Halogenated flame retardants (HFRs) may disrupt thyroid hormone homeostasis, potentially affecting neurodevelopment in children. However, studies integrating multi-matrix HFR exposure assessment, thyroid function biomarkers, and multimodal neurodevelopmental outcomes in children remain limited. We examined associations of HFR exposures with thyroid function biomarker levels and, in turn, neurodevelopmental outcomes in children aged 8-12 years and evaluated thyroid function biomarkers as potential mediators. We utilized cross-sectional data within the prospective GESTation and Environment (GESTE) birth cohort in Canada. Among 167 children (57.5% female) with plasma HFRs and thyroid function biomarker data, 111 also provided stool samples, and 97-106 completed various attention-deficit/hyperactivity disorder-related trait scales, cognitive tests, and resting-state functional MRI. Higher plasma 2,2',4,4',5,5'-Hexabromodiphenyl ether (BDE-153) was associated with lower thyroid-stimulating hormone (TSH) (β = -0.20; 95% CI, -0.37 to -0.03), whereas higher stool 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) was associated with higher TSH (β = 0.14; 95% CI, 0.02 to 0.25). Higher TSH level was associated with lower block design score (β = -0.64; 95% CI, -1.17 to -0.11) and default mode network functional connectivity (β = -0.03; 95% CI, -0.05 to -0.01). Mediation analysis suggested an indirect effect of TSH in the association between stool BDE-47 and block design score (β = -0.14; 95% CI, -0.37 to -0.01). However, none of these associations above remained statistically significant after controlling for the false discovery rate. Despite the potential relationships between HFR exposures and TSH alterations that are linked to neurodevelopmental outcomes in school-aged children, the inconsistent results of HFRs from various studies suggest further evidence is needed to reveal the complex relationship.

Diffusion MRI (dMRI) provides a powerful, non-invasive window into white matter (WM) development. Yet, most existing processing pipelines are not well-suited to the rapidly evolving neurophysiology of the pediatric brain. Here, we introduce sf-pediatric, a scalable, end-to-end, age-adaptable dMRI pipeline that integrates normative models of brain diffusivities to enable optimal subject-specific analysis from birth through 18 years old. Leveraging normative trajectories derived from nearly 2,000 participants from six cohorts, sf-pediatric dynamically calibrates diffusion priors, template selection, segmentation, and WM atlases based on the subject′s age. By incorporating automatic quality control into a portable, tested, containerized, open-access, and press-button framework across computing environments, sf-pediatric provides a robust pipeline for large-scale pediatric dMRI studies. We validated this approach by showing improved local modeling and cortical fanning while preserving reproducibility and the ability to derive brain-behavior relationships. Additionally, we demonstrated robust recovery of known developmental trajectories of WM microstructure and connectome-derived network organization. ### Competing Interest Statement Author MD is a co-founder and shareholder at Imeka Solutions Inc (www.imeka.ca). All other authors declare no financial or non-financial competing interests. Canadian Institutes of Health Research, https://ror.org/01gavpb45, 493956

BACKGROUND:Normative modeling of brain development has gained traction for quantifying individual deviations in maturation. The brain age gap (BAG), the difference between predicted age from magnetic resonance imaging features and chronological age, offers a potential individualized normative metric of neurodevelopment. However, consistent patterns across psychiatric disorders remain elusive, and no studies have examined whether BAG can predict developmental trajectories within an inclusive continuous model of youth's cognition and behavior. METHODS:Using longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (ages 9-15, n = 9074), we built 8 region-specific brain age models using volumes, thicknesses, and surface areas of parcels from the Brainnetome adolescent atlas. We derived psychiatric diagnoses from a parental questionnaire. Multivariate linear regression analysis was used to assess case-control differences and cross-sectional continuous cognitive/behavioral profiles. We modeled cognitive/behavioral trajectories using a multivariate joint latent class mixed model and assessed the relationship with BAG values using multinomial logistic regression. RESULTS:Children with attention-deficit/hyperactivity disorder showed negative BAGs across multiple regions (Cohen's d = -0.12 to -0.08), while subcortical BAG emerged as a transdiagnostic indicator of younger-appearing brains (d = -0.07, false discovery rate-corrected p = .024). Older-appearing brains were associated with a high-cognition, low-symptom profile, whereas younger-appearing brains were associated with a low-cognition profile. Three developmental trajectories were identified: stable, toward externalizing behaviors, and toward internalizing behaviors. Widespread positive BAG predicted evolution toward internalizing behaviors but reduced the likelihood of the externalizing trajectory. CONCLUSIONS:Integrating BAG with continuous cognitive and behavioral profiles yielded a plausible framework for early identification of atypical trajectories, potentially contributing to personalized medicine in psychiatry.

The safety of antenatal corticosteroid administration during the late preterm period is currently questioned. This experimental study conducted in a CD-1 mouse model aimed to determine if exposure to betamethasone in the late preterm period 1) induces behavioral changes in adulthood and 2) alters cerebral anatomy. In the prenatal group, four gravid mice were randomly assigned to receive 0.1 mg of betamethasone (around 1.82 mg/kg based on an average body weight of 55 g) or an equivalent volume of phosphate buffered saline (PBS) on gestation day 18, and yielded a total of 43 pups. This model was selected to test the impact of cumulative exposure to exogenous and endogenous steroids. In the postnatal group, six gravid mice yielded a total of 69 pups which were randomly assigned to receive betamethasone or PBS. Pups in the intervention group received 0.03 mg of betamethasone subcutaneously on postnatal day 5, at which time mouse brain development is equivalent to that of humans at 34-36 weeks' gestation. To evaluate objective 1, pups were subjected to behavioral tests on postnatal days 21-50. On postnatal day 60, structural magnetic resonance imaging (MRI) was performed to assess objective 2. Outcomes were compared between treatment groups using linear mixed models including random effects for litter and a fixed term for the interaction of treatment and sex. We used a statistical significance threshold of p < 0.05. Male mice exposed to betamethasone ante- or postnatally engaged in more social contact than those exposed to PBS (interaction of betamethasone and male sex: prenatal β = 0.09, 95 % CI (0.02, 0.17), p = 0.02; postnatal β = 0.08, 95 %CI (0.01, 0.14), p = 0.03), while female mice engaged in less social contact. MRI showed that male mice exposed to betamethasone prenatally had larger habenulas and smaller amygdala than those exposed to PBS (interaction of betamethasone and male sex: habenula β = 0.01, 95 %CI (0.004, 0.02), p = 0.01, amygdala β = -1.43, 95 %CI (-2.67, -0.21), p = 0.03), while female mice had larger amygdala and smaller habenulas. Postnatal exposure to betamethasone was associated with lower combined volume of the parietal cortex and hypothalamus (interaction of betamethasone and male sex: β = -0.32, 95 %CI (-0.58, -0.03), p = 0.04). No other significant differences in behavioral outcomes or brain volumes were identified. These results suggest that exposure to betamethasone in the late preterm period is associated with small but significant sex-specific disruptions of the limbic system, associated with social behavior disturbances.

BACKGROUND:Sleep and fatigue complaints during pregnancy may increase risk for cognitive impairment among offspring, yet this relationship is difficult to disentangle from related risk factors such as perinatal depression. This longitudinal study examined the role of prenatal sleep/fatigue disturbances, independent of pre- and postnatal depression, and offspring cognition at age 24-36 months in relation with the gestational timing of sleep/fatigue disturbances. METHODS:Participants included 127 mother-child dyads. Maternal sleep (i.e., difficulties falling/staying sleep or sleeping too much), fatigue, and depression were self-reported monthly via the Patient Health Questionnaire-9 (PHQ-9) across the second and third trimesters. The Bayley Scales of Infant Development-4 cognition subscale was administered at 24-36 months. Hypothesis-driven and data-driven (fuzzy c-mean clustering) analyses assessed relationships between prenatal sleep/fatigue, separately by trimester, and toddler cognition after accounting for pre- and postnatal depression symptoms and prenatal medications. RESULTS:Maternal sleep and fatigue disturbances in the second, but not third, trimester were associated with poorer offspring cognition at 24-36 months (β = -0.24, p = 0.038). Fuzzy c-mean clustering analysis of PHQ-9 data returned a 7-profile solution characterizing depressive symptom clusters. A cluster profile defined by high sleep/fatigue complaints and low mood symptoms in the second trimester was associated with lower offspring cognition at 24-36 months (β = -1.39, p = 0.028). CONCLUSIONS:Maternal sleep and fatigue disturbances during the second trimester were associated with poorer toddler cognition. Further studies should assess maternal biological mechanisms (e.g., stress, cortisol, oxygenation, inflammation, immunity modulation) as well as the impact of clinical sleep interventions in pregnancy on cognitive development of offspring.

Halogenated flame retardants (HFRs) are widely used chemicals with potential neurotoxicity, yet limited epidemiologic evidence exists for their association with childhood neurodevelopment. We investigated associations between HFR exposures and attention-deficit/hyperactivity disorder (ADHD)-related traits and brain functional connectivity in 194 children aged 8-12 years from the GESTation and Environment (GESTE) birth cohort in Sherbrooke, Canada. We assessed 16 legacy and emerging HFRs in plasma and stool, with 5 in plasma and 9 in stool samples included in the final analysis. ADHD-related traits were assessed using behavioral questionnaires and the Conners Continuous Performance Test. Resting-state functional magnetic resonance imaging was used to assess brain functional connectivity in four ADHD-relevant brain networks. We applied covariate-adjusted linear regression models to examine associations between HFRs and outcomes, applying a false discovery rate correction of 0.1 for multiple comparisons. Several nominally significant associations were identified before correction, including a positive association between anti-DP and attention problems, negative associations between Dec602 and hyperactivity, and BB153 and hit reaction time variability. However, none remained significant after multiple comparison correction. Overall, we observed no significant associations between HFR concentrations in plasma or stool and ADHD-related traits or brain functional connectivity, suggesting that there is limited evidence for a link between them.

Psychiatry is undergoing a shift toward precision medicine, demanding personalized approaches that capture the complexity of cognition and behavior. Here, we introduce a novel referential of four robust, replicable, and generalizable cognitive and behavioral profiles. These were derived from a large pediatric cohort (ABCD: n = 10,843) and validated in two independent cohorts (BANDA: n = 195 and GESTE: n = 271) regrouping children aged 9–17 years. We demonstrate the profiles’ longitudinal stability and consistency with clinical diagnoses in the general population while exposing critical discrepancies across parent-reported, youth-reported, and expert-derived diagnoses. Beyond validation, we showcase the real-world utility of our approach by linking profiles to environmental factors, revealing associations between parental influences and youths’ cognition and behavior. Our fuzzy profiling framework moves beyond discrete classification, offering a powerful tool to refine psychiatric evaluation and intervention. We provide an open-source framework, enabling researchers and clinicians to fast-track implementation and foster a data-driven, domain-based approach to diagnosis.

Background The association between bacterial strains and clinical outcomes in Clostridioides difficile infection (CDI) has yielded conflicting results across studies. We conducted a systematic review and meta-analyses to assess the impact of these strains.Methods Five electronic databases were used to identify studies reporting CDI severity, complications, recurrence, or mortality according to strain type from inception to June 2022. Random effect meta-analyses were conducted to assess outcome proportions and risk ratios (RRs).Results A total of 93 studies were included: 44 reported recurrences, 50 reported severity or complications, and 55 reported deaths. Pooled proportions of complications were statistically comparable between NAP1/BI/R027 and R001, R078, and R106. Pooled attributable mortality was 4.8% with a gradation in patients infected with R014/20 (1.7%), R001 (3.8%), R078 (5.3%), and R027 (10.2%). Higher 30-day all-cause mortality was observed in patients infected with R001, R002, R027, and R106 (range, 20%-25%). NAP1/BI/R027 was associated with several unfavorable outcomes: recurrence 30 days after the end of treatment (pooled RR, 1.98; 95% CI, 1.02-3.84); admission to intensive care, colectomy, or CDI-associated death (1.88; 1.09-3.25); and 30-day attributable mortality (1.96; 1.23-3.13). The association between harboring the binary toxin gene and 30-day all-cause mortality did not reach significance (RR, 1.6 [0.9-2.9]; 7 studies).Results A total of 93 studies were included: 44 reported recurrences, 50 reported severity or complications, and 55 reported deaths. Pooled proportions of complications were statistically comparable between NAP1/BI/R027 and R001, R078, and R106. Pooled attributable mortality was 4.8% with a gradation in patients infected with R014/20 (1.7%), R001 (3.8%), R078 (5.3%), and R027 (10.2%). Higher 30-day all-cause mortality was observed in patients infected with R001, R002, R027, and R106 (range, 20%-25%). NAP1/BI/R027 was associated with several unfavorable outcomes: recurrence 30 days after the end of treatment (pooled RR, 1.98; 95% CI, 1.02-3.84); admission to intensive care, colectomy, or CDI-associated death (1.88; 1.09-3.25); and 30-day attributable mortality (1.96; 1.23-3.13). The association between harboring the binary toxin gene and 30-day all-cause mortality did not reach significance (RR, 1.6 [0.9-2.9]; 7 studies).Conclusions Numerous studies were excluded due to discrepancies in the definition of the outcomes and the lack of reporting of important covariates. NAP1/BI/R027, the most frequently reported and assessed strain, was associated with unfavorable outcomes. However, there were not sufficient data to reach significant conclusions on other strains. A systematic review (93 studies) and meta-analysis were conducted to assess the association between bacterial strains and complications, recurrence, and mortality in Clostridioides difficile infection. NAP1/BI/R027 was associated with unfavorable outcomes. Data on other strains were insufficient for significant conclusions.

Regional anesthesia may favour postoperative rehabilitation by inhibiting peripheral sensitization and secondary hyperalgesia. The literature on this subject is limited. In the present FUNCTION study, we sought to compare the functional recovery post orthopedic wrist surgery with regional versus general anesthesia. We conducted a single-centre prospective observational cohort study in adult patients with a distal radial fracture. Functional recovery was assessed with validated psychometrics questionnaires (Quick Disabilities of Arm, Shoulder and Hand [QuickDASH] and Patient-Rated Wrist Evaluation [PRWE]), range of motion, and grip strength. We used a linear mixed regression model to assess the impact of the anesthesia technique on functional recovery. Postoperative pain and patient satisfaction were evaluated using a visual analog scale. We recruited 76 patients. At 12 weeks post surgery, there was no difference between the type of anesthesia and functional recovery with the QuickDASH (higher scores worse; regional anesthesia [RA], 22.7 vs general anesthesia [GA], 19.3; adjusted mean difference [aMD], −0.3; 95

Structural and functional magnetic resonance imaging (MRI) studies have suggested a neuroanatomical basis that may underly attention-deficit-hyperactivity disorder (ADHD), but the anatomical ground truth remains unknown. In addition, the role of the white matter (WM) microstructure related to attention and impulsivity in a general pediatric population is still not well understood. Using a state-of-the-art structural connectivity pipeline based on the Brainnetome atlas extracting WM connections and its subsections, we applied dimensionality reduction techniques to obtain biologically interpretable WM measures. We selected the top 10 connections-of-interests (located in frontal, parietal, occipital, and basal ganglia regions) with robust anatomical and statistical criteria. We correlated WM measures with psychometric test metrics (Conner's Continuous Performance Test 3) in 171 children (27 Dx ADHD, 3Dx ASD, 9-13 years old) from the population-based GESTation and Environment cohort. We found that children with lower microstructural complexity and lower axonal density show a higher impulsive behavior on these connections. When segmenting each connection in subsections, we report WM alterations localized in one or both endpoints reflecting a specific localization of WM alterations along each connection. These results provide new insight in understanding the neurophysiology of attention and impulsivity in a general population.

Background: Prenatal exposure to persistent organic pollutants (POPs), widespread in North America, is associated with increased Attention Deficit/Hyperactivity Disorder (ADHD) symptoms and may be a modifiable risk for ADHD phenotypes. However, the effects of moderate exposure to POPs on task-based inhibitory control performance, related brain function, and ADHD-related symptoms remain unknown, limiting our ability to develop interventions targeting the neural impact of common levels of exposure. Objectives: The goal of this study was to examine the association between prenatal POP exposure and inhibitory control performance, neural correlates of inhibitory control and ADHD-related symptoms. Methods: Prospective data was gathered in an observational study of Canadian mother-child dyads, with moderate exposure to POPs, including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), as part of the GESTation and the Environment (GESTE) cohort in Sherbrooke, Quebec, Canada. The sample included 87 eligible children, 46 with maternal plasma samples, functional magnetic resonance imaging (fMRI) data of Simon task performance at 9-11 years, and parental report of clinical symptoms via the Behavioral Assessment System for Children 3 (BASC-3). Simon task performance was probed via drift diffusion modeling, and parameter estimates were related to POP exposure. Simon task-based fMRI data was modeled to examine the difference in incongruent vs congruent trials in regions of interest (ROIs) identified by meta analysis. Results: Of the 46 participants with complete data, 29 were male, and mean age was 10.42 +/- 0.55 years. Increased POP exposure was associated with reduced accuracy (e.g. PCB molar sum rate ratio = 0.95; 95% CI [0.90, 0.99]), drift rate (e.g. for PCB molar sum beta =-0.42; 95% CI [-0.77,-0.07]), and task-related brain activity (e.g. in inferior frontal cortex for PCB molar sum beta =-0.35; 95% CI [-0.69,-0.02]), and increased ADHD symptoms (e.g. hyperactivity PCB molar sum beta = 2.35; 95%CI [0.17, 4.53]), supporting the possibility that prenatal exposure to POPs is a modifiable risk for ADHD phenotypes. Discussion: We showed that exposure to POPs is related to task-based changes in neural activity in brain regions important for inhibitory control, suggesting a biological mechanism underlying previously documented associations between POPs and neurobehavioral deficits found in ADHD phenotypes.

The apparent increase in the prevalence of the attention deficit hyperactivity disorder (ADHD) diagnosis raises many questions regarding the variability of the subjective diagnostic method. This comprehensive review reports findings in studies assessing white matter (WM) bundles in diffusion MRI and symptom severity in children with ADHD. These studies suggested the involvement of the connections between the frontal, parietal, and basal ganglia regions. This review discusses the limitations surrounding diffusion tensor imaging (DTI) and suggests novel imaging techniques allowing for a more reliable representation of the underlying biology. We propose a more inclusive approach to studying ADHD that includes known endophenotypes within the ADHD diagnosis. Aligned with the Research Domain Criteria Initiative, we also propose to investigate attentional capabilities and impulsive behaviours outside of the borders of the diagnosis. We support the existing hypothesis that ADHD originates from a developmental error and propose that it could lead to an accumulation in time of abnormalities in WM microstructure and pathways. Finally, state-of-the-art diffusion processing and novel artificial intelligence approaches would be beneficial to fully understand the pathophysiology of ADHD.