervical incompetence is unclear. In this case report, the literature on cervical myomectomies is reviewed as well as that on the potential benefits of cervical cerclage. Case presentation: A 30-year-old woman, nulligravida, with a 12 cm cervical leiomyoma consulted for heavy menstrual bleeding and pelvic pain. After failure of multiple medical therapies, a laparoscopic cervical myomectomy was successfully performed after pre-operative uterine artery embolization using absorbable gelatin sponges to reduce surgical blood loss. Discussion: A concomitant laparoscopic cerclage was achieved in order to prevent cervical incompetence, given that the full thickness of the anterior cervix was penetrated during the myomectomy.