Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.

WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms1-5. Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This compound selectively engages a cysteine (C727) located in a region of the helicase domain subject to interdomain movement during DNA unwinding. VVD-133214 binds WRN protein cooperatively with nucleotide and stabilizes compact conformations lacking the dynamic flexibility necessary for proper helicase function, resulting in widespread double-stranded DNA breaks, nuclear swelling and cell death in MSI-high (MSI-H), but not in microsatellite-stable, cells. The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers.

Perforated Appendicitis in Children: Management, Microbiology, and Antibiotic Stewardship.

Although appendicitis has been described for more than 300 years, its optimal management remains a topic of active investigation. Acute appendicitis is the most common cause of peritonitis in children, and rates of perforated appendicitis are much higher in children than in adults. Increased risk for perforated appendicitis in children is related to a delay in diagnosis due to age, size, access to care, and more. Surgical options include immediate appendectomy versus nonoperative management with intravenous antibiotics ± a drainage procedure, with a subsequent interval appendectomy. Microbiota of perforated appendicitis in children most often includes Escherichia coli, Bacteroides fragilis, Streptococcus, and more. Even though the most common organisms are known, there is a large variety of practice when it comes to postoperative antibiotic management in these patients. Studies discuss the benefits of mono- versus dual or triple therapy without a particular consensus regarding what to use. This is reflected across differing practices at various institutions. In this review, we aim to explore the implications of perforated appendicitis in pediatrics, common organisms seen, antibiotic regimen coverage, and the implications of variations of practice. Resistance to commonly used broad-spectrum antibiotics is evolving, therefore minimization of care variability is needed for improved patient outcomes and proper antibiotic stewardship.

Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population.

While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13-38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10-5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33-43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

Electrophysiological investigation of active-assisted vs recumbent cycling: A pilot study in healthy older adults.

There is a relationship between acute bouts of aerobic exercise and cognition in adults, yet the exact nature of this relationship remains unclear. The current pilot study aims to investigate how different modes of cycling (active-assisted cycling vs recumbent cycling) at different moderate-to-vigorous physical activity (MVPA) intensity levels (prescribed 65-70% Heart Rate Max and self-selected 12-13 Rate of Perceived Exertion) modulate neurocognitive, and behavioral markers of cognition in healthy older adults. A sample of 10 adults (aged 50-74years) participated in baseline (no exercise), active-assisted, and recumbent cycling interventions at different intensity levels. The P3 event-related potential (ERP), a neural index of executive functions, was recorded at baseline and following each exercise condition during an auditory odd-ball paradigm. Results revealed that greater amplitudes within the P3 ERP component were associated with post-exercise recumbent bike cycling compared to baseline and active-assisted cycling. Further, post-exercise behavioral cognitive measures (i.e., button press accuracy) were significantly greater than baseline for both active-assisted and recumbent bikes at both intensity levels. These findings suggest that exercise modulated both neurocognitive and behavioral measures of executive functions in older healthy adults, and that exercise modalities and intensity levels differentially modulate neurocognitive measures.

Racial and ethnic disparities in psychological care for individuals with FASD: a dis/ability studies and critical race theory perspective toward improving prevention, assessment/diagnosis, and intervention.

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.

Racial/Ethnic Disparities in Psychiatric Traits and Diagnoses within a Community-based Sample of Children and Youth: Disparités raciales/ethniques dans les traits et diagnostics psychiatriques au sein d'un échantillon communautaire d'enfants et de jeunes.

OBJECTIVE: Racial/ethnic disparities in the prevalence of psychiatric disorders have been reported, but have not accounted for the prevalence of the traits that underlie these disorders. Examining rates of diagnoses in relation to traits may yield a clearer understanding of the degree to which racial/ethnic minority youth in Canada differ in their access to care. We sought to examine differences in self/parent-reported rates of diagnoses for obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders after adjusting for differences in trait levels between youth from three racial/ethnic groups: White, South Asian and East Asian. METHOD: We collected parent or self-reported ratings of OCD, ADHD and anxiety traits and diagnoses for 6- to 17-year-olds from a Canadian general population sample (Spit for Science). We examined racial/ethnic differences in trait levels and the odds of reporting a diagnosis using mixed-effects linear models and logistic regression models. RESULTS: East Asian (N = 1301) and South Asian (N = 730) youth reported significantly higher levels of OCD and anxiety traits than White youth (N = 6896). East Asian and South Asian youth had significantly lower odds of reporting a diagnosis for OCD (odds ratio [OR]East Asian = 0.08 [0.02, 0.41]; ORSouth Asian = 0.05 [0.00, 0.81]), ADHD (OREast Asian = 0.27 [0.16, 0.45]; ORSouth Asian = 0.09 [0.03, 0.30]) and anxiety (OREast Asian = 0.21 [0.11, 0.39]; ORSouth Asian = 0.12 [0.05, 0.32]) than White youth after accounting for psychiatric trait levels. CONCLUSIONS: These results suggest a discrepancy between trait levels of OCD, ADHD and anxiety and rates of diagnoses for East Asian and South Asian youth. This discrepancy may be due to increased barriers for ethnically diverse youth to access mental health care. Efforts to understand and mitigate these barriers in Canada are needed.

We know that there is there are differences in the prevalence of childhood mental illnesses by race/ethnic group, which may be related to disproportionate access to mental health care. What is unknown is whether there this difference in prevalence is related to differences in the presence of symptoms for mental illness or whether children and youth from marginalized racial/ethnic groups have symptoms but are not getting diagnosed. This information is needed to understand the degree to which children and youth from marginalized race/ethnicity groups are accessing mental health care in Canada. We tested the differences in reported symptoms and diagnosis of three common and impairing childhood-onset disorders (obsessive-compulsive disorder­OCD), attention-deficit/hyperactivity disorder­ADHD and anxiety disorders) in children and youth (6­17 years of age) living in Canada that were from three racial/ethnic groups: White, South Asian and East Asian. East Asian and South Asian youth reported significantly higher levels of OCD and anxiety traits than White youth. However, East Asian and South Asian youth were significantly less likely than White youth to have a reported diagnosis of OCD, ADHD or anxiety even after accounting for symptom levels for each disorder. Our findings suggest that East and South Asian children are less likely than White children to get a diagnosis for common mental illness even if they have symptoms of that mental illness. This gap in receiving a diagnosis might be because of more barriers to mental health care for children and youth from marginalized racial/ethnic groups but we need more research to pinpoint the cause.

The genetic architecture of youth anxiety: a study protocol.

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.

Higher morning cortisol is associated with lower intuitive eating in midlife women.

BACKGROUND: Stress is associated with negative health outcomes in adults, including increased adiposity. Eating behaviors to cope with stress can have a negative effect on adiposity. There is limited research on positive eating behaviors, such as intuitive eating (IE), and their relationship to stress and adiposity. Thus, this study aimed to examine the association between stress and adiposity and to assess whether IE is a mediator of that pathway. METHODS: Data were analyzed from a cross-sectional study of 114 women between 40-64 years of age. Participants completed in-person visits and self-reported questionnaires, including the Intuitive Eating Scale and Perceived Stress Scale. Adiposity was assessed using dual energy x-ray absorptiometry. Measurements included total body fat percentage and android/gynoid (AG) ratio as a measure of abdominal adiposity. Participants provided ten salivary cortisol samples over two days, collected upon waking, 30-, 45-, and 60-minutes after waking, and prior to bed. Several methods were used to characterize cortisol secretion and exposure, including the diurnal cortisol slope and the cortisol area under the curve with respect to ground (AUCg). Linear regression was used to assess the associations between perceived stress and IE and between features of diurnal cortisol and IE. Mediation models were tested to examine the indirect effects of IE on the relationship between perceived stress and adiposity and to test the indirect effects of IE on the relationship between cortisol measures and adiposity. RESULTS: Linear regression analyses indicated that higher cortisol AUCg was associated with lower scores on the eating for physical reasons subscale (ß: -0.01, p = 0.008). After adjusting for covariates, neither higher perceived stress nor diurnal cortisol were associated with intuitive eating. There was no evidence of mediation of the association of stress on adiposity through IE. CONCLUSION: Our findings demonstrate a relationship between higher overall morning cortisol and lower scores on the eating for physical reasons subscale of the Intuitive Eating Scale. Future research should seek to understand how intuitive eating may be used as a technique for individuals who engage in emotional eating to cope with stress, and to prevent excess adiposity resulting from stress in midlife women.

Developing a Quality Improvement Implementation Taxonomy for Organizational Employee Wellness Initiatives.

BACKGROUND: Standardized taxonomies (STs) facilitate knowledge representation and semantic interoperability within health care provision and research. However, a gap exists in capturing knowledge representation to classify, quantify, qualify, and codify the intersection of evidence and quality improvement (QI) implementation. This interprofessional case report leverages a novel semantic and ontological approach to bridge this gap. OBJECTIVES: This report had two objectives. First, it aimed to synthesize implementation barrier and facilitator data from employee wellness QI initiatives across Veteran Affairs health care systems through a semantic and ontological approach. Second, it introduced an original framework of this use-case-based taxonomy on implementation barriers and facilitators within a QI process. METHODS: We synthesized terms from combined datasets of all-site implementation barriers and facilitators through QI cause-and-effect analysis and qualitative thematic analysis. We developed the Quality Improvement and Implementation Taxonomy (QIIT) classification scheme to categorize synthesized terms and structure. This framework employed a semantic and ontological approach. It was built upon existing terms and models from the QI Plan, Do, Study, Act phases, the Consolidated Framework for Implementation Research domains, and the fishbone cause-and-effect categories. RESULTS: The QIIT followed a hierarchical and relational classification scheme. Its taxonomy was linked to four QI Phases, five Implementing Domains, and six Conceptual Determinants modified by customizable Descriptors and Binary or Likert Attribute Scales. CONCLUSION: This case report introduces a novel approach to standardize the process and taxonomy to describe evidence translation to QI implementation barriers and facilitators. This classification scheme reduces redundancy and allows semantic agreements on concepts and ontological knowledge representation. Integrating existing taxonomies and models enhances the efficiency of reusing well-developed taxonomies and relationship modeling among constructs. Ultimately, employing STs helps generate comparable and sharable QI evaluations for forecast, leading to sustainable implementation with clinically informed innovative solutions.

Estimating the heritability of nitrogen and carbon isotopes in the tail hair of beef cattle.

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.

Is irritability multidimensional: Psychometrics of The Irritability and Dysregulation of Emotion Scale (TIDES-13).

Irritability is a common, impairing, and potentially multifaceted manifestation of psychopathology. We designed The Irritability and Dysregulation of Emotion Scale (TIDES-13) to determine whether various expressions of irritability in children and youth form multiple subdimensions with distinct correlates. We administered parent-report (n = 3875, mean age = 8.9) and youth self-report (n = 579, mean age = 15.1) versions of TIDES-13 in a population and community-based sample. We conducted exploratory/confirmatory factor analyses and regression analyses to examine the dimensionality of TIDES-13 and the associations of the scale with age, gender, anxiety, depression, ODD, ADHD traits, and the Affective Reactivity Index (ARI). A higher-order model with a global irritability dimension and four subdimensions, including proneness to anger (PA), internalized negative emotional reactivity (iNER), externalized negative emotional reactivity (eNER), and reactive aggression (RA), showed good to excellent fit in both parent-report and self-report. The global irritability dimension showed excellent internal reliability (⍵Total; parent-report = 0.97, ⍵Total; self-report = 0.95), explained a majority of the item variance (⍵Hierarchical; parent-report = 0.94, ⍵Hierarchical; self-report = 0.90), and was moderately correlated with the ARI (rparent = 0.68, rself = 0.77). Subdimensions PA, eNER, and RA were negatively associated with age in males, whereas iNER was positively associated with age in females. Traits of ODD and ADHD were associated primarily with the global irritability dimension, whereas iNER was strongly associated with anxiety and depression traits over and above the global irritability dimension. Our results support a unidimensional interpretation of irritability in a population sample. However, limited evidence of specific behavioral, age, and sex correlates with particular irritability subdimensions may warrant further investigation.

Exercise-Induced Functional Changes in People with Parkinson's Disease following External Cueing and Task-Based Intervention.

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.

End Users' Perceived Engagement with Clinical Dashboards: A Rapid Review.

Clinical dashboards are an emerging and fast-evolving technology used to support frontline clinicians' practice. Understanding end users' perceived engagement with clinical dashboards is essential to co-design, implementation, and adoption. There is a lack of literature exploring the integration of dashboards into clinical workflow. This rapid review explores clinical end users' perceived engagement with dashboards that support workflow. We conducted a literature search in PubMed and CINAHL. Four articles met our eligibility criteria. Findings reveal variations in taxonomy and measures used to evaluate clinicians' perceived engagement. There are also a variety of reported barriers and facilitators to adoption. Standardized frameworks and vocabulary are needed to facilitate a common understanding of clinical end users' perceived engagement with dashboards.

Extension for Community Healthcare Outcomes fetal alcohol spectrum disorder (ECHO FASD): Tele-mentoring program to increase healthcare capacity for FASD diagnosis.

BACKGROUND: Children with fetal alcohol spectrum disorder (FASD) often experience delayed, missed, or incorrect diagnosis due to low FASD awareness and diagnostic capacity. Current strategies to expand awareness and diagnostic capacity are insufficient or impractical. METHODS: This project examined the feasibility of Extension for Community Healthcare Outcomes (ECHO) tele-mentoring to train community clinicians about FASD. Participants attended ten 1-h weekly ECHO sessions that included presentations, vignettes, and discussions. Measurement utilized Bowen's feasibility domains. RESULTS: Robust webpage traffic yielded 19 participants (demand). Fidelity scores, hub team field notes, and participant ratings indicated feasibility based on acceptability, implementation, practicality, and adaptation. Clinicians' knowledge and confidence improved and case-based diagnostic accuracy was high (limited efficacy). CONCLUSIONS: ECHO FASD is a feasible training method that shows promise in increasing diagnostic capacity across many geographic regions.

Ultrasound assessment of diaphragm thickness, contractility, and strain in healthy pediatric patients.

BACKGROUND: Ultrasound-based diaphragmatic assessments are becoming more common in pediatric acute care, but baseline pediatric diaphragm thickness and contractility values remain unknown. METHODS: We conducted a prospective, observational study of healthy children aged <18 years undergoing elective surgery. Diaphragm thickness at end-expiration (Tdi-exp), thickening fraction (DTF) and excursion were measured by ultrasound during spontaneous breathing and during mechanical ventilation. Diaphragm strain and peak strain rate were ascertained post hoc. Measurements were compared across a priori specified age groups (<1 year, 1 to <3, 3 to <6, 6 to <12, and 12 to <18 years) and with versus without mechanical ventilation. RESULTS: Fifty subjects were evaluated (n = 10 per age group). Baseline mean Tdi-exp was 0.19 ± 0.04 cm, DTF 0.19 ± 0.09, excursion 1.69 ± 0.97 cm, strain -10.3 ± 4.9, peak strain rate -0.48 ± 0.21 s-1 . No significant difference in Tdi-exp or DTF was observed across age groups (p > .05). Diaphragm excursion increased with age (p < .0001). Diaphragm strain was significantly greater in the 12-17-year age group (-14.3 ± 6.4), p = .048, but there were no age-related differences in peak strain rate (p = .08). During mechanical ventilation, there were significant decreases in DTF 0.12 ± 0.04 (p < .0001), excursion 1.08 ± 0.31 cm (p < .0001), strain -4.60 ± 1.93 (p < .0001), and peak strain rate -0.20 ± 0.10 s-1 (p < .0001) while there was no change in Tdi-exp 0.18 ± 0.03 cm (p = .25) when compared to baseline values. CONCLUSION: Pediatric Tdi-exp, DTF, and diaphragm peak strain rate were similar across age groups. Diaphragm excursion and strain varied across age groups. All measures of diaphragm contractility were diminished during mechanical ventilation.

Developing a Quality Improvement Implementation Taxonomy for Organizational Employee Wellness Initiatives.

BACKGROUND: Standardized taxonomies (STs) facilitate knowledge representation and semantic interoperability within health care provision and research. However, a gap exists in capturing knowledge representation to classify, quantify, qualify, and codify the intersection of evidence and quality improvement (QI) implementation. This interprofessional case report leverages a novel semantic and ontological approach to bridge this gap. OBJECTIVES: This report had two objectives. First, it aimed to synthesize implementation barrier and facilitator data from employee wellness QI initiatives across Veteran Affairs health care systems through a semantic and ontological approach. Second, it introduced an original framework of this use-case-based taxonomy on implementation barriers and facilitators within a QI process. METHODS: We synthesized terms from combined datasets of all-site implementation barriers and facilitators through QI cause-and-effect analysis and qualitative thematic analysis. We developed the Quality Improvement and Implementation Taxonomy (QIIT) classification scheme to categorize synthesized terms and structure. This framework employed a semantic and ontological approach. It was built upon existing terms and models from the QI Plan, Do, Study, Act phases, the Consolidated Framework for Implementation Research domains, and the fishbone cause-and-effect categories. RESULTS: The QIIT followed a hierarchical and relational classification scheme. Its taxonomy was linked to four QI Phases, five Implementing Domains, and six Conceptual Determinants modified by customizable Descriptors and Binary or Likert Attribute Scales. CONCLUSION: This case report introduces a novel approach to standardize the process and taxonomy to describe evidence translation to QI implementation barriers and facilitators. This classification scheme reduces redundancy and allows semantic agreements on concepts and ontological knowledge representation. Integrating existing taxonomies and models enhances the efficiency of reusing well-developed taxonomies and relationship modeling among constructs. Ultimately, employing STs helps generate comparable and sharable QI evaluations for forecast, leading to sustainable implementation with clinically informed innovative solutions.

Substantial downregulation of mitochondrial and peroxisomal proteins during acute kidney injury revealed by data-independent acquisition proteomics.

Acute kidney injury (AKI) manifests as a major health concern, particularly for the elderly. Understanding AKI-related proteome changes is critical for prevention and development of novel therapeutics to recover kidney function and to mitigate the susceptibility for recurrent AKI or development of chronic kidney disease. In this study, mouse kidneys were subjected to ischemia-reperfusion injury, and the contralateral kidneys remained uninjured to enable comparison and assess injury-induced changes in the kidney proteome. A ZenoTOF 7600 mass spectrometer was optimized for data-independent acquisition (DIA) to achieve comprehensive protein identification and quantification. Short microflow gradients and the generation of a deep kidney-specific spectral library allowed for high-throughput, comprehensive protein quantification. Upon AKI, the kidney proteome was completely remodeled, and over half of the 3945 quantified protein groups changed significantly. Downregulated proteins in the injured kidney were involved in energy production, including numerous peroxisomal matrix proteins that function in fatty acid oxidation, such as ACOX1, CAT, EHHADH, ACOT4, ACOT8, and Scp2. Injured kidneys exhibited severely damaged tissues and injury markers. The comprehensive and sensitive kidney-specific DIA-MS assays feature high-throughput analytical capabilities to achieve deep coverage of the kidney proteome, and will serve as useful tools for developing novel therapeutics to remediate kidney function.

Coping Factors for Caregivers of Children With Medical Complexity During Hospitalization.

OBJECTIVES: This study aimed to identify coping factors for caregivers of children with medical complexity (CMC) to manage the stressors and experience associated with their child's hospitalization. METHODS: We conducted semistructured interviews with CMC caregivers over a video-conferencing platform to examine factors that they perceive impact their coping while their children are hospitalized. Interviews were audio-recorded, transcribed, and imported into a qualitative coding software (MAXQDA). Using a modified grounded theory approach, we assigned process and in vivo codes to the transcripts and conducted interpretive analysis to identify themes. Once we reached thematic saturation, we finalized themes by discussing them to achieve group consensus and processed themes through triangulation with our institution's pediatric family advisory council. RESULTS: We interviewed 14 caregivers (11 mothers and 3 fathers) and identified 3 major themes. The factors that contributed to CMC caregiver coping with their child's hospitalizations included caregivers: feeling that they are prioritizing their child's needs over their own, feeling trust in their child's interdisciplinary healthcare team, and feeling their self-care practices are well adjusted to the hospital setting. CONCLUSIONS: Our study found 3 coping factors for caregivers of CMC during their child's hospitalization. Development and testing of interventions that enhance these coping practices may better support CMC caregivers during their child's hospitalizations. Potential interventions could include developing structured processes to establish caregiver involvement in their child's hospital care and helping caregivers modify their existing coping mechanisms to the hospital setting.

Latin American Trans-ancestry INitiative for OCD genomics (LATINO): Study protocol.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, https://www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5000 richly phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity.