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BackgroundWhile walking in nature has been shown to improve affect in adults from the community to a greater extent than walking in urban settings, it is unknown whether such findings can be generalized to individuals suffering from depression. Using a parallel group design, this randomized controlled trial examined the effects of a single walk in nature versus urban settings on negative and positive affect in adult psychiatric outpatients diagnosed with major depressive disorder (MDD).MethodParticipants recruited from a psychiatric outpatient clinic for adults with MDD were randomly assigned to a nature or urban walk condition. Thirty-seven adults (mean age=49 years) completed a single 60-minute walk. Negative and positive affect were assessed using The Positive and Negative Affect Schedule or PANAS at 6 time points: before the walk, halfway during the walk, immediately post-walk, at home before bedtime, 24 hours post-walk, and 48 hours post-walk.ResultsControlling for baseline levels of affect before the walk, individuals who walked in nature experienced overall lower levels of negative affect, F(1, 35.039)=4.239, p=.047, compared to those who walked in urban settings. Positive affect did not differ across walk conditions.LimitationsThe generalizability of results are limited by the small sample size and the presence of more female than male participants.ConclusionsWalking in nature might be a useful strategy to improve the affect of adults with MDD. Future research should investigate different ways to integrate the beneficial effects of nature exposure into existing treatment plans for psychiatric outpatients with MDD.

Given the importance of writing for academic achievement, this study aimed to understand how early oral language contributes to later writing skills. The first objective was to determine if preschool language skills were associated with high school writing, and if so, whether they contributed directly or indirectly through school age language. The second aim was to explore the extent to which genetic and environmental factors explained these potential associations. The sample was drawn from the Quebec Newborn Twin Study, a longitudinal follow-up of twins born in the greater Montreal area, Quebec, Canada. Language skills were assessed when children were 1.5, 2.5, 6, 7, 10, and 12 years old. Writing skills were measured at 15 years old. Participants who completed the writing task in French were included in the study (

The Secretary General of the United Nations described the impact of COVID-19-related school closures as a “generational catastrophe.” What will be the legacy of the 2020–2021 pandemic-related disruptions in 5, 10, 20 years from now, as regards education and well-being of children and youth? Addressing the disproportionate impact on those growing up in socio-economically disadvantaged areas or on those with pre-existing learning challenges is key to sustainable recovery. This commentary builds on the four literature reviews presented in this Special Section on a Pandemic Recovery Plan for Children and proposes strategies to understand and attenuate the impact of pandemic-related lockdown measures. Importantly, we need a monitoring strategy to assess indicators of child development in three areas of functioning: education and learning, health, and well-being (or mental health). Surveillance needs to begin in the critical prenatal period (with prenatal care to expectant parents), and extend to the end of formal high school/college education. Based on child development indicators, a stepped strategy for intervention, ranging from all-encompassing population-based health and education promotion initiatives to targeted prevention programs and targeted remedial/therapeutic interventions, can be offered. As proposed in the UN plan for recovery, ensuring healthy present and future generations involves a concerted and intensive intersectoral effort from the education, health, psychosocial services, and scientific communities., Selon les Nations Unis, les perturbations scolaires associées à la pandémie de COVID-19 pourraient mener à une « catastrophe générationnelle » en gaspillant un potentiel humain incalculable, sapant des décennies de progrès et exacerbant des inégalités bien ancrées. Le déploiement du vaccin chez les moins de 12 ans n’a pas débuté avant la rentrée scolaire 2021, ce qui laisse présager de nombreuses perturbations pour cette 3e année scolaire pandémique. Quel sera le legs des perturbations entrainées par la pandémie de COVID-19 en matière d’éducation et de bien-être dans 5, 10, ou 20 ans? Une relance durable dépendra des mesures prises pour prévenir l’impact négatif disproportionné sur les enfants/adolescents de milieux socioéconomiques défavorisés et ceux qui ont des défis d’apprentissage préexistants. Ce commentaire propose des stratégies pour comprendre et atténuer l’impact des perturbations pandémiques en se fondant sur les quatre articles de la présente « Section spéciale sur un plan de relance pour les enfants suite à la pandémie ». Trois lignes d’action prioritaires émergent à la lumière des connaissances scientifiques actuelles. Premièrement, le contexte pandémique met en évidence la nécessité d’accéder à données intersectorielles (éducation, santé, services psychosociaux) permettant de distinguer les conséquences à court et à long terme. Deuxièmement, il faut être prêt à déployer une stratégie interventionnelle par étape, avec des interventions universelles en promotion, jusqu’aux interventions plus ciblées et intensives. Troisièmement, il faudra mettre en place des programmes particuliers pour les enfants/adolescents de milieux défavorisés et pour ceux qui présentent des facteurs de risque personnels (défis de santé mentale, retards d’apprentissage). À titre d’exemple, le tutorat scolaire devrait être facilement accessible dans tous les milieux défavorisés. Tel que proposé dans le plan de relance de l’ONU, un effort concerté, intensif et intersectoriel de la part des sciences de l’éducation, de la santé, et des services psychosociaux sera nécessaire pour assurer la santé et l’éducation des générations présentes et futures.

Background Exposure–response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib. Methods Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety endpoints were adverse events typical for FGFR inhibitors. Results Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 [95% CI 0.46–0.72] per mg/dL of PO4; p = 0.01), PFS (hazard ratio 0.80 [0.67–0.94] per mg/dL of PO4; p = 0.01), and ORR (odds ratio 1.38 [1.02–1.86] per mg/dL of PO4; p = 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4. Conclusions The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib’s therapeutic benefit/risk ratio. Clinical trial registration number NCT02365597.

Several empirical studies have shown that women who experience violence in intimate personal relationships (IPV) commonly experience more than one form of violence. While it is recognized that individual trajectories of IPV vary over time, little is known about the temporal dynamics of this co-occurrence or its consequences. This study describes the different forms of violence experienced by women and looks at whether it is possible to predict when severe violence (physical and sexual) is most likely to occur. Data in the study comes from interviews with 70 women who had been victims of intimate partner violence. The life history calendar method was used to facilitate identifying kinds and levels of violence and the month in which violence took place. Individual victimization trajectories were found to be heterogenous and likely to change in the short term. The women in our sample experienced more than one form of intimate partner violence and co-occurrence of different forms of violence was common in individual trajectories. The characteristics of the kind of violence experienced were important in understanding the temporal aspects of acts of severe violence. The increased knowledge about patterns of violence provided by these results should help to develop better ways to intervene to prevent such events.

In Québec, one in three people is at risk of being affected by a mental health problem during his lifetime. Women are twice as likely as men to suffer from mild mental health issues such as depression and anxiety. Poverty, violence and sexual abuse, difficulty to have access to adequate and affordable housing and poor working conditions are among the risk for women of being affected by a mental health problem. Objectives This study was conducted upon the request of a Réseau des groupes de femmes and provides a portrait of women's mental health who attend community organizations in a Quebec region. Method A quantitative descriptive research design was used to collect data guided by the theoretical model of Desjardins et al. (2008). A total of 171 volunteers from 16 different community organizations completed a self-administered questionnaire. Results The analysis of the data highlights the protective factors of mental health such as self-esteem and social support and risk factors such as low income and stressful life. It reveals that while the majority of the women have good mental health, some of them live with poorer mental health associated with several other factors, especially violence and poverty. Conclusion Results could lead to the development of actions meeting the specific needs of women living with poor mental health. This study also highlights the contribution of the community organizations for supporting the people living with mental health issues.

A population pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK-PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once-daily oral continuous (0.5-12 mg) and intermittent (10-12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib-related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23-mediated signaling. PK-PD model-based simulations were performed to assess the approved PD-guided dosing algorithm of erdafitinib (8 mg once-daily continuous dosing, with up-titration to 9 mg based on phosphate levels [5.5 mg/dl] and tolerability at 14-21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8-fold increase in drug-related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of95% maximal serum phosphate concentration. The peak-to-trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68-5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate-parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8-mg with up-titration to 9-mg on Days 14-21 maximized the number of patients within the target serum phosphate concentrations (5.5-7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK-PD model provided a detailed understanding of the erdafitinib concentration-related phosphate changes over time, which supports erdafitinib's dosing algorithm.

The objective of this study was to examine the effect of isonitrogenous substitution of solvent-extracted soybean meal (SBM) with solvent-extracted canola meal (CM) on enteric CH4 production, ruminal fermentation characteristics (including protozoa), digestion (in situ and apparent total-tract digestibility), N excretion, and milk production of dairy cows. For this purpose, 16 lactating Holstein cows, of which 12 were ruminally cannulated, were used in a replicated 4 × 4 Latin square (35-d periods; 14-d adaptation). The cows averaged (mean ± SD) 116 ± 23 d in milk, 692 ± 60 kg of body weight, and 47.5 ± 4.9 kg/d of milk production. The experimental treatments were control diet (no CM; 0%CM) and diets supplemented [dry matter (DM) basis] with 7.9% CM (8%CM), 15.8% CM (16%CM), or 23.7% CM (24%CM) on a DM basis. The forage:concentrate ratio was 52:48 (DM basis) and was similar among the experimental diets. Canola meal was included in the diet at the expense of SBM and soybean hulls, whereas the percentages of the other diet ingredients were the same. Intake of DM increased linearly, whereas apparent total-tract digestibility of DM, crude protein, neutral detergent fiber, and gross energy (GE) declined linearly as CM inclusion in the diet increased. Total volatile fatty acids concentration and butyrate molar proportion decreased linearly, whereas molar proportion of propionate increased linearly, and that of acetate was unaffected by CM inclusion in the diet. Ruminal ammonia concentration was not affected by inclusion of CM in the diet. Energy-corrected milk (ECM) yield increased linearly (up to 2.2 kg/d) with increasing CM percentage in the diet, whereas milk production efficiency averaged 1.63 kg of ECM/kg of DM intake and was unaffected by CM inclusion in the diet. Daily CH4 production decreased linearly with increasing CM percentage in the diet (489, 475, 463, and 461 g/d for 0%CM, 8%CM, 16%CM and 24%CM diets, respectively). As a consequence, CH4 emission intensity (g of CH4/kg of ECM) also declined linearly by up to 10% as the amount of CM increased in the diet. Methane production also decreased linearly when expressed relative to GE intake (5.7, 5.2, 5.1, and 4.9% for 0%CM, 8%CM, 16%CM and 24%CM diet, respectively). Quantity of manure N excretion was not affected by replacing SBM with CM; however, N excretion shifted from urine to feces as dietary percentage of CM increased, suggesting reduced potential for N volatilization. Results from this study show that replacing SBM with CM as a protein source in dairy cow diets reduced enteric CH4 emissions (g/d, % of GE intake, and adjusted for milk production) and increased milk production. The study indicates that CM can successfully, partially or fully, replace SBM in lactating dairy cow diets, with positive effects on animal productivity and the environment (i.e., less enteric CH4 emission and urinary N excreted). We conclude that compared with SBM, inclusion of CM meal in dairy cow diets can play a key role in reducing the environmental footprint of milk production.

The objective of this research was to evaluate the potential economic and environmental effects of the formulation model used to balance dairy rations for metabolizable protein (MP) or 3 essential AA (EAA: His, Lys, and Met) in 3 regions of Canada with different farming systems. The Maritimes, Central Canada, and the Prairies reference dairy farms averaged 63, 71, 144 mature cows per herd and 135, 95, 255 ha of land, respectively. Using N-CyCLES, a whole-farm linear program model, dairy rations were balanced for (1) MP, based on National Research Council (NRC) requirements (MP_2001); (2) MP plus Lys and Met, based on NRC (AA_2001); (3) MP (MP_Rev); or (4) for His, Lys, and Met (AA_Rev), both based on a revised factorial approach revisiting both supply and requirements of MP and EAA. Energy was balanced to meet requirements based on NRC (2001). Assuming the requirements were met within each approach, it was considered that milk yield and composition were not affected by the type of formulation. Given the assumptions of the study, when compared with MP_2001 formulation, balancing dairy rations using the AA_Rev approach reduced calculated farm N balance by 3.8%, on average from 12.71 to 12.24 g/kg of fat- and protein-corrected milk; it also enhanced farm net income by 4.5%, from 19.00 to 19.70 $CAN/100 kg of fat- and protein-corrected milk, by reducing inclusion of protein concentrate in dairy rations. Calculated animal N efficiency was on average 4.3% higher with AA_Rev than with MP_2001 for mid-lactation cows. This gain in N efficiency would result in a reduction in N2O emission by manure, contributing to a partial decrease of total greenhouse gas emission by 1.7%, through a reduction of N excreted in manure. With the AA_2001 formulation, farm N balance was 1% higher than with MP_2001 formulation while reducing farm net income by 6.4%, due to the need to purchase rumen-protected AA, with no effect on total greenhouse gas emission. Both MP formulations lead to fairly similar outputs. The AA_Rev formulation also indicated that His might be a co-limiting AA with Met in dairy rations balanced with ingredients usually included in Canadian dairy rations. Given the assumptions of the study, balancing dairy rations for 3 EAA (His, Lys, and Met) rather than MP, has some potential positive effects on Canadian dairy farms by increasing net incomes through a reduction of crude protein supply, leading to a decreased environmental effect.

Background Chronic health conditions associated with long-term drug use may pose additional risks to people who use drugs (PWUD) when coupled with COVID-19 infection. Despite this, PWUD, especially those living in rural areas, may be less likely to seek out health services. Previous research has highlighted the increased disease burden of COVID-19 among PWUD. Our manuscript supplements this literature by exploring unique attitudes of PWUD living in rural areas toward the pandemic, COVID-19 vaccination, and the role of harm reduction (HR) organizations in raising health awareness among PWUD. Methods Semi-structured interviews were conducted with 20 PWUD living in rural southern Illinois. Audio recordings were professionally transcribed. A preliminary codebook was created based on interview domains. Two trained coders conducted iterative coding of the transcripts, and new codes were added through line-by-line coding and thematic grouping. Results Twenty participants (45% female, mean age of 38) completed interviews between June and November 2021. Participants reported negative impacts of the pandemic on mental health, financial wellbeing, and drug quality. However, the health impacts of COVID-19 were often described as less concerning than its impacts on these other aspects of life. Many expressed doubt in the severity of COVID-19 infection. Among the 16 unvaccinated participants who reported receiving most of their information from the internet or word of mouth, uncertainty about vaccine contents and distrust of healthcare and government institutions engendered wariness of the vaccination. Distrust of healthcare providers was related to past stigmatization and judgement, but did not extend to the local HR organization, which was unanimously endorsed as a positive institution. Among participants who did not access services directly from the HR organization, secondary distribution of HR supplies by other PWUD was a universally cited form of health maintenance. Participants expressed interest in low-threshold healthcare, including COVID-19 vaccination, should it be offered in the local HR organization’s office and mobile units. Conclusion COVID-19 and related public health measures have affected this community in numerous ways. Integrating healthcare services into harm reduction infrastructures and mobilizing secondary distributors of supplies may promote greater engagement with vaccination programs and other healthcare services. Trial number NCT04427202.

Occupational exposure to antineoplastic drugs (ANPs) occurs mainly through dermal contact. Our study was set up to assess the potential exposure of hospital sanitation (HS) personnel, for whom almost no data are available, through contamination of surfaces they regularly touch. In the oncology departments of two hospitals around Montreal, surface wipe samples of 120–2000 cm2 were taken at 10 sites cleaned by the HS personnel and five other sites frequently touched by nursing and pharmacy personnel. A few hand wipe samples were collected to explore skin contamination. Wipes were analyzed by ultra-performance liquid chromatography tandem–mass spectrometry for 10 ANPs. Overall, 60.9% of 212 surface samples presented at least one ANP above the limits of detection (LOD). Cyclophosphamide and gemcitabine were most often detected (52% and 31% of samples respectively), followed by 5–fluorouracil and irinotecan (15% each). Highest concentrations of five ANPs were found in outpatient clinics on toilet floors (5–fluorouracil, 49 ng/cm2; irinotecan, 3.6 ng/cm2), a perfusion pump (cyclophosphamide, 19.6 ng/cm2) and on a cytotoxic waste bin cover (gemcitabine, 4.97 ng/cm2). Floors in patient rooms had highest levels of cytarabine (0.12 ng/cm2) and methotrexate (6.38 ng/cm2). Hand wipes were positive for two of 12 samples taken on HS personnel, seven of 18 samples on nurses, and two of 14 samples on pharmacy personnel. A notable proportion of surfaces showed measurable levels of ANPs, with highest concentrations found on surfaces cleaned by HS personnel, who would benefit from appropriate preventive training. As potential sources of worker exposure, several hospital surfaces need to be regularly monitored to evaluate environmental contamination and efficacy of cleaning.

This study examines the influence of gender on mental health services utilization and on perceived barriers to treatment one year after the 2016 Fort McMurray wildfires. Data was collected through a phone survey from May to July 2017 (N = 1510). Participants were English-speaking evacuees aged 18 and older. Mental health services utilization and barriers to mental health care were assessed with the Perceived Need for Care questionnaire. Probable diagnoses of posttraumatic stress disorder, depression and insomnia were assessed with validated self-report questionnaires. Multiple logistic regressions confirmed that gender was a significant predictor of services utilization, after controlling for associated sociodemographic variables and presence of probable diagnoses. Women were respectively 1.50, 1.55 and 1.86 times more likely than men to receive information, medication and psychological help. Self-reliance was the most frequently reported reason for not receiving help, and motivational barriers, such as pessimism and stigma, were reported in a higher proportion than structural barriers, including nonresponse and finance. No significant gender differences were found in the types of perceived barriers to services. Among the Fort McMurray fire evacuees, mental health services utilization was similar to other studies on natural disaster victims, and higher in women than in men. Efforts to increase services utilization in natural disaster victims should focus on motivational barriers and offering treatments fostering people’s autonomy, such as online treatments. Supplementary Information The online version contains supplementary material available at 10.1007/s10488-021-01114-w .

This study used a longitudinal design from age six through age 19 (N = 1206 (603 girls)) to examine the associations between anxious-withdrawal and reactive aggression during childhood, distinct profiles of peer victimization from kindergarten to grade 11 and victimization in college or at work in emerging adulthood. In particular, it was tested whether the predictive effect of personal characteristics on victimization in emerging adulthood would be mediated via chronic peer victimization experiences during the school years. Teachers evaluated children's personal characteristics, whereas peer nominations and self-reports were used to assess victimization. Control variables included sex, parent-reported harsh parenting and SES. Longitudinal latent profile analysis revealed four distinct profiles of peer victimization during the school years: Consistently-Low (39.7%), Low-Moderate (42.8%), High-Decreasing (8.8%) and High-Increasing-Decreasing (8.7%). A subsequent 3-step regression-based path analysis supported the mediation hypothesis - albeit differently for different profiles of peer victimization. Specifically, compared to a Consistently-Low profile of peer victimization in school, a High-Decreasing profile was predicted by reactive aggression, but not anxious-withdrawal. In contrast, a High-Increasing-Decreasing profile was predicted by reactive aggression and anxious-withdrawal. In turn, elevated peer victimization profiles were associated with higher levels of later victimization in college or at work. The indirect effects linking the childhood behaviors to later victimization in college or at work - via elevated peer victimization profiles during childhood and adolescence - were significant. These results highlight the need for tailored interventions to optimize reactively aggressive or anxious-withdrawn children's response strategies to challenging and potentially threatening peer interactions.

Multiparous, nonlactating pregnant cows are negatively affected by heat stress, but the effect of heat stress on more thermotolerant pregnant heifers has received less attention. Our objective was to characterize the effect of late-gestation heat abatement on thermoregulatory responses and subsequent milk production of nulliparous Holstein heifers. Pregnant heifers, blocked by body condition score (BCS) and predicted transmitting ability (PTA) for milk, were enrolled in either heat stress (HT, shade of freestall barn; n = 16) or cooling (CL, shade of freestall barn, water soakers, and fans; n = 15) environments during the last 60 d of pregnancy (~8 weeks). Rectal temperature (RT; thermometer), respiration rate (RR; breaths/min), sweating rate (SR; VapoMeter, Delfin Technologies, Kuopio, Finland), and skin temperature (ST; infrared thermometer) were measured thrice weekly from enrollment to calving. Vaginal temperature (VT; i-button intravaginal device) was measured every 10 min for 7 consecutive days at wk -8, -6, -4, and -2 relative to calving and averaged hourly. Daily thermoregulatory patterns assessed by SR and ST, were measured every 4 h over a 36-h time interval at wk -6, -4, and -2 relative to calving. Upon calving, milk, protein, and fat yields were recorded twice daily for 15 wk. The average temperature-humidity index (Hobo Pro temperature probe, Onset Computer Corporation, Pocasset, MA) in the barn during the precalving period was 77 (minimum of 72, maximum of 82). Only heifers that gave birth to a female calf (CL = 12, HT = 14) were included in the statistical analysis. In the precalving period, CL heifers had lower RR (44.3 vs. 60.0 ± 1.6 breaths/min), RT (38.7 vs. 38.8 ± 0.04°C), unshaved ST (34.7 vs. 35.3 ± 0.17°C), and unshaved SR (19.0 vs. 35.2 ± 1.9 g/m2h), relative to HT heifers. Additionally, VT was lower in CL heifers during wk -4, and -2, specifically during early morning and early afternoon hours. When measured over a 36-h time interval, ST and SR were lower in CL heifers, when compared with HT heifers for all weeks. Notably, ST was reduced overnight and SR was reduced during the daytime. Cooled heifers had higher milk yield (35.8 vs. 31.9 ± 1.4 kg/d), when compared with HT heifers. Similar to multiparous cows, our data indicate that actively cooling heifers in late pregnancy is effective in promoting thermoregulation and results in elevated milk production postcalving.

Two His deletion studies were conducted to examine the mechanisms used by dairy cows to support milk true protein yield (MTPY) when His supply is altered. The potential mechanisms involved in how the efficiency of utilization of His varied included reduced catabolism, more efficient mammary usage, and use of His labile pools. For the first study, 5 multicatheterized cows were used in a 4 × 4 Latin square plus 1 cow with 14-d periods. Treatments were abomasal infusion of increasing doses of His (0, 7.6, 15.2, and 20.8 g/d) in addition to a mixture of AA (595 g/d; casein profile excluding His). Cows were fed the same protein-deficient diet throughout the study. The MTPY increased linearly with a quadratic tendency with increasing doses of His. Muscle concentrations of carnosine, a His-based dipeptide, tended to increase in a quadratic manner with increasing His supply, suggesting that the 0- and 7.6-g doses were insufficient to cover His requirement. Liver catabolism of His decreased as His supply decreased. Mammary fractional removal of His was considerably greater at low His supply, but the ratio of His mammary net uptake to milk output was not affected by the rate of His infusion, averaging 1.02. The mechanisms to face a reduced His supply included reduced His hepatic catabolism, more efficient His mammary use of lowered arterial supply, and, to a lesser extent, use of His labile pools. Two independent estimates of His efficiency were calculated, one based on the sum of exported proteins (measured MTPY plus estimated metabolic fecal protein and scurf; i.e., the anabolic component, EffMTPY) and the other based on liver removal (i.e., the catabolic component). These 2 estimates followed the same pattern of response to His supply, decreasing with increasing His supply. The EffMTPY at which MTPY peaked was 0.785. For the second study, 6 cows were used in a 6 × 6 Latin square with 7-d periods. Two greater doses of His (30.4 and 38.0 g/d) were added; otherwise, the nutritional design was similar to the first study. In this second study, the indicator AA oxidation technique was used instead of the multiorgan approach, with labeled Leu as the indicator of His utilization. The MTPY peaked and Leu oxidation reached the nadir at an average EffMTPY of 0.763. Combined across both studies, the data indicate that optimal usage of His would occur at a threshold EffMTPY of 0.77. The agreement between experimental approaches across both studies indicates that the biological optimal supply of His expressed in grams per day could be calculated as the sum of exported proteins divided by this EffMTPY plus estimated endogenous urinary excretion.

Funder: Fonds du Québec en Recherche, Santé (FRQS), Funder: Parkinson Quebec., Funder: Lund University, The direct reprogramming of adult skin fibroblasts to neurons is thought to be controlled by a small set of interacting gene regulators. Here, we investigate how the interaction dynamics between these regulating factors coordinate cellular decision making in direct neuronal reprogramming. We put forward a quantitative model of the governing gene regulatory system, supported by measurements of mRNA expression. We found that nPTB needs to feed back into the direct neural conversion network most likely via PTB in order to accurately capture quantitative gene interaction dynamics and correctly predict the outcome of various overexpression and knockdown experiments. This was experimentally validated by nPTB knockdown leading to successful neural conversion. We also proposed a novel analytical technique to dissect system behaviour and reveal the influence of individual factors on resulting gene expression. Overall, we demonstrate that computational analysis is a powerful tool for understanding the mechanisms of direct (neuronal) reprogramming, paving the way for future models that can help improve cell conversion strategies.

Objectives About half of young adults with early psychosis also have substance use disorders (SUD). For young adults with first episode psychosis (FEP), the persistence of SUD negatively impacts the symptomatic and functional outcome as well as the management of the problems. This article aims to identify and synthetize the best therapeutic approaches for the treatment of young adults with concurrent disorders (FEP and SUD) and to present avenues for practical and adapted approaches for the assessment and follow-up of people with concurrent FEP and SUD. Method Narrative literature review on the treatment of young adults with concurrent disorder (FEP and SUD). Results Several studies demonstrate the usefulness of early intervention for psychosis services (EIS) in the management of SUD with approximately 50% decrease in SUD during the first year of follow-up. A variety of therapeutic interventions have been studied, but none have demonstrated substantial long-term superiority over the standard treatment offered in EIS. The studies also have several methodological limitations. To date, clinical guidelines suggest offering an adapted and integrated treatment for psychosis and SUD and recommend the use of various approaches such as case management, comprehensive assessment and feedback on SUD and psychosis as well as their interplay, harm reduction interventions, motivational interviewing, cognitive behavioural therapy, and pharmacotherapy. It is proposed here to proactively adjust the treatment to consider the severity of the disorders, their impact on the various dimensions of psychosis outcomes, the developmental stage of the young person and his or her stage of change with respect to substance use. Conclusion Data on best practice in the treatment of concurrent PEP-SUD disorders are relatively limited. Some approaches appear to have the potential to improve the clinical course of young people living with such conditions, especially if they are adapted to this population. Furthermore, research and innovations in the management of concurrent disorders must continue to offer better adapted care to young adults with early psychosis and SUD.

Adolescent idiopathic scoliosis is the most prevalent spine deformity and the molecular mechanisms underlying its pathophysiology remain poorly understood. We have previously found a differential impairment of melatonin receptor signaling in AIS osteoblasts allowing the classification of patients into three biological endophenotypes or functional groups (FG1, FG2 and FG3). Here, we provide evidence that the defect characterizing each endophenotype lies at the level of Gαi proteins leading to a systemic and generalized differential impairment of Gi-coupled receptor signaling. The three Gαi isoforms exhibited a selective serine phosphorylation patterns for each AIS endophenotype resulting in a differential reduction in Gαi protein activity as determined by cellular dielectric spectroscopy and small interfering RNA methods. We found that one endophenotype (FG2) with phosphorylated Gαi1 and Gαi2 was consistently associated with a significantly high risk of spinal deformity progression when compared to the other two endophenotypes (FG1 and FG3). We further demonstrated that each endophenotype is conserved among affected family members. This study expands our understanding of the mechanism underlying the Gi-coupled receptor signaling dysfunction occurring in AIS and provides the first evidence for its hereditary nature. Collectively, our findings offers a new perspective on Gαi hypofunctionality in a human disease by revealing specific serine phosphorylation signatures of Gαi isoforms that may facilitate the identification of AIS patients at risk of spinal deformity progression.

Facet joint osteoarthritis is prevalent in young patients with adolescent idiopathic scoliosis (AIS) and might contribute to back pain. Toll‐like receptors (TLR) have been linked to cartilaginous tissue degeneration but their involvement in facet joint osteoarthritis in AIS patients is still unknown. We compared baseline gene expression levels of TLRs ‐1, ‐2, ‐4, and ‐6 in scoliotic and non‐scoliotic chondrocytes and found higher expression levels in scoliotic chondrocytes with significantly higher TLR2 levels. Furthermore, TLR expression correlated strongly and significantly with inflammatory and catabolic markers in scoliotic but not in non‐scoliotic chondrocytes. TLR activation with a synthetic TLR2/6 agonist resulted in a robust induction and release of pro‐inflammatory and catabolic factors which exacerbated proteoglycan loss in scoliotic but not in non‐scoliotic cartilage. We also detected a higher abundance of alarmins including S100A8/9 and biglycan in scoliotic cartilage. Finally, the small‐molecule antagonists Sparstolonin B and o‐Vanillin reduced catabolism following induction with naturally occurring alarmins and the synthetic TLR2/6 agonist. The high baseline expression, robust responsiveness and strong and significant correlation with proteases and pro‐inflammatory cytokines suggest that TLRs are key regulators of facet joint degeneration in AIS. Blocking their activity could therefore potentially modify disease progression.

Records of late-gestation heat stress studies conducted over 10 consecutive years in Florida were pooled and analyzed to test the hypothesis that maternal hyperthermia during late gestation impairs performance of the offspring across multiple generations and lactations, ultimately impeding the profitability of the US dairy sector. Dry-pregnant multiparous dams were actively cooled (CL; shade of a freestall barn, fans and water soakers, n = 196) or not (HT; shade only, n = 198) during the last 46 d of gestation, concurrent with the entire dry period. After data mining, records of 156 daughters (F1) that were born either to CL (CLF1, n = 77) or HT dams (HTF1, n = 79) and 45 granddaughters (F2) that were born either to CLF1 (CLF2, n = 24) or HTF1 (HTF2, n = 21) were used in the analysis. Life events and daily milk yield for 3 lactations of daughters and granddaughters were obtained. Milk yield, reproductive performance, and productive life data were analyzed using MIXED and GLIMMIX procedures, and lifespan was analyzed using PHREG and LIFETEST procedures of SAS (SAS Institute Inc., Cary, NC). Milk production of HTF1 was reduced in their first (2.2 kg/d), second (2.3 kg/d), and third lactations (6.5 kg/d) compared with CLF1. More HTF1 were culled before first calving, and the productive life and lifespan of HTF1 were reduced relative to CLF1 (4.9 and 11.7 mo, respectively). The granddaughters (HTF2) born to HTF1 produced less milk in their first lactation (1.3 kg/d) relative to granddaughters (CLF2) born to CLF1. More HTF2 were culled before first breeding relative to CLF2; however, productive life and lifespan were not different between HTF2 and CLF2 animals. An economic analysis was then performed based on the number of heat stress days, dry cows per state, and the aforementioned impairments on daughters' lifespans and milk production. Collectively in the United States, the economic losses for additional heifer rearing cost, reduced productive life, and reduced milk yield of the F1 offspring were estimated at $134, $90, and $371 million per year, respectively. In summary, late-gestation heat stress exerts carryover effects on at least 2 generations. Providing heat abatement to dry-pregnant dams is important to rescue milk loss of the dam and to prevent losses in their progeny.

Aim An accurate biomarker for metabolic acidosis at birth is needed. Our aims were to investigate the link between umbilical artery pCO2 and the risk for hypoxic-ischaemic encephalopathy (HIE) and to compare false-negative screen results in newborn infants with HIE using three umbilical artery blood gas biomarkers. Methods From a cohort of newborn infants ≥35 weeks born in Ottawa, Canada, between January 2007 and December 2016, we highlighted those with HIE or who died. We compared the umbilical artery pCO2 for matched pH >mean versus matched pH ≤mean. We compared false-negative rates for three umbilical artery biomarkers-pH Results This study included 51 286 newborn infants, 51% male and a mean gestational age of 38.9 ± 1.5 weeks. The rate for HIE or death with umbilical artery pCO2 for matched pH >mean was 22%, compared to 78% for matched pH ≤mean. In 60 HIE or deaths, the false-negative rate for umbilical artery neonatal eucapnic pH ≤7.14 was 8%; compared to 31% for pH Conclusion The rate of HIE or death is lower in newborn infants with higher pCO2 . Using neonatal eucapnic pH decreases the risk of missing newborn infants with HIE.

Background Peer victimization has been associated with long-lasting risks for mental health. Prior research suggests that stress-related systems underlying adaptation to changing environments may be at play. To date, inconsistent findings have been reported for the hypothalamic-pituitary-adrenal (HPA) axis, and its end product cortisol. This study tested whether peer victimization was associated with hair cortisol concentrations (HCC), and whether this association varied according to sex, timing, and changes in exposure. We also examined whether peer victimization differentially predicted depressive symptoms according to HCC. Methods The sample comprised 556 adolescents (42.0%; 231 males) who provided hair for cortisol measurement at 17 years of age. Peer victimization was reported at seven occasions between the ages of 6 and 15 years. Results Peer victimization was nonlinearly associated with HCC for boys only, whereas changes in peer victimization were related to HCC for boys and girls. Peer victimization predicted more depressive symptoms for all participants, except those with lower HCC. Conclusions Our findings provide further support for persistent dysregulation of the HPA axis following exposure to chronic adversity, of which the expression may change according to sex and the severity of victimization.

Objectives. Acute pain trajectories are associated with long-term outcomes such as persistent pain and functional disability in adults. However, there are limited data on acute postoperative pain trajectories in the pediatric population. The aims of this study were to investigate acute postoperative pain trajectories, their predictors, and their impact on long- term outcomes in adolescents with idiopathic scoliosis. Methods. We evaluated the preoperative pain intensity, use of analgesics, psychosocial measures and physical functioning of adolescents scheduled to undergo spinal fusion, and their average 6-hour self-reported pain intensity scores for their entire hospital stay. Six months after surgery, baseline variables were reassessed. We used growth mixture modeling to conduct acute postoperative pain trajectory analysis and to identify predictors of pain trajectories. Generalized linear models were conducted to determine whether acute pain trajectories predict long-term outcomes. Results. One hundred and six patients were included in the best-fitted acute pain trajectory model that included four classes that differed in initial pain intensity and rates of change over time. Preoperative pain catastrophizer status and use of analgesics significantly predicted pain trajectory membership. Furthermore, at the 6-month follow-up, patients experiencing moderate-to-severe pain in the acute postoperative period were more likely to report higher levels of pain severity, use pain medication, and miss a greater number of school/work days due to back pain in the last three months. Discussion. Preoperative assessment and analyzing the progression of pain in the acute postoperative period can help identify those at risk of negative long-term outcomes after surgery.

Background Cross-sectional associations have been documented between cybervictimization and suicidal risk; however, prospective associations remain unclear. Methods Participants were members of the Quebec Longitudinal Study of Child Development (QLSCD), a prospective birth cohort of 2,120 individuals followed from birth (1997/98) to age 17 years (2014/15). Cybervictimization and face-to-face victimization experienced since the beginning of the school year, as well as serious suicidal ideation and/or suicide attempt were self-reported at ages 13, 15 and 17 years. Results In cross-sectional analyses at 13, 15 and 17 years, adolescents cybervictimized at least once had, respectively, 2.3 (95% CI = 1.64-3.19), 4.2 (95% CI = 3.27-5.41) and 3.5 (95% CI = 2.57-4.66) higher odds of suicidal ideation/attempt after adjusting for confounders including face-to-face victimization, prior mental health symptoms and family hardship. Sensitivity analyses suggested that cybervictimization only and both cyber- and face-to-face victimization were associated with a higher risk of suicidal ideation/attempt compared to face-to-face victimization only and no victimization; however, analyses were based on small n. In prospective analyses, cybervictimization was not associated with suicidal ideation/attempt 2 years later after accounting for baseline suicidal ideation/attempt and other confounders. In contrast, face-to-face victimization was associated with suicidal ideation/attempt 2 years later in the fully adjusted model, including cybervictimization. Conclusions The cross-sectional association between cybervictimization and suicidal ideation/attempt is independent from face-to-face victimization. The absence of a prospective association suggested short-term effects of cybervictimization on suicidal ideation/attempt.

Background Genetic, biologic and clinical data suggest that Parkinson's disease (PD) is an umbrella for multiple disorders with clinical and pathological overlap, yet with different underlying mechanisms. To better understand these and to move towards neuroprotective treatment, we have established the Quebec Parkinson Network (QPN), an open-access patient registry, and data and bio-samples repository. Objective To present the QPN and to perform preliminary analysis of the QPN data. Methods A total of 1,070 consecutively recruited PD patients were included in the analysis. Demographic and clinical data were analyzed, including comparisons between males and females, PD patients with and without RBD, and stratified analyses comparing early and late-onset PD and different age groups. Results QPN patients exhibit a male:female ratio of 1.8:1, an average age-at-onset of 58.6 years, an age-at-diagnosis of 60.4 years, and average disease duration of 8.9 years. REM-sleep behavior disorder (RBD) was more common among men, and RBD was associated with other motor and non-motor symptoms including dyskinesia, fluctuations, postural hypotension and hallucinations. Older patients had significantly higher rates of constipation and cognitive impairment, and longer disease duration was associated with higher rates of dyskinesia, fluctuations, freezing of gait, falls, hallucinations and cognitive impairment. Since QPN's creation, over 60 studies and 30 publications have included patients and data from the QPN. Conclusions The QPN cohort displays typical PD demographics and clinical features. These data are open-access upon application (http://rpq-qpn.ca/en/), and will soon include genetic, imaging and bio-samples. We encourage clinicians and researchers to perform studies using these resources.

Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that peripheral nerve injury induces the generation of a male-specific inflammatory microglia subtype, and demonstrate increased proliferation of microglia in male as compared to female mice. We also show time- and sex-specific transcriptional changes in different microglial subpopulations following peripheral nerve injury. Apolipoprotein E (Apoe) is the top upregulated gene in spinal cord microglia at chronic time points after peripheral nerve injury in mice. Furthermore, polymorphisms in the APOE gene in humans are associated with chronic pain. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia, and identify a link between ApoE and chronic pain in humans.

This cross-sectional study assesses how patient-identified top health priorities can be incorporated into the care of older adults with multiple chronic conditions while facilitating decision-making that aligns with these priorities.

Serotonin (5-HT) is an autocrine-paracrine molecule within the mammary gland regulating homeostasis during lactation and triggering involution after milk stasis. Exposure of dairy cows to hyperthermia during the dry period alters mammary gland involution processes leading to reduced subsequent yields. Herein, primary bovine mammary epithelial cells (pBMEC) under thermoneutral (TN, 37 °C) or heat shock (HS, 41.5 °C) conditions were cultured with either 0, 50, 200, or 500 μM 5-Hydroxy-L-tryptophan (5-HTP; 5-HT precursor) for 8-, 12- or 24-h. Expression of 95 genes involved in 5-HT signaling, involution and tight junction regulation were evaluated using a Multiplex RT-qPCR BioMark Dynamic Array Circuit. Different sets of genes were impacted by 5-HTP or temperature, or by their interaction. All 5-HT signaling genes were downregulated after 8-h of HS and then upregulated after 12-h, relative to TN. After 24-h, apoptosis related gene, FASLG, was upregulated by all doses except TN-200 μM 5-HTP, and cell survival gene, FOXO3, was upregulated by HS-50, 200 and 500 μM 5-HTP, suggesting 5-HTP involvement in cell turnover under HS. Supplementing 5-HTP at various concentrations in vitro to pBMEC modulates the expression of genes that might aid in promoting epithelial cell turn-over during involution in dairy cattle under hyperthermia.

Feed evaluation models (FEM) are a core part in dairy cow feeding. As these models are developed using different biological and mathematical approaches mainly tested in a research context, their abilities to predict production in commercial farms need to be validated, even more so when they are used outside the context of their development. Four FEM-National Research Council, 2001 (NRC_2001); Cornell Net Carbohydrate and Protein System, 2015 (CNCPS); NorFor, 2011; and INRA, 2018 (INRA_2018)-were evaluated on their abilities to predict daily milk protein yield (MPY) of 541 cows from 23 dairy herds in the province of Québec, Canada. The effects of cow and diet characteristics were tested on the residuals of MPY. Sensitivity and uncertainty analyses were then performed to evaluate the influence of the uncertainty of the main characteristics of cows and feed ingredients measured on the farm and used in the 4 FEM on the predictions of metabolizable protein (MP) supply and MPY. The 4 models had acceptable predictions of MPY, with concordance correlation coefficients (CCC) ranging from 0.75 to 0.82 and total bias ranging from 12.8% to 19.3% of the observed mean. The Scandinavian model NorFor had the best predictions with a CCC of 0.82, whereas the 3 other models had similar CCC at 0.75 to 0.76. The INRA_2018 and NRC_2001 models presented strong central tendency biases. Removing herd effect put the 4 FEM at the same level of performance, with 11.9 to 12.4% error. Analyzing model behavior within a herd seems to partly negate the effect of using predicted dry matter intake (DMI) in the comparison of models. Diet energy density, days in milk, and MPY estimated breeding value were related to the residual in the 4 models, and Lys and Met (as percent of MP) only in NRC_2001 and NorFor. This suggests that inclusion of these factors in these models would improve MPY predictions. From the sensitivity analysis, for the 4 FEM, DMI and factors affecting its prediction had the greatest influence on the predictions of MP supply and MPY. Of the feed ingredients, forage composition had the greatest effect on these predictions, including a strong effect of legume proportion with NorFor. Diet acid detergent fiber concentration had a very strong effect on MP supply and MPY predictions only in INRA_2018, because of its effect on organic matter digestibility estimation. The range of predictions of MP supply and MPY when combining all these potential uncertainties varied depending on the models. The INRA_2018 model presented the lowest standard deviation (SD) and NorFor the highest SD for the predictions of both MP supply and MPY. Overall, despite the fact that FEM were developed in a research context, their use in a commercial context yields acceptable predictions, with NorFor yielding the best predictions overall, although within-herd responses varied similarly for the 4 tested models.

Umbilical cord arterial and venous blood gas values reflect the acid-base balance status of a newborn at birth. Derangement in these values has been linked to poor neonatal outcomes in term and late preterm neonates; however, the utility of these values in preterm neonates of29 weeks' gestation is unclear.This study aimed to determine the associations of umbilical cord arterial and venous blood gas values with neonatal mortality and severe neurologic injury in extremely preterm neonates and to identify the cutoff values associated with 2.5-fold increases or decreases in the posttest probabilities of outcomes.This was a retrospective cohort study of neonates who were born at 23+0 to 28+6 weeks' gestation between January 1, 2018 and December 31, 2019, and who were admitted to neonatal units in Canada.Various cut-offs of umbilical cord blood gas values and lactate values were studied.The main outcomes were mortality before discharge from the neonatal unit and severe neurologic injury defined as grade 3 or 4 periventricular or intraventricular hemorrhage or periventricular leukomalacia. The outcome rates were calculated for various cutoff values of umbilical cord blood gas parameters and were adjusted for birthweight, gestational age, sex, and multiple births. Likelihood ratios were calculated to derive posttest probabilities.A total of 1040 and 1217 neonates had analyzable umbilical cord arterial and venous blood gas values, respectively. In the cohort, the mean (standard deviation) gestational age was 26.5 (1.5) weeks, the mean birthweight was 936 (215) g, the prevalence of mortality was 10% (105/1040), and the prevalence of severe neurologic injury was 9% (92/1016). An umbilical cord arterial pH of ≤7.1 and base excess of ≤-12 mmol/L were associated with2.5-fold higher posttest probability of mortality, and an umbilical cord arterial or venous lactate value of3 was associated with a 2.5-fold lower posttest probability of mortality. An umbilical cord arterial lactate value of3 was associated with a lower posttest probability of severe neurological injury.In preterm neonates of29 weeks' gestation, low umbilical cord arterial pH and high umbilical cord arterial base excess values were associated with a clinically important increase in the posttest probability of mortality, whereas low umbilical cord arterial or venous lactate values were associated with a decrease in the posttest probability of mortality.

Objective: To evaluate the association of a combined exposure to antenatal steroids and prophylactic indomethacin with the outcome of spontaneous intestinal perforation (SIP) among neonates born at 7 days before birth) exposures. The co-exposure was prophylactic indomethacin. The primary outcome was SIP. Multivariable logistic regression analysis was used to calculate aORs. Results: Among 4720 eligible infants, 4121 (87%) received antenatal steroids and 1045 (22.1%) received prophylactic indomethacin. Among infants exposed to antenatal steroids, those who received prophylactic indomethacin had higher odds of SIP (aOR 1.61, 95% CI 1.14-2.28) compared with no prophylactic indomethacin. Subgroup analyses revealed recent antenatal steroids exposure with prophylactic indomethacin had higher odds of SIP (aOR 1.67, 95% CI 1.15-2.43), but latent antenatal steroids exposure with prophylactic indomethacin did not (aOR 1.24, 95% CI 0.48-3.21), compared with the respective groups with no prophylactic indomethacin. Among those not exposed to antenatal steroids, mortality was lower among those who received prophylactic indomethacin (aOR 0.45, 95% CI 0.28-0.73) compared with no prophylactic indomethacin. Conclusions: In preterm neonates of

Alfalfa has a lower fiber digestibility and a greater concentration of degradable protein than grasses. Dairy cows could benefit from an increased digestibility of alfalfa fibers, or from a better match between nitrogen and energy supplies in the rumen. Alfalfa cultivars with improved fiber digestibility represent an opportunity to increase milk production, but no independent studies have tested these cultivars under the agroclimatic conditions of Canada. Moreover, decreasing metabolizable protein (MP) supply could increase N use efficiency while decreasing environmental impact, but it is often associated with a decrease in milk protein yield, possibly caused by a reduced supply of essential AA. This study evaluated the performance of dairy cows fed diets based on a regular or a reduced-lignin alfalfa cultivar and measured the effect of energy levels at low MP supply when digestible His (dHis), Lys (dLys), and Met (dMet) requirements were met. Eight Holstein cows were used in a double 4 × 4 Latin square design, each square representing an alfalfa cultivar. Within each square, 4 diets were tested: the control diet was formulated for an adequate supply of MP and energy (AMP_AE), whereas the 3 other diets were formulated to be deficient in MP (DMP; formulated to meet 90% of the MP requirement) with deficient (94% of requirement: DMP_DE), adequate (99% of requirement: DMP_AE), or excess energy supply (104% of requirement; DMP_EE). Alfalfa cultivars had no significant effect on all measured parameters. As compared with cows receiving AMP_AE, the dry matter intake of cows fed DMP_AE and DMP_EE was not significantly different but decreased for cows fed DMP_DE. The AMP_AE diet provided 103% of MP and 108% of NEL requirements whereas DMP_DE, DMP_AE, and DMP_EE diets provided 84, 87, and 87% of MP and 94, 101, and 107% of NEL requirements, respectively. In contrast to design, feeding DMP_EE resulted in a similar energy supply compared with AMP_AE, although MP supply has been effectively reduced. This resulted in a maintained milk and milk component yields and improved the efficiency of utilization of N, MP, and essential AA. The DMP diets decreased total N excretion, whereas DMP_AE and DMP_EE diets also decreased milk urea-N concentration. Reducing MP supply without negative effects on dairy cow performance is possible when energy, dHis, dLys, and dMet requirements are met. This could reduce N excretion and decrease the environmental impact of milk production.

Importance Low school preparedness is linked to high school dropout, poor employment, and negative outcomes. Childcare attendance may increase school readiness and foster academic achievement. Objective To explore whether childcare attendance was associated with academic achievement at the end of compulsory schooling (age 16 years in the UK), whether maternal education level was a moderator, and the benefit-cost ratio of childcare regarding productivity returns of academic achievement. Design, Setting, and Participants In this cohort study, data were included from the Avon Longitudinal Study of Parents and Children (ALSPAC) born from April 1991 to December 1992 and the UK National Pupil Database for examination results. Data on academic achievement at age 16 years were available for 11 843 participants. Data were collected from June 2006 to June 2008, and data were analyzed from September 2019 to May 2020. Exposures On average, 3.7%, 5.9%, and 90.4% attended childcare full time, part time, and less than 10 hours per week, respectively. Maternal education was assessed by questionnaire during pregnancy. Analyses included weights for population representativeness and propensity score weights to account for parental selection into childcare. Main Outcomes and Measures Academic achievement was defined as no certificate, Level 1 General Certificate of Secondary Education (GCSE; limited training), or Level 2 GCSE (qualification for academic post-16 education; high school diploma equivalent). Lifetime productivity return estimates were withdrawn from previous economic analysis based on pupil’s qualifications. Results Of 14 541 children in the ALSPAC study, 8936 children had complete data on childcare attendance, academic achievement, and maternal education levels. Of these, 4499 (50.3%) were male. Attending childcare was associated with higher probabilities of obtaining a Level 1 or 2 GCSE qualification (Level 1: relative risk, 1.41; 95% CI, 1.16-1.73; Level 2: relative risk, 1.62; 95% CI, 1.30-2.01); however, this association was moderated by the child’s maternal education level. When children of mothers with low education attended childcare, their probability of no GCSE qualification went from 28.9% (95% CI, 26.8-31.0) to 20.3% (95% CI, 18.0-22.8), whereas children of mothers with higher education had a probability of no qualification of less than 10% regardless of childcare attendance. The benefit-cost ratio for each £1 (US $1.40) invested in full-time childcare attendance for children of mothers with low education was £1.71 (95% CI, 1.03-2.45; US $2.39; 95% CI, 1.44-3.43) for those who reached a Level 2 GCSE qualification. Conclusions and Relevance Promoting universal childcare with facilitated access for children of lower socioeconomic backgrounds deserves to be considered as a way to reduce the intergenerational transmission of low academic achievement.

ObjectiveTo develop a 180-day readmission risk model for older adults with acute myocardial infarction (AMI) that considered a broad range of clinical, demographic and age-related functional domains.MethodsWe used data from ComprehenSIVe Evaluation of Risk in Older Adults with AMI (SILVER-AMI), a prospective cohort study that enrolled participants aged ≥75 years with AMI from 94 US hospitals. Participants underwent an in-hospital assessment of functional impairments, including cognition, vision, hearing and mobility. Clinical variables previously shown to be associated with readmission risk were also evaluated. The outcome was 180-day readmission. From an initial list of 72 variables, we used backward selection and Bayesian model averaging to derive a risk model (N=2004) that was subsequently internally validated (N=1002).ResultsOf the 3006 SILVER-AMI participants discharged alive, mean age was 81.5 years, 44.4% were women and 10.5% were non-white. Within 180 days, 1222 participants (40.7%) were readmitted. The final risk model included 10 variables: history of chronic obstructive pulmonary disease, history of heart failure, initial heart rate, first diastolic blood pressure, ischaemic ECG changes, initial haemoglobin, ejection fraction, length of stay, self-reported health status and functional mobility. Model discrimination was moderate (0.68 derivation cohort, 0.65 validation cohort), with good calibration. The predicted readmission rate (derivation cohort) was 23.0% in the lowest quintile and 65.4% in the highest quintile.ConclusionsOver 40% of participants in our sample experienced hospital readmission within 180 days of AMI. Our final readmission risk model included a broad range of characteristics, including functional mobility and self-reported health status, neither of which have been previously considered in 180-day risk models.

A population pharmacokinetic (PK) model was developed using data pooled from 6 clinical studies (3 in healthy volunteers and 3 in cancer patients) to characterize total and free plasma concentrations of erdafitinib following single- and multiple-dose administration, to understand clinically relevant covariates, and to quantify the inter- and intraindividual variability in erdafitinib PK. An open, linear, 3-compartment disposition model with first-order absorption and a lag time was used to describe the PK profile of total and free erdafitinib plasma concentrations. The PK of erdafitinib were linear and time independent. After oral administration, erdafitinib was rapidly absorbed, with a time to maximum concentration between 2 and 4 hours. In patients, erdafitinib total apparent oral clearance was 0.200 L/h (median free fraction = 0.24%), and the effective terminal half-life of total drug was 76.4 hours. Interindividual variability in PK parameters was moderate for oral clearance and central volume of distribution, and large for absorption rate and peripheral volume of distribution. Sex and renal function were significant covariates on free oral clearance, while weight, sex, and α1 -acid-glycoprotein were significant on oral central volume of distribution. Age, race, and mild hepatic impairment were not significant covariates of erdafitinib exposure. Given that the magnitude of the covariate effects were within 25% of reference values and that the recommended dosing regimen of erdafitinib comprises individual dose up-titrations and reductions based on presence or absence of toxicities, the clinical relevance of the investigated covariates is expected to be limited, and no dose adjustments are warranted.

This paper is a revised and updated edition of a previous description of the Quebec Newborn Twin Study (QNTS), an ongoing prospective longitudinal follow-up of a birth cohort of twins born between 1995 and 1998 in the greater Montreal area, Québec, Canada. The goal of QNTS is to document individual differences in the cognitive, behavioral, and social-emotional aspects of developmental health across childhood, their early genetic and environmental determinants, as well as their putative role in later social-emotional adjustment, school, health, and occupational outcomes. A total of 662 families of twins were initially assessed when the twins were aged 6 months. These twins and their family were then followed regularly. QNTS now has 16 waves of data collected or planned, including 5 in preschool. Over the last 24 years, a broad range of physiological, cognitive, behavioral, school, and health phenotypes were documented longitudinally through multi-informant and multimethod measurements. QNTS also entails extended and detailed multilevel assessments of proximal (e.g., parenting behaviors, peer relationships) and distal (e.g., family income) features of the child’s environment. QNTS children and a subset of their parents have been genotyped, allowing for the computation of a variety of polygenic scores. This detailed longitudinal information makes QNTS uniquely suited for the study of the role of the early years and gene–environment transactions in development.

Erdafitinib, a potent oral fibroblast growth factor receptor inhibitor, is a low extraction ratio drug highly bound to alpha-1-acid glycoprotein (AGP) with free fraction (fu ) varying across populations. This analysis aimed to characterize the impact of plasma protein binding on erdafitinib pharmacokinetics (PK). Plasma protein-binding data (fu , AGP, albumin) and PK parameters were pooled from 6 phase 1 studies in healthy participants and 1 first-in-human study in patients with cancer. Binding kinetics were characterized using a nonlinear mixed-effects model. Mean (coefficient of variation, CV%) fu was 0.510% (39.4%) for healthy participants and 0.316% (64.0%) for patients, with a 2.1-fold higher AGP and 10% lower albumin. Linear binding of erdafitinib to AGP and albumin was observed, with >1000-fold higher binding constant for AGP than albumin (17.6 vs 0.017 µM-1 ). The fu decreased with increasing AGP in a nonlinear relationship. Despite its abundance in plasma relative to AGP, albumin contributed to

Studies have linked maternal pre-pregnancy obesity and hyperglycaemia with metabolic and neurodevelopmental complications in childhood. DNA methylation (DNAm) might enable foetal adaptations to environmental adversities through important gene loci. NEGR1 is involved in both energy balance and behaviour regulation. The aim of this study was to investigate associations between placental DNAm at the NEGR1 gene locus and childhood anthropometric and neurodevelopmental profiles in preschoolers. We analysed 276 mother-child dyads from Gen3G, a prospective birth cohort from Sherbrooke. At 3yo (40.4 ± 3.0 months), we measured body mass index (BMI) and the mothers reported on offspring neurobehavior using the Strengths and Difficulties Questionnaire (SDQ). We quantified DNAm levels at 30 CpGs at the NEGR1 locus using the MethylationEPIC Array in placental biopsies. DNAm at four CpGs located before NEGR1 second exon predicted child’s BMI z-score (cg26153364: β=−0.16 ± 0.04; p=0.008, cg23166710: β=0.14 ± 0.08; p=0.03) and SDQ total score (cg04932878: β=0.22 ± 1.0; p= 3.0x10(−4), cg16525738: β=−0.14 ± 0.18; p=0.01, cg23166710: β=−0.13 ± 0.36; p= 0.04), explaining 4.2% (p=0.003) and 7.3% (p= 1.3 x 10(−4)) of BMI-z and SDQ variances. cg23166710 was associated with both childhood phenotypes and correlated with NEGR1 placental expression (r=−0.22, p=0.04), suggesting its possible functional role. Together, maternal metabolic characteristics during pregnancy with NEGR1 DNAm levels explained 7.4% (p=4.2 x 10(−4)) of BMI-z and 14.2% (p=2.8 x 10(−7)) of SDQ variance at 3yo. This longitudinal study suggests that placental NEGR1 DNAm is associated with adiposity and neurodevelopment in preschool children and highlights its potential role in their comorbidity.

Temperature-humidity index (THI) calculation following the equation developed by the National Research Council (A Guide to Environmental Research on Animals, 1971) requires ambient temperature (AT) and relative humidity (RH). Those data are widely and readily available at local meteorological stations. However, studies showed that using average AT and RH retrieved from the closest stations is not appropriate for estimating on-farm conditions. The present objectives were (1) to study summer on-farm environmental conditions, (2) to explore the relationship between summer THI calculated with on-farm data and summer THI calculated with local weather station data, and (3) to verify whether THI calculated with summer meteorological station data could be adapted to better represent summer on-farm conditions. Six tiestall dairy farms located in 2 regions of the province of Québec [Eastern Québec (EQ) and Southwestern Québec (SWQ)] were enrolled in this study. Within-barn conditions were monitored using 3 remote data loggers from August 2016 through August 2017. Two loggers were installed inside at varying distances relative to the ventilation inlet (L1: closest to inlet; L2: farthest from inlet) and a third was installed just outside of the barn (L3). Values retrieved from each logger and the closest local meteorological station were used to calculate daily THI according to the National Research Council formula and were ultimately compared. Our results showed that THI varied within the barn depending on the proximity relative to the inlet because THI measured by L1 was lower than THI measured by L2 in both regions. Moreover, our results showed that in both regions AT measured on-farm was consistently higher than AT measured at the weather station. The opposite was observed with RH, as it was significantly lower on-farm in EQ and numerically lower in SWQ compared with RH extracted from weather stations. Overall, this led to THI being lower by 4.6 and 3.7 units at the weather stations compared with within-barn conditions for EQ and SWQ farms, respectively. Hence, using local meteorological station data to estimate on-farm conditions would lead to an underestimation of heat stress level in dairy cows. Adapting THI calculations by including daily maximum AT and minimum RH retrieved from the local weather station instead of their average counterparts led to a better estimation of within-barn conditions. However, the difference between THI measured on-farm and the adapted THI calculated with weather station data remained significant. Although the adaption made to THI allowed for a closer relation to on-farm conditions, THI calculated with weather station data should only be used to assess heat stress level in dairy cows when heat stress thresholds are adapted for such data.

International audience; BACKGROUND: Most preschool children in Western industrialized countries attend child care during the day while parents work. Studies suggest that child care may be stressful to young children, perhaps because they still lack the social skills to interact daily in a group setting away from parents. This gap in social abilities may be greater for children in lower-income families, who may face more adversity at home, with fewer resources and more social isolation. METHODS: We conducted a cluster-randomized controlled trial in 2013-2014 to test whether a social skills intervention led by early childhood educators within the child care center could reduce diurnal cortisol levels to more typical patterns expected of children this age. We randomized 19 public child care centers (n = 361 children) in low-income neighborhoods of Montreal, Canada, to either: 1) the Minipally program - intervention group (n = 10 centers; 186 children), or 2) waiting list - control group (n = 9 centers; 175 children). Saliva samples for cortisol levels were collected 3 times/day, pre- and post-implementation. The Minipally puppet program consists of 2 workshops/month for 8 months for the development of social skills and self-regulation in 2-5-year-olds, with reinforcement activities between workshops. Educators received 2-days' training and 12 h' supervision in Minipally. RESULTS: Linear mixed models for repeated measures revealed a significant interaction between intervention status and time of day of cortisol sampling (beta = -0.18, p = 0.04). The intervention group showed patterns of decreasing diurnal cortisol secretion (beta = -0.32, p < 0.01), whereas the control group showed increasing slopes (beta = 0.20, p < 0.01). Moreover, family income was a moderator; children in lower-income families benefited most from the intervention. CONCLUSION: Results suggest that a social skills training program, when integrated into a preschool education curriculum, can foster an environment more conducive to typical childhood patterns of cortisol secretion.

BACKGROUND CONTEXT Although 40% of adolescent idiopathic scoliosis (AIS) patients present with chronic back pain, the pathophysiology and underlying pain mechanisms remain poorly understood. We hypothesized that development of chronic pain syndrome in AIS is associated with alterations in pain modulatory mechanisms. PURPOSE To identify the presence of sensitization in nociceptive pathways and to assess the efficacy of the diffuse noxious inhibitory control in patients with AIS presenting with chronic back pain. STUDY DESIGN Cross-sectional study. PATIENT SAMPLE Ninety-four patients diagnosed with AIS and chronic back pain. OUTCOME MEASURES Quantitative sensory testing (QST) assessed pain modulation and self-reported questionnaires were used to assess pain burden and health-related quality of life. METHODS Patients underwent a detailed pain assessment using a standard and validated quantitative sensory testing (QST) protocol. The measurements included mechanical detection thresholds (MDT), pain pressure threshold (PPT), heat pain threshold (HPT), heat tolerance threshold (HTT), and a conditioned pain modulation (CPM) paradigm. Altogether, these tests measured changes in regulation of the neurophysiology underlying the nociceptive processes based on the patient's pain perception. Funding was provided by The Louise and Alan Edwards Foundation and The Shriners Hospitals for Children. RESULTS Efficient pain inhibitory response was observed in 51.1% of patients, while 21.3% and 27.7% had sub-optimal and inefficient CPM, respectively. Temporal summation of pain was observed in 11.7% of patients. Significant correlations were observed between deformity severity and pain pressure thresholds (p=.023) and CPM (p=.017), neuropathic pain scores and pain pressure thresholds (p=.015) and temporal summation of pain (p=.047), and heat temperature threshold and pain intensity (p=.048). CONCLUSIONS Chronic back pain has an impact in the quality of life of adolescents with idiopathic scoliosis. We demonstrated a high prevalence of impaired pain modulation in this group. The association between deformity severity and somatosensory dysfunction may suggest that spinal deformity can be a trigger for abnormal neuroplastic changes in this population contributing to chronic pain syndrome.

Background The dual syndrome hypothesis of cognitive impairment in PD suggests that two cognitive profiles exist with distinct pathological mechanisms and a differential risk for further cognitive decline. How these profiles relate to network dysfunction has never been explicitly characterized. Objective First, to assess intranetwork functional connectivity while considering global connectivity, and second, to relate network connectivity with measures of the dysexecutive and posterior cortical profiles. Methods Eighty-two subjects with idiopathic PD and 37 age-matched controls underwent resting-state functional MRI and comprehensive neuropsychological assessment. Intranetwork and global connectivity was compared between groups. Measures of the dysexecutive and posterior cortical profiles were related to network connectivity while considering demographic and disease-related covariates. Results PD subjects show decreased connectivity within several cortical networks. However, only the sensorimotor network displayed a loss of connectivity independent of the observed decreased global connectivity. The dysexecutive factor was independently related to increased motor severity, less education, and decreased connectivity in the sensorimotor network. The posterior cortical factor was related to increased age, less education, decreased connectivity in the central executive network, as well as increased connectivity in the temporal network. Conclusions Our results provide evidence supporting a network-specific process of degeneration in the sensorimotor network which contributes to the dysexecutive cognitive profile. In contrast, connectivity of the temporal and central executive network is related to the posterior cortical profile, representing a distinct network signature of this syndrome. © 2019 International Parkinson and Movement Disorder Society.