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Abstract Background Venous thromboembolism (VTE) is a preventable medical condition which has substantial impact on patient morbidity, mortality, and disability. Unfortunately, adherence to the published best practices for VTE prevention, based on patient centered outcomes research (PCOR), is highly variable across U.S. hospitals, which represents a gap between current evidence and clinical practice leading to adverse patient outcomes. This gap is especially large in the case of traumatic brain injury (TBI), where reluctance to initiate VTE prevention due to concerns for potentially increasing the rates of intracranial bleeding drives poor rates of VTE prophylaxis. This is despite research which has shown early initiation of VTE prophylaxis to be safe in TBI without increased risk of delayed neurosurgical intervention or death. Clinical decision support (CDS) is an indispensable solution to close this practice gap; however, design and implementation barriers hinder CDS adoption and successful scaling across health systems. Clinical practice guidelines (CPGs) informed by PCOR evidence can be deployed using CDS systems to improve the evidence to practice gap. In the Scaling AcceptabLE cDs (SCALED) study, we will implement a VTE prevention CPG within an interoperable CDS system and evaluate both CPG effectiveness (improved clinical outcomes) and CDS implementation. Methods The SCALED trial is a hybrid type 2 randomized stepped wedge effectiveness-implementation trial to scale the CDS across 4 heterogeneous healthcare systems. Trial outcomes will be assessed using the RE2-AIM planning and evaluation framework. Efforts will be made to ensure implementation consistency. Nonetheless, it is expected that CDS adoption will vary across each site. To assess these differences, we will evaluate implementation processes across trial sites using the Exploration, Preparation, Implementation, and Sustainment (EPIS) implementation framework (a determinant framework) using mixed-methods. Finally, it is critical that PCOR CPGs are maintained as evidence evolves. To date, an accepted process for evidence maintenance does not exist. We will pilot a “Living Guideline” process model for the VTE prevention CDS system. Discussion The stepped wedge hybrid type 2 trial will provide evidence regarding the effectiveness of CDS based on the Berne-Norwood criteria for VTE prevention in patients with TBI. Additionally, it will provide evidence regarding a successful strategy to scale interoperable CDS systems across U.S. healthcare systems, advancing both the fields of implementation science and health informatics. Trial registration Clinicaltrials.gov – NCT05628207. Prospectively registered 11/28/2022, https://classic.clinicaltrials.gov/ct2/show/NCT05628207 .

Abstract The global scientific response to COVID 19 highlighted the urgent need for increased throughput and capacity in bioanalytical laboratories, especially for the precise quantification of proteins that pertain to health and disease. Acoustic ejection mass spectrometry (AEMS) represents a much-needed paradigm shift for ultra-fast biomarker screening. Here, a quantitative AEMS assays is presented, employing peptide immunocapture to enrich (i) 10 acute phase response (APR) protein markers from plasma, and (ii) SARS-CoV-2 NCAP peptides from nasopharyngeal swabs. The APR proteins were quantified in 267 plasma samples, in triplicate in 4.8 h, with %CV from 4.2% to 10.5%. SARS-CoV-2 peptides were quantified in triplicate from 145 viral swabs in 10 min. This assay represents a 15-fold speed improvement over LC-MS, with instrument stability demonstrated across 10,000 peptide measurements. The combination of speed from AEMS and selectivity from peptide immunocapture enables ultra-high throughput, reproducible quantitative biomarker screening in very large cohorts.

Abstract Background Anxiety disorders are the most common psychiatric problems among Canadian youth and typically have an onset in childhood or adolescence. They are characterized by high rates of relapse and chronicity, often resulting in substantial impairment across the lifespan. Genetic factors play an important role in the vulnerability toward anxiety disorders. However, genetic contribution to anxiety in youth is not well understood and can change across developmental stages. Large-scale genetic studies of youth are needed with detailed assessments of symptoms of anxiety disorders and their major comorbidities to inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. Methods The Genetic Architecture of Youth Anxiety (GAYA) study is a Pan-Canadian effort of clinical and genetic experts with specific recruitment sites in Calgary, Halifax, Hamilton, Toronto, and Vancouver. Youth aged 10–19 (n = 13,000) will be recruited from both clinical and community settings and will provide saliva samples, complete online questionnaires on demographics, symptoms of mental health concerns, and behavioural inhibition, and complete neurocognitive tasks. A subset of youth will be offered access to a self-managed Internet-based cognitive behavioral therapy resource. Analyses will focus on the identification of novel genetic risk loci for anxiety disorders in youth and assess how much of the genetic risk for anxiety disorders is unique or shared across the life span. Discussion Results will substantially inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. Given that the GAYA study will be the biggest genomic study of anxiety disorders in youth in Canada, this project will further foster collaborations nationally and across the world.

The human immunodeficiency virus (HIV) integrates into the host genome forming latent cellular reservoirs that are an obstacle for cure or remission strategies. Viral transcription is the first step in the control of latency and depends upon the hijacking of the host cell RNA polymerase II (Pol II) machinery by the 5' HIV LTR. Consequently, "block and lock" or "shock and kill" strategies for an HIV cure depend upon a full understanding of HIV transcriptional control. The HIV trans-activating protein, Tat, controls HIV latency as part of a positive feed-forward loop that strongly activates HIV transcription. The recognition of the TATA box and adjacent sequences of HIV essential for Tat trans-activation (TASHET) of the core promoter by host cell pre-initiation complexes of HIV (PICH) has been shown to be necessary for Tat trans-activation, yet the protein composition of PICH has remained obscure. Here, DNA-affinity chromatography was employed to identify the mitotic deacetylase complex (MiDAC) as selectively recognizing TASHET. Using biophysical techniques, we show that the MiDAC subunit DNTTIP1 binds directly to TASHET, in part via its CTGC DNA motifs. Using co-immunoprecipitation assays, we show that DNTTIP1 interacts with MiDAC subunits MIDEAS and HDAC1/2. The Tat-interacting protein, NAT10, is also present in HIV-bound MiDAC. Gene silencing revealed a functional role for DNTTIP1, MIDEAS, and NAT10 in HIV expression in cellulo. Furthermore, point mutations in TASHET that prevent DNTTIP1 binding block the reactivation of HIV by latency reversing agents (LRA) that act via the P-TEFb/7SK axis. Our data reveal a key role for MiDAC subunits DNTTIP1, MIDEAS, as well as NAT10, in Tat-activated HIV transcription and latency. DNTTIP1, MIDEAS and NAT10 emerge as cell cycle-regulated host cell transcription factors that can control activated HIV gene expression, and as new drug targets for HIV cure strategies.

Abstract Background The natural abundance of nitrogen (δ15N) and carbon (δ13C) isotopes in animal tissues are used to estimate an animal’s efficiency in nitrogen utilization, and their feed conversion efficiency, especially in tropical grazing systems with prolonged protein restriction. It is postulated that selection for improving these two characteristics (δ15N and δ13C) would assist the optimisation of the adaptation in ever-changing environments, particularly in response to climate change. The aim of this study was to determine the heritability of δ15N and δ13C in the tail hair of tropically adapted beef cattle to validate their inclusion in genetic breeding programs. Methods In total, 492 steers from two breeds, Brahman (n = 268) and Droughtmaster (n = 224) were used in this study. These steers were managed in two mixed breed contemporary groups across two years (year of weaning): steers weaned in 2019 (n = 250) and 2020 (n = 242). Samples of tail switch hair representing hair segments grown during the dry season were collected and analysed for δ15N and δ13C with isotope-ratio mass spectrometry. Heritability and variance components were estimated in a univariate multibreed (and single breed) animal model in WOMBAT and ASReml using three generations of full pedigree. Results The estimated heritability of both traits was significantly different from 0, i.e. 0.43 ± 0.14 and 0.41 ± 0.15 for δ15N and δ13C, respectively. These traits had favourable moderate to high genetic and phenotypic correlations (− 0.78 ± 0.16 and − 0.40 ± 0.04, respectively). The study also provides informative single-breed results in spite of the limited sample size, with estimated heritability values of 0.37 ± 0.19 and 0.19 ± 0.17 for δ15N and δ13C in Brahman, and 0.36 ± 0.21 and 0.46 ± 0.22 for δ15N and δ13C in Droughtmaster, respectively. Conclusions The findings of this study show, for the first time, that the natural abundances of both nitrogen and carbon isotopes in the tail hair in cattle may be moderately heritable. With further research and validation, tail hair isotopes can become a practical tool for the large-scale selection of more efficient cattle.

Fetal alcohol spectrum disorders (FASD) are among the most common neurodevelopmental disorders and substantially impact public health. FASD can affect people of all races and ethnicities; however, there are important racial and ethnic disparities in alcohol-exposed pregnancy prevention, assessment and diagnosis of FASD, and interventions to support individuals with FASD and their families. In this article we use the Dis/Ability Studies and Critical Race Theory (Dis/Crit) framework to structure the exploration of disparities and possible solutions within these three areas (prevention, diagnosis, intervention). Dis/Crit provides a guide to understanding the intersection of dis/ability and race, while framing both as social constructs. Following the Dis/Crit framework, the systemic, historical, and contemporary racism and ableism present in psychological care is further discussed. We aim to elucidate these racial and ethnic disparities within the fields of psychology and neuropsychology through the Dis/Crit framework and provide potential points of action to reduce these disparities.

Introduction. The purpose of this study was to evaluate change in motor function, gait speed, dynamic balance, balance confidence, and quality of life (QoL) in nine participants with Parkinson’s disease (PwPD) completing Lee Silverman Voice Treatment BIG (LSVT-BIG), an external cueing and task-based intervention. Although supported as an efficacious treatment in PwPD, there is limited research examining clinically meaningful change in outcome measures related to external cueing and task-based interventions. Materials and Methods. This was a case series of nine PwPD (age range 64-76 years, 55% male) who completed the LSVT-BIG protocol. Disease duration ranged from 1 to 17 years and was classified as moderate in all participants (Hoehn and Yahr=2 or 3). Outcome measures included motor function (MDS-UPDRS Part III Motor), gait speed, dynamic balance (MiniBEST), Activities-specific Balance Confidence (ABC), and Summary Index for PD Quality of Life 39 (PDQ-SI). Assessments were completed at baseline (BASE), end of treatment (EOT), and 4 weeks after EOT (EOT+4). Results. Minimal detectable change (MDC) or minimal clinical important difference (MCID) was observed in one or more outcome measures in 8 of 9 participants at EOT and EOT+4 across domains of motor function (67%, 78%), gait speed (78%, 67%), balance confidence (44%, 33%), quality of life (44%, 78%), and dynamic balance (22%, 22%). Discussion. In this case series, 8 of 9 participants showed MDC or MCID changes across multiple functional domains. Improvements were observed immediately post (EOT) and 4-week post-treatment (EOT+4) suggesting a temporal component of the LSVT-BIG impact on functional change. Future research should include clinical trials to examine additional external cueing and task-based intervention efficacy with consideration of intensity, frequency, and mode of delivery across disease severity.

Background Parent and child mental health has suffered during the pandemic and transition phase. Structured and shared parenting may be intervention targets beneficial to families who are struggling with parent or child mental health challenges. Aims First, we investigated associations between structured and shared parenting and parent depression symptoms. Second, we investigated associations between structured and shared parenting and depression, hyperactivity/inattention and irritability symptoms in children. Method A total of 1027 parents in two-parent households (4797 observations total; 85.1% mothers) completed online surveys about themselves and their children (aged 2–18 years) from April 2020 to July 2022. Structured parenting and shared parenting responsibilities were assessed from April 2020 to November 2021. Symptoms of parent depression, child depression, child hyperactivity and inattention, child irritability, and child emotional and conduct problems were assessed repeatedly (one to 14 times; median of four times) from April 2020 to July 2022. Results Parents who reported higher levels of shared parenting responsibilities had lower depression symptoms (β = −0.09 to −0.32, all P < 0.01) longitudinally. Parents who reported higher levels of shared parenting responsibilities had children with fewer emotional problems (ages 2–5 years; β = −0.07, P < 0.05), fewer conduct problems (ages 2–5 years; β = −0.09, P < 0.01) and less irritability (ages 13–18 years; β = −0.27, P < 0.001) longitudinally. Structured parenting was associated with fewer conduct problems (ages 2–5 years; β = −0.05, P < 0.05). Conclusions Shared parenting is beneficial for parent and child mental health, even under chaotic or inflexible life conditions. Structured parenting is beneficial for younger children.

Plain Language Summary Management of uncontrollable motor movements in patients with advanced Parkinson’s disease rely on oral levodopa-based treatments. Non-motor symptoms such as depression and anxiety are managed with additional oral medications. Over time, higher and more frequent dosing of oral medications is required, resulting in complex medication regimens that impact quality of life and adherence. A real-world study of 10,752 Parkinson’s disease patients between 2014 and 2018 evaluated the effectiveness of two device-aided therapies to reduce pill burden, carbidopa/levodopa enteral suspension and deep brain stimulation. Carbidopa/levodopa suspension treatment involves continuous delivery of levodopa to the intestines through a surgical port attached to a portable pump. Brain stimulation involves surgery to attach metal wires to the brain to send electrical pulses via an implanted stimulator. As Parkinson’s disease predominately affects the elderly, we compared Medicare patients on carbidopa/levodopa suspension to a matched control group receiving no suspension and to those receiving brain stimulation. Average pill burden/day was measured prior to receiving a device-aided treatment (baseline) and at 0–6 months and 7–12 months post-treatment (follow-up). The top graph shows that by 6-months post-treatment, patients on carbidopa/levodopa suspension required fewer pills than those without suspension (4.7 versus 11.4), with further pill reduction at 12 months (3.5 versus 11.1). The bottom graph shows that by 6 months, patients on carbidopa/levodopa suspension required fewer pills than patients treated with brain stimulation (4.8 versus 7.4), with further reduction at 12 months (3.6 versus 7.0). The reduction in oral pill burden suggests that the carbidopa/levodopa suspension may present an opportunity to simplify treatment regimens.

Abstract Objective Early administration of tranexamic acid (TXA) has been shown to save lives in trauma patients, and some U.S. emergency medical systems (EMS) have begun providing this therapy prehospital. Treatment protocols vary from state to state: Some offer TXA broadly to major trauma patients, others reserve it for patients meeting vital sign criteria, and still others defer TXA entirely pending a hospital evaluation. The purpose of this study is to compare the avoidable mortality achievable under each of these strategies, and to report on the various approaches used by EMS. Methods We used the National Center for Health Statistics Underlying Cause of Death data to identify a TXA-naïve population of trauma patients who died from 2007 to 2012 due to hemorrhage. We estimated the proportion of deaths where the patient was hypotensive or tachycardic using the National Trauma Data Bank. We used avoidable mortality risk ratios from the landmark CRASH 2 study to calculate lives saved had TXA been given within one hour of injury based on a clinician’s gestalt the patient was at risk for significant hemorrhage; had it been reserved only for hypotensive or tachycardic patients; or had it been given between hours one to three of injury, considered here as a surrogate for deferring the question to the receiving hospital. Results Had TXA been given within 1 hour of injury, an average of 3409 deaths per year could have been averted nationally. Had TXA been given between one and three hours after injury, 2236 deaths per year could have been averted. Had TXA only been given to either tachycardic or hypotensive trauma patients, 1371 deaths per year could have been averted. Had TXA only been given to hypotensive trauma patients, 616 deaths per year could have been averted. Similar trends are seen at the individual state level. A review of EMS practices found 15 statewide protocols that allow EMS providers to administer TXA for trauma. Conclusion Providing early TXA to persons at risk of significant hemorrhage has the potential to prevent many deaths from trauma, yet most states do not offer it in statewide prehospital treatment protocols.

Abstract Hoarding Disorder (HD) is a mental disorder characterized by persistent difficulties discarding or parting with possessions, often resulting in cluttered living spaces, distress, and impairment. Its etiology is largely unknown, but twin studies suggest that it is moderately heritable. In this study, we pooled phenotypic and genomic data from seven international cohorts (N = 27,537 individuals) and conducted a genome wide association study (GWAS) meta-analysis of parent- or self-reported hoarding symptoms (HS). We followed up the results with gene-based and gene-set analyses, as well as leave-one-out HS polygenic risk score (PRS) analyses. To examine a possible genetic association between hoarding symptoms and other phenotypes we conducted cross-trait PRS analyses. Though we did not report any genome-wide significant SNPs, we report heritability estimates for the twin-cohorts between 26–48%, and a SNP-heritability of 11% for an unrelated sub-cohort. Cross-trait PRS analyses showed that the genetic risk for schizophrenia and autism spectrum disorder were significantly associated with hoarding symptoms. We also found suggestive evidence for an association with educational attainment. There were no significant associations with other phenotypes previously linked to HD, such as obsessive-compulsive disorder, depression, anxiety, or attention-deficit hyperactivity disorder. To conclude, we found that HS are heritable, confirming and extending previous twin studies but we had limited power to detect any genome-wide significant loci. Much larger samples will be needed to further extend these findings and reach a “gene discovery zone”. To move the field forward, future research should not only include genetic analyses of quantitative hoarding traits in larger samples, but also in samples of individuals meeting strict diagnostic criteria for HD, and more ethnically diverse samples.

The purpose of this narrative review is to identify health and performance consequences associated with LCA in female endurance athletes. The intake of carbohydrates (CHO) before, during, and after exercise has been demonstrated to support sport performance, especially endurance activities which rely extensively on CHO as a fuel source. However, low energy availability (LEA) and low carbohydrate availability (LCA) are common in female athletes. LEA occurs when energy intake is insufficient compared to exercise energy expenditure, and LEA-related conditions (e.g., Female Athlete Triad (Triad) and Relative Energy Deficiency in Sport (RED-S)) are associated with a myriad of health and performance consequences. The RED-S model highlights 10 health consequences and 10 performance consequences related to LEA. The independent effect of LCA on health and performance has been under-researched, despite current CHO intake being commonly insufficient in athletes. It is proposed that LCA may not only contribute to LEA but also have independent health and performance consequences in athletes. Furthermore, this review highlights current recommendations for CHO intake, as well as recent data on LCA prevalence and menstrual cycle considerations. A literature review was conducted on PubMed, Science Direct, and ResearchGate using relevant search terms (i.e., “low carbohydrate/energy availability”, “female distance runners”). Twenty-one articles were identified and twelve met the inclusion criteria. The total number of articles included in this review is 12, with 7 studies illustrating that LCA was associated with direct negative health and/or performance implications for endurance-based athletes. Several studies included assessed male athletes only, and no studies included a female-only study design. Overall, the cumulative data show that female athletes remain underrepresented in sports science research and that current CHO intake recommendations and strategies may fail to consider female-specific adaptations and hormone responses, such as monthly fluctuations in estrogen and progesterone throughout the menstrual cycle. Current CHO guidelines for female athletes and exercising women need to be audited and explored further in the literature to support female athlete health and performance.

Abstract Background SYNJ1 encodes Synaptojanin‐1, a dual‐function poly‐phosphoinositide phosphatase that is expressed in the brain to regulate neuronal synaptic vesicle dynamics. Biallelic SYNJ1 variants cause a spectrum of clinical manifestations, from early onset parkinsonism to developmental and epileptic encephalopathy. Methods Proband‐only exome sequencing was used to identify a homozygous SYNJ1 pathogenic variant in an individual with epileptic encephalopathy. Sanger sequencing was used to confirm the variant. Results We present an Afro‐Caribbean female who developed uncontrollable seizures shortly after birth, accompanied by developmental delay and severe generalized dystonia. She had homozygosity for a novel c.242‐2A > G variant in SYNJ1 with both parents being heterozygous carriers. An older sister was reported to have had a similar presentation but was not examined. Both siblings died at an approximate age of 16 years. Conclusions We report a novel pathogenic variant in SYNJ1 present in homozygosity leading to developmental and epileptic encephalopathy. Currently, there are only 4 reports describing 10 individuals with SYNJ1‐related developmental and epileptic encephalopathy. This case expands the clinical knowledge and the allelic heterogeneity associated with SYNJ1 variants.

The comorbidity of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) diagnoses is well established. An ASD diagnosis is associated with elevated ADHD traits and symptoms, as well as strengths in attention. In the ASD literature, attentional strengths have been described as maladaptive (e.g., hyperfocus), in contrast with positive portrayals in the typically developing population (e.g., flow). The objective of this study was to (1) compare profiles of attentional strengths and weaknesses in ASD and ADHD and (2) determine whether attentional strengths in ASD are associated with impairment, poorer cognitive flexibility, and perseveration/perfectionism. In a community sample of 5,744 children and youth, 131 children were reported as having a diagnosis of ASD (mean age 10.3 years) and 346 children were reported as having a diagnosis of ADHD (mean age 10.7 years). We used the Strengths and Weaknesses of Attention-Deficit/Hyperactivity-symptoms and Normal-behaviors (SWAN) rating scale to calculate attentional and hyperactive/impulse control strength and weakness counts and scores. The Autism-Spectrum Quotient Switching factor served as a measure of cognitive flexibility. Impairment was assessed with the Columbia Impairment Scale. We used the symmetry/ordering factor on the Toronto Obsessive-Compulsive Scale as a measure of perseveration/perfectionism. No differences were found between the ADHD and ASD groups in SWAN weakness scores, symptoms, or hyperactive/impulse control strengths; however, autistic children had higher rates of attentional strengths [odds ratio: 5.7, 95% CI (2.8, 11.6), p < 0.0001]. Post-hoc pairwise testing identified four attentional strengths with significantly higher rates in ASD than in ADHD. Attentional strength scores were not associated with impairment or poor cognitive flexibility, but predicted levels of perseveration/perfectionism. The effect of attentional strengths on impairment and cognitive flexibility did not differ between autistic and Control children, but the higher perseveration/perfectionism scores seen in ASD were not found in Control children. ASD is associated with a pattern of attentional strengths that is not found in ADHD Characterizing the full range of attentional abilities in autistic children may explain variability in outcomes such as quality-of-life indicators and identify protective factors, providing targets for strength-based behavioral interventions. The clinical and etiological implications of the subgroup of autistic children with attentional strengths require further investigation.

In Ontario, Canada, school extracurricular activities and sports were modified or canceled for a prolonged period due to public health restrictions resulting from the COVID-19 pandemic. The present study aims to examine the association of changes to extracurricular and sport participation and child and youth mental health. Data were collected on child and youth mental health symptoms (n = 908) and participation in extracurricular activities and sports in the 2019–2020 and 2020–2021 academic years. Results indicated that pre-COVID (2019–2020) participation in either extracurricular activities or sports was associated with reduced anxiety, inattention, and hyperactivity during the pandemic (β range −0.08 to −0.11, p < 0.05). Participation in either extracurricular activities or sports during-COVID (2020–2021) was associated with lower depressive symptoms (β range −0.09 to −0.10, p < 0.05). Findings suggest that participation in extracurricular activities and/or school sports both before or during the COVID-19 pandemic were associated with better mental health outcomes in children and youth. Implications of this work consider future situations where restrictions on extracurricular and sport participation are reinstated and the impact of child and youth mental health.

Abstract Background Informal caregivers providing unpaid assistance may be vulnerable to changes in health behaviors due to modifications in caregiving during the COVID-19 pandemic. Therefore, this cross-sectional study explored self-reported changes in physical activity (PA), sedentary behavior, and screen time among informal caregivers providing care for older adults aged 50+ during the pandemic. Methods Study participants were recruited via Amazon’s Mechanical Turk and reported their perceived changes (increased a lot, increased a little, remained the same, decreased a little, decreased a lot) in moderate-intensity PA (MPA), vigorous-intensity PA (VPA), sedentary behavior, and screen time (weekday and weekend) during the pandemic. For analytic purposes, response categories were categorized into three-level ordinal variables—increased (increased a lot, increased a little), no change (remained the same), decreased (decreased a little, decreased a lot). Multinomial logistic regression models assessed the likelihood of changes (vs. no change) in MPA, VPA, sedentary behavior, and screen time (weekday, weekend) based on caregiving and demographic characteristics. Results In total, 2574 individuals accessed the study link, 464 of whom did not meet eligibility requirements. In addition, people who completed 80% or less of the survey (n = 1171) and/or duplicate IP addresse (n = 104) were excluded, resulting in an analytic sample of n = 835. The sample was 69% male, had a mean age of 34 (SD = 9.7), and 48% reported increased VPA, while 55% reported increased MPA. The majority also reported increased sedentary behavior, as well as increased screen time. Respondents living with their care recipient were more likely to report increased weekday screen time (Odds Ratio [OR] = 1.55, 95% CI 1.11–2.16) and sedentary behavior (OR = 1.80, 95% CI 1.28–2.53) than respondents not living with the care recipient. Those living with their care recipient were also more likely to reported increased MPA (OR = 1.64, 95% CI 1.16–2.32), and VPA (OR = 1.53, 95% CI 1.09–2.15), but also more likely to report a decrease in VPA (OR = 1.75, 95% CI 1.14–2.70). Conclusion The majority of respondents reported that their MPA, VPA PA, sedentary behavior, and screen time had changed during the pandemic. Living with the care recipient was associated with both positive and negative changes in behavior. Future research can explore factors associated with these reported changes in behavior.

Abstract Background Although largely preventable through diet management and topical fluoride use, early childhood caries (ECC) often progresses to severity that necessitates surgical repair. Yet repair often fails to mitigate caries progression. Needed is an effective behavioral intervention to address underlying behavioral causes. Methods This randomized controlled trial will evaluate the efficacy of a behaviorally focused, family-centered intervention, the MySmileBuddy Program (MSB Program), to reduce ECC progression in high-risk preschoolers in New York City. Recruitment will target 858 children ages 24–71 months with ECC and their parents from primary care medical and dental clinics. The study aims to assess the MSB Program’s efficacy to: (1) decrease ECC progression measured 12-months post-randomization; and (2) enhance adoption of a low cariogenic diet and twice-daily fluoridated toothpaste use compared to control group. Potential causal pathways (mediators and moderators) will be explored. The MSB Program equips community health workers (CHWs) with an app that facilitates multilevel risk assessment and provides motivational interviewing-based counseling to inform parents about the caries process, develop personalized goals, and create family-level action plans to achieve targeted behaviors. Social support from CHWs (4 interactions during the 6-month intervention, supplemented by up to 4 in-person/remote contacts throughout the 12-month study period, based on need) is bolstered by automated text messages. Participants will be randomized to a Control Group (paper-based educational handout plus toothbrushes and fluoridated toothpaste for the child) or Intervention Group (MSB Program, two tooth-brushing observations with feedback and instruction, and toothbrushes and toothpaste for the entire family). All children will receive visual ICDAS dental examinations and parents will complete study measures at baseline and 12-months. An incentive up to $150 plus round-trip transit cards ($5.50 value) will be provided. Discussion This study hypothesizes that the MSB Program can reduce ECC progression in a high-risk population. Sufficient incentives and a focus on establishing rapport between participants and CHWs are anticipated to mitigate recruitment and retention challenges. If successful, this study will advance the long-term goal of reducing pediatric oral health disparities by demonstrating the efficacy of an acceptable and feasible intervention that shifts attention from dental repair to behavioral risk mitigation. Trial registration: Trial registration was completed on 4/13/2021 through the U.S. National Library of Medicine ClinicalTrials.gov website (Identifier: NCT04845594).

PurposeThe age-related decline in physical function is ameliorated by physical activity; however, less is known about changes in physical function in active vs. inactive older women. The purpose of this study was to determine the longitudinal associations between physical activity and physical function in community-dwelling older women.Methods238 participants (age 79.0 ± 5.1) were dichotomized into two activity groups [inactive (IG); n = 144 or active (AG); n = 94] based on self-reported exercise at baseline. Repeated measures ANCOVA, controlling for age, measured differences in physical function between activity groups at baseline and 48-months using the Timed Up and Go, 30-s chair stand, and 30-second arm curl. Differences in Timed Up and Go classification [normal (≤ 8.23 s); preclinical limitations/limited physical function (>8.23 s)] were analyzed using chi-square tests for activity group and for activity-age group (AG, 8.23 s (p < 0.001). At 48-months, individuals in the AG were more likely to have normal Timed Up and Go scores compared to those in the IG in both age groups [χ(3, N=236)2 = 42.56, p < 0.001].ConclusionOlder women who engaged in regular exercise at baseline had higher levels of objectively measured physical function and were less likely to have abnormal Timed Up and Go scores. These findings help illustrate the long-term benefit of exercise on physical function in older women.

Abstract Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10−8). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p’s

College students can be sedentary for a majority of the day, which may exacerbate mental health issues or lead to declines in cognitive task performance; however, interventions to address sedentary behaviors may not positively influence everyone. Therefore, the present study sought to identify inter-individual cognitive performance and mood changes of college students during the performance of a cognitive task battery, while seated, standing and with intermittent bouts of walking. Participants (n = 31, age = 25.80 ± 3.61 yrs, 7 male) completed a series of baseline questionnaires including the Trait Mental and Physical Energy and Fatigue survey. Using a randomized controlled cross-over design, participants completed 3 separate testing sessions. At each session, they performed a series of three rounds of cognitive tasks for 27 min and self-reporting mood states for 1 min in the seated position. Each round of cognitive testing was followed by a 2 min break. Each testing day had participants spend the 2 min break in a different condition: sitting, standing, or walking. A series of mixed ANOVAs were used for the primary analysis and a combination of machine learning regressors and classifiers were used for the secondary analysis. Our results suggest that there are unique inter-individual responses to each of the interventions used during the 2 min break. Participants who were low-trait mental and low-trait physical energy benefited the most from the standing desk intervention, while also reporting significant benefits of intermittent walking. However, participants who were low-trait mental fatigue had significant negative consequences of using both standing desks and walking intermittently, while those who were high-trait mental fatigue saw no change in cognitive responses or moods in those conditions. Post hoc machine learning analyses had modest accuracy rates (MAEs < 0.7 for regressors and accuracy rates >60% for classifiers), suggesting that trait mental and physical energy and fatigue may predict inter-individual responses to these interventions. Incorporating standing desks into college classroom settings may result in some students receiving cognitive benefits when inter-individual variability in mood and cognitive responses are accounted for.

Abstract Background Recent work has established that Parkinson’s disease (PD) patients have an altered gut microbiome, along with signs of intestinal inflammation. This could help explain the high degree of gastric disturbances in PD patients, as well as potentially be linked to the migration of peripheral inflammatory factors into the brain. To our knowledge, this is the first study to examine microbiome alteration prior to the induction of a PD murine model. Methods We presently assessed whether pre-treatment with the probiotic, VSL #3, or the inflammatory inducer, dextran sodium sulphate (DSS), would influence the PD-like pathology provoked by a dual hit toxin model using lipopolysaccharide (LPS) and paraquat exposure. Results While VSL #3 has been reported to have anti-inflammatory effects, DSS is often used as a model of colitis because of the gut inflammation and the breach of the intestinal barrier that it induces. We found that VSL#3 did not have any significant effects (beyond a blunting of LPS paraquat-induced weight loss). However, the DSS treatment caused marked changes in the gut microbiome and was also associated with augmented behavioral and inflammatory outcomes. In fact, DSS markedly increased taxa belonging to the Bacteroidaceae and Porphyromonadaceae families but reduced those from Rikencellaceae and S24-7, as well as provoking colonic pro-inflammatory cytokine expression, consistent with an inflamed gut. The DSS also increased the impact of LPS plus paraquat upon microglial morphology, along with circulating lipocalin-2 (neutrophil marker) and IL-6. Yet, neither DSS nor VSL#3 influenced the loss of substantia nigra dopamine neurons or the astrocytic and cytoskeleton remodeling protein changes that were provoked by the LPS followed by paraquat treatment. Conclusions These data suggest that disruption of the intestinal integrity and the associated microbiome can interact with systemic inflammatory events to promote widespread brain-gut changes that could be relevant for PD and at the very least, suggestive of novel neuro-immune communication.

In a 90-day GLP-compliant study groups of Sprague-Dawley rats (10/sex/group) were fed diets containing β-ionone epoxide, a fragrance material and a flavoring substance, at dietary concentrations providing target intakes of 0, 20, 40 and 80 mg/kg bw/day. There were no deaths and no adverse changes in clinical observations, ophthalmological examinations, body weight, body weight gain, food consumption, food efficiency; hematology, serum chemistry, urinalysis parameters; or in macroscopic findings attributable to β-ionone epoxide administration. Increased absolute and relative liver weights in high dose females without correlating hepatic histopathological findings were considered non-adverse. Cortical vacuolation of adrenal zona fasciculata was observed in high-dose males but was considered non-adverse due to the nondegenerative nature of this alteration. β-Ionone epoxide did not influence estrus cyclicity in females and did not affect sperm morphology or epididymal sperm count, homogenization-resistant spermatid count and motility measurements in male rats. The no-observed-adverse-effect level (NOAEL) for administration of β-ionone epoxide in the diet was determined to be the highest dose tested of 80 mg/kg bw/day.

In vitro maturation (IVM) is a promising assisted reproductive technology (ART) for human infertility treatment. However, when cumulus oocyte complexes (COCs) are removed from their follicular environment when manipulated in vitro, it can lead to a decrease of intra-oocyte cyclic adenosine 3’, 5’-monophosphare (cAMP) causing spontaneous nuclear maturation and an asynchrony with the oocytes’ cytoplasmic maturation, resulting in poor embryo developmental outcomes. Nuclear and cytoplasmic synchrony is important during oocyte maturation within antral follicles. It is maintained partially by the actions of c-type natriuretic peptide (CNP) binding with natriuretic peptide receptor 2 (NPR2), supporting high cAMP levels thus holding the oocyte in meiotic arrest. Addition of CNP to pre-IVM media has the capacity of maintaining cAMP levels and thus improve synchrony. Moreover, in women with advanced maternal age, successful IVM of aging oocytes faces significant challenges due to the morphological and cellular changes. Inhibiting initiation of nuclear maturation by cAMP modulator, CNP during pre-IVM period and thus improve oocyte developmental competence regardless of oocyte age.

Abstract Background A growing body of research has demonstrated associations between specific neurodevelopmental disorders and variation in DNA methylation (DNAm), implicating this molecular mark as a possible contributor to the molecular etiology of these disorders and/or as a novel disease biomarker. Furthermore, genetic risk variants of neurodevelopmental disorders have been found to be enriched at loci associated with DNAm patterns, referred to as methylation quantitative trait loci (mQTLs). Methods We conducted two epigenome-wide association studies in individuals with attention-deficit/hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD) (aged 4–18 years) using DNA extracted from saliva. DNAm data generated on the Illumina Human Methylation 450 K array were used to examine the interaction between genetic variation and DNAm patterns associated with these disorders. Results Using linear regression followed by principal component analysis, individuals with the most endorsed symptoms of ADHD or OCD were found to have significantly more distinct DNAm patterns from controls, as compared to all cases. This suggested that the phenotypic heterogeneity of these disorders is reflected in altered DNAm at specific sites. Further investigations of the DNAm sites associated with each disorder revealed that despite little overlap of these DNAm sites across the two disorders, both disorders were significantly enriched for mQTLs within our sample. Conclusions Our DNAm data provide insights into the regulatory changes associated with genetic variation, highlighting their potential utility both in directing GWAS and in elucidating the pathophysiology of neurodevelopmental disorders.

Abstract Background In tropically-adapted beef heifers, application of genomic prediction for age at puberty has been limited due to low prediction accuracies. Our aim was to investigate novel methods of pre-selecting whole-genome sequence (WGS) variants and alternative analysis methodologies; including genomic best linear unbiased prediction (GBLUP) with multiple genomic relationship matrices (MGRM) and Bayesian (BayesR) analyses, to determine if prediction accuracy for age at puberty can be improved. Methods Genotypes and phenotypes were obtained from two research herds. In total, 868 Brahman and 960 Tropical Composite heifers were recorded in the first population and 3695 Brahman, Santa Gertrudis and Droughtmaster heifers were recorded in the second population. Genotypes were imputed to 23 million whole-genome sequence variants. Eight strategies were used to pre-select variants from genome-wide association study (GWAS) results using conditional or joint (COJO) analyses. Pre-selected variants were included in three models, GBLUP with a single genomic relationship matrix (SGRM), GBLUP MGRM and BayesR. Five-way cross-validation was used to test the effect of marker panel density (6 K, 50 K and 800 K), analysis model, and inclusion of pre-selected WGS variants on prediction accuracy. Results In all tested scenarios, prediction accuracies for age at puberty were highest in BayesR analyses. The addition of pre-selected WGS variants had little effect on the accuracy of prediction when BayesR was used. The inclusion of WGS variants that were pre-selected using a meta-analysis with COJO analyses by chromosome, fitted in a MGRM model, had the highest prediction accuracies in the GBLUP analyses, regardless of marker density. When the low-density (6 K) panel was used, the prediction accuracy of GBLUP was equal (0.42) to that with the high-density panel when only six additional sequence variants (identified using meta-analysis COJO by chromosome) were included. Conclusions While BayesR consistently outperforms other methods in terms of prediction accuracies, reasonable improvements in accuracy can be achieved when using GBLUP and low-density panels with the inclusion of a relatively small number of highly relevant WGS variants.

Abstract Background There is a need to develop a multipurpose obsessive–compulsive disorder (OCD) measure that is useful for cross disorder research and as a reliable clinical rating scale. The current study examined the psychometric properties and established clinical cutoffs for the parent‐report version of the Toronto Obsessive–Compulsive Scale (TOCS), a 21‐item rating scale of obsessive–compulsive traits. Method Participants ranged in age from 6 to 21 years old and had a primary diagnosis of OCD (n = 350, 50% female), attention‐deficit/hyperactivity disorder (ADHD) (n = 820, 25% female), autism spectrum disorder (ASD) (n = 794, 22% female), or were typically developing controls (n = 391, 51% female). Confirmatory factor analyses, internal consistency reliability, and convergent and divergent validity of the TOCS were examined in the OCD group. Using various scoring approaches, receiver operating characteristic (ROC) analyses were used to establish a clinical cut‐off by splitting the OCD group into a discovery sample (166 OCD cases, 164 controls) and a validation sample (184 OCD cases, 227 controls). Classification accuracy and TOCS scores were compared across OCD, ADHD, and ASD groups. Results The psychometric properties of the TOCS were confirmed. ROC analyses across TOCS scoring approaches in the discovery sample indicated excellent diagnostic discrimination (AUC ≥0.95, sensitivity 77%–92%, specificity 92%–98%). Established cutoffs, when applied in the independent validation sample of OCD cases and controls, showed an overall classification accuracy of 85%–90%. The TOCS total score and symptom count showed good discrimination of OCD from ADHD (AUC ≥0.86) and ASD (AUC ≥0.81). The OCD group scored significantly higher on all TOCS dimensions (except Hoarding) than the ADHD and ASD groups. Conclusion The TOCS is a reliable and valid rating scale with strong sensitivity and specificity in discriminating OCD cases from controls, as well as from ASD and ADHD. It is a quantitative OCD measure with important clinical and research applications, with particular relevance for cross disorder phenotyping and population‐based studies.

Obesity during childhood has been associated with many important physiological and neurological health considerations. Specifically concerning are the associations between youth obesity and declines in mental health, as shown with increasing rates of adolescent depression and anxiety worldwide. The emergence of mental health disorders commonly arises during adolescent development, and approximately half the global population satisfy the criteria for at least one psychiatric disorder in their lifetime, suggesting a need for early intervention. Adolescence is critical time whereby brain structure and functions are not only negatively associated with obesity and declines in mental health, while also coinciding with significant declines in rates of physical activity among individuals in this age group. Physical activity is thus a prime candidate to address the intersection of obesity and mental health crises occurring globally. This review addresses the important considerations between physiological health (obesity, aerobic fitness, physical activity), brain health (structure and function), and mental wellbeing symptomology. Lastly, we pose a theoretical framework which asks important questions regarding the influence of physiological health on the association between brain health and the development of depression and anxiety symptoms in adolescence. Specifically, we hypothesize that obesity is a mediating risk factor on the associations between brain health and psychopathology, whereas physical activity is a mediating protective factor. We conclude with recommendations for promoting physical activity and reducing sedentary time.

Tonsillectomy is one of the most common surgical procedures performed in the United States with approximately 339,000 ambulatory tonsillectomies performed in 2010. Of these, an estimated 299,000 tonsillectomies were performed on patients less than 15 years of age. Damage to the internal carotid artery during routine tonsillectomy is a rare but feared complication of this relatively routine surgical procedure. We present the case of a medialized internal carotid artery encountered prior to pediatric tonsillectomy, as well as a review of the literature on internal carotid artery development and anatomic variations.

The androgen receptor (AR) is known for masculinization of behavior and brain. To better understand the role that AR plays, mice bearing humanized Ar genes with varying lengths of a polymorphic N-terminal glutamine (Q) tract were created (Albertelli et al., 2006). The length of the Q tract is inversely proporitional to AR activity. Biological studies of the Q tract length may also provide a window into potential AR contributions to sex-biases in disease risk. Here we take a multi-pronged approach to characterizing AR signaling effects on brain and behavior in mice using the humanized Ar Q tract model. We first map effects of Q tract length on regional brain anatomy, and consider if these are modified by gonadal sex. We then test the notion that spatial patterns of anatomical variation related to Q tract length could be organized by intrinsic spatiotemporal patterning of AR gene expression in the mouse brain. Finally, we test influences of Q tract length on four behavioral tests.Altering Q tract length led to neuroanatomical differences in a non-linear dosage-dependent fashion. Gene expression analyses indicated that adult neu- roanatomical changes due to Q tract length are only associated with neurode- velopment (as opposed to adulthood). No significant effect of Q tract length was found on the behavior of the three mouse models. These results indicate that AR activity differentially mediates neuroanatomy and behavior, that AR activity alone does not mediate sex differences, and that neurodevelopmen- tal processes are associated with spatial patterns of volume changes due to Q tract length in adulthood. They also indicate that androgen sensitivity in adulthood is not likely to lead to autism-related behaviors or neuroanatomy, although neurodevelopmental processes may play a role earlier. Further study into sex differences, development, other behaviors, and other sex-specific mech- anisms are needed to better understand AR sensitivity, neurodevelopmental disorders, and the sex difference in their prevalence.

The Teaching and Learning Network (TLN) at the University of Guelph, Ontario, Canada, represents an effective network model for faculty and educational leadership development. Grounded in the principles of communities of practice (Wenger, 1998), the TLN is a collaborative network that fosters interdisciplinary dialogue, relationship building, knowledge exchange, and professional development for its members and the broader campus community. This article explains the TLN's structure, goals, and activities, with special attention to practical examples and suggestions for advancing faculty development through this network model.

Objectives To determine if adults with overweight or obesity received counselling from their healthcare providers (HCPs) to lose weight and/or adopt healthful behaviours associated with weight loss, and whether they took action on their HCPs’ recommendations.Design Cross-sectional analysis of 2011–2018 National Health and Nutrition Examination Survey (NHANES) data.Sample NHANES respondents aged 18+ who were overweight/obese and had seen an HCP in the previous 12 months (n=13 158).Methods Respondents reported if their HCPs recommended they control/lose weight, increase exercise/physical activity (PA) and/or reduce fat/calorie intake, and if they adopted the offered recommendation(s). Weighted logistic regression models examined receipt of HCP counselling by sex, age, race/ethnicity, and weight status accounting for demographic characteristics and complex sampling. Similar analyses examined reported adoption of HCPs’ recommendations.Results The sample was 53.1% women, 45.0% were overweight and 55.0% had obesity. In total, 40.4% received counselling to control/lose weight, 49.5% to increase exercise/PA and 38.9% to reduce fat/calorie intake. The following groups were less likely (p

Introduction Unified critical care training within residency education is a necessity. We created a simulation-based curriculum designed to educate residents on core topics and procedural skills, which crossed all adult disciplines caring for critically ill patients. Methods Residents from seven adult disciplines participated in this annual program during intern year. Learners were grouped into mixed discipline cohorts. Each cohort attended three distinct 4-hour simulation-based sessions, each consisting of four scenarios followed by postevent debriefing. The curriculum included 12 total clinical scenarios. Scenarios covered a broad array of complex critical care topics facing all adult specialties and reinforced important system-specific initiatives. Assessments evaluated clinical performance metrics, self-reported confidence in curricular topics, procedural and communication skills, resident satisfaction, and interdisciplinary attitudes. Results Quantitative and qualitative data analyzed in three published works over the past 9 years of curricular programming has demonstrated highly satisfied learners along with improved: clinical performance; self-reported confidence in clinical topics, procedural, and communication skills; and interdisciplinary collegiality. Discussion Purposeful focus on curricular development that integrates basic, clinical, and procedural content, while promoting the development of interdisciplinary relationships and the practice of critical thinking skills, is vital for successful education and patient care. This curriculum was well received by interns, covered difficult to obtain GME milestones, and provided an opportunity for interdisciplinary education. In an era of limited time for devoted bedside teaching and variable training exposures to certain disease processes, the development and implementation of this curriculum has filled a void within our system for unified resident education.

Zika virus (ZIKV) is a mosquito-transmitted flavivirus, recently linked to microcephaly and central nervous system anomalies following infection in pregnancy. Striking findings of disproportionate growth with a smaller than expected head relative to body length have been observed more commonly among fetuses with exposure to ZIKV in utero compared to pregnancies without ZIKV infection regardless of other signs of congenital infection including microcephaly. This study's objective was to determine the diagnostic accuracy of femur-sparing profile of intrauterine growth restriction for the identification of ZIKV-associated congenital injuries on postnatal testing. A retrospective cohort study of pregnant women with possible or confirmed ZIKV infection between January 1, 2016 and December 31, 2017 were included. Subjects were excluded if no prenatal ultrasound was available. A femur-sparing profile of growth restriction determined using INTERGROWTH-21st sonographic standard for head circumference to femur length (HC: FL). Congenital injuries were determined postnatally by imaging, comprehensive eye exam and standard newborn hearing screen. A total of 111 pregnant women diagnosed with ZIKV infection underwent fetal ultrasound and 95 neonates had complete postnatal evaluation. Prenatal microcephaly was detected in 5% of fetuses (6/111). Postnatal testing detected ZIKV-associated congenital injuries in 25% of neonates (24/95). A HC: FL Z-score ≤ -1.3 had a 52% specificity (95% CI 41-63%), 82% negative predictive value (NPV, 95% CI 73-88%) for the detection of ZIKV-associated congenital injuries in the neonatal period. A more stringent threshold with a Z-score ≤ -2 was associated with a 90% specificity (95% CI 81-95%), 81% NPV (95% CI 77-85%). Excluding cases of fetal microcephaly, HC: FL (Z-score ≤ -2) demonstrated a similar specificity (89%, 95% CI 81-95%) with superior NPV (87%, 95% CI 84-90%). The sonographic recognition of a normally proportioned fetus may be useful prenatally to exclude a wider spectrum of ZIKV-associated congenital injuries detected postnatally.

SWATH-mass spectrometry consists of a data-independent acquisition and a targeted data analysis strategy that aims to maintain the favorable quantitative characteristics on the scale of thousands of proteins. Here, using data generated by eleven groups worldwide, the authors show that SWATH-MS is capable of generating highly reproducible data across different laboratories.