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Abstract Background Anhedonia and suicidal ideation are symptoms of major depressive disorder (MDD) that are not regularly captured in structured scales but may be captured in unstructured clinical notes. Natural language processing (NLP) techniques may be used to extract longitudinal data on suicidal behaviors and anhedonia within unstructured clinical notes. This study assessed the accuracy of using NLP techniques on electronic health records (EHRs) to identify these symptoms among patients with MDD. Methods EHR-derived, de-identified data were used from the NeuroBlu Database (version 23R1), a longitudinal behavioral health real-world database. Mental health clinicians annotated instances of anhedonia and suicidal symptoms in clinical notes creating a ground truth. Interrater reliability (IRR) was calculated using Krippendorff’s alpha. A novel transformer architecture-based NLP model was trained on clinical notes to recognize linguistic patterns and contextual cues. Each sentence was categorized into one of four labels: (1) anhedonia; (2) suicidal ideation without intent or plan; (3) suicidal ideation with intent or plan; (4) absence of suicidal ideation or anhedonia. The model was assessed using positive predictive values (PPV), negative predictive values, sensitivity, specificity, F1-score, and AUROC. Results The model was trained, tested, and validated on 2,198, 1,247, and 1,016 distinct clinical notes, respectively. IRR was 0.80. For anhedonia, suicidal ideation with intent or plan, and suicidal ideation without intent or plan the model achieved a PPV of 0.98, 0.93, and 0.87, an F1-score of 0.98, 0.91, and 0.89 during training and a PPV of 0.99, 0.95, and 0.87 and F1-score of 0.99, 0.95, and 0.89 during validation. Conclusions NLP techniques can leverage contextual information in EHRs to identify anhedonia and suicidal symptoms in patients with MDD. Integrating structured and unstructured data offers a comprehensive view of MDD’s trajectory, helping healthcare providers deliver timely, effective interventions. Addressing current limitations will further enhance NLP models, enabling more accurate extraction of critical clinical features and supporting personalized, proactive mental health care.

Abstract Background Approximately one in six children has a disability, and effective, evidence-based rehabilitation can ameliorate the impact of these conditions over the lifespan. However, implementing interventions in real-world settings remains a challenge. This scoping review aimed to summarize the characteristics, implementation strategies, and outcomes of implementation studies in pediatric rehabilitation. Methods A comprehensive search was conducted in PubMed/MEDLINE, EMBASE, CINAHL, SCOPUS, and Web of Science from the database inception to December 2, 2022. Studies testing implementation strategies in pediatric rehabilitation interventions were included. Data extracted included study characteristics (e.g., country, intervention type, field of rehabilitation), implementation strategies characterized using the Expert Recommendations for Implementing Change taxonomy, and outcomes based on the Implementation Outcomes Framework. Results Of the 11,740 studies identified, 44 met the inclusion criteria. Most studies were conducted in the United States (n = 15, 34%) or Canada (n = 10, 23%) and used a mixed-methods design (n = 13, 30%). Interventions primarily targeted motor skills (n = 19, 43%) and were conducted in outpatient settings (n = 14, 32%) or homes (n = 11, 23%). The most commonly used implementation strategies were “train and educate key informant” (n = 21, 48%) and “use evaluative/iterative strategies” (n = 19, 43%). Feasibility (n = 19, 43%) and acceptability (n = 16, 36%) were the most frequently targeted implementation outcomes. Conclusions Reporting implementation strategies and outcomes in pediatric rehabilitation studies is limited and highly variable. Most strategies focused on developing and sharing educational materials, while administrative and systems-level interventions were largely absent. Standardized documentation of implementation strategies and outcomes could advance the field’s understanding of the effective development of interventions designed for implementation, encouraging faster uptake of effective interventions.

Abstract Histological assessment is essential for the diagnosis and management of celiac disease. Current scoring systems, including modified Marsh (Marsh–Oberhuber) score, lack inter-pathologist agreement. To address this unmet need, we aimed to develop a fully automated, quantitative approach for histology characterisation of celiac disease. Convolutional neural network models were trained using pathologist annotations of hematoxylin and eosin-stained biopsies of celiac disease mucosa and normal duodenum to identify cells, tissue and artifact regions. Biopsies of duodenal mucosa of varying celiac disease severity, and normal duodenum were collected from a large central laboratory. Celiac disease slides (N = 318) were split into training (n = 230; 72.3%), validation (n = 60; 18.9%) and test (n = 28; 8.8%) datasets. Normal duodenum slides (N = 58) were similarly divided into training (n = 40; 69.0%), validation (n = 12; 20.7%) and test (n = 6; 10.3%) datasets. Human interpretable features were extracted and the strength of their correlation with Marsh scores were calculated using Spearman rank correlations. Our model identified cells, tissue regions and artifacts, including distinguishing intraepithelial lymphocytes and differentiating villous epithelium from crypt epithelium. Proportional area measurements representing villous atrophy negatively correlated with Marsh scores (r = − 0.79), while measurements indicative of crypt hyperplasia positively correlated (r = 0.71). Furthermore, features distinguishing celiac disease from normal duodenum were identified. Our novel model provides an explainable and fully automated approach for histology characterisation of celiac disease that correlates with modified Marsh scores, potentially facilitating diagnosis, prognosis, clinical trials and treatment response monitoring.

Abstract Introduction Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) are scarce. The OPUS/OrPHeUS studies enrolled patients with PAH newly initiating macitentan, including those with PAH associated with CHD (CHD-PAH). Methods OPUS was a prospective, United States, multicenter, long-term, observational drug registry (April 2014–June 2020). OrPHeUS was a retrospective, United States, multicenter medical chart review (October 2013–March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CHD-PAH and the subgroups Eisenmenger syndrome, left-to-right shunts and small/coincidental CHD were descriptively compared. Results The combined OPUS/OrPHeUS population included 272 (6.1%) patients with CHD-PAH (80 patients with Eisenmenger syndrome; 82 patients with left-to-right shunts and 92 patients with small/coincidental defects). Most patients across the CHD-PAH subgroups were in World Health Organization Functional Class II/III (82.9–94.6%). Macitentan was initiated as combination therapy in 65.0% of patients with CHD-PAH. During follow-up, 81.4% of patients experienced ≥ 1 adverse event (AE), the most common being dyspnea (23.5%), nausea (13.7%), dizziness (12.7%), headache (12.7%) and edema (10.8%). The 1- and 2-year Kaplan–Meier (95% confidence limits) estimates of patients with CHD-PAH being free from hospitalization were 64.5% (57.9, 70.4) and 49.3% (41.9, 56.3); for survival, the 1- and 2-year Kaplan–Meier estimates were 93.5% (89.3, 96.1) and 90.2% (84.9, 93.7). Conclusions Macitentan was used in clinical practice in patients with CHD-PAH and its subgroups, including as combination therapy in the majority of patients. Safety in this population was consistent with the known profile of macitentan. Trial Registration OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; URL www.clinicaltrials.gov .

Abstract Background In April 2019, Mozambique was hit by Cyclone Idai leaving substantial damage to infrastructure and nearly two million people in need of humanitarian assistance. Malaria risk has been associated with living in a rural setting, vicinity to water, and household structure, all factors which are impacted by severe storms. This study quantified the association between damage to infrastructure (health care facilities and schools) following Cyclone Idai and malaria outcomes: malaria incidence, severe malaria, and administration of intermittent preventative treatment in pregnancy (IPTp) in Sofala Province, Mozambique. Methods To quantify infrastructure damage, historical satellite imagery was assessed visually using Google Earth Pro®. Damage to 66 school and 105 health centres was assessed for severity and duration. Location data was imported to QGIS and joined with district level data on malaria outcomes and environmental covariates. Multivariable Poisson regression models were used to quantify the associations between facility damage and malaria incidence and severe malaria. Generalized linear models were used to determine the association between facility damage and changes in malaria incidence and administration of IPTp from 2018 to 2019. Results An increase in facility damage was associated with an increase in malaria incidence and severe malaria. An increase in proportion of facilities damaged by 10% was associated with a 7.3% (95% CI 6.8–7.8%) increase in malaria incidence. Risk of severe malaria was 2.16 (95% CI 1.42–3.32) times higher in districts with any damage compared to those with no damage. However, proportional facility damage was associated with decreased malaria incidence and increased access to IPTp from 2018 to 2019, but these were not statistically significant. Conclusion An increase in proportion of facilities damaged following Cyclone Idai was associated with increased risk of malaria and severe malaria at the district level. This may be a function of decreased access to healthcare and an increased exposure to risk factors for malaria. A non-statistically significant decrease in malaria incidence was also found at the district level from 2018 to 2019, indicating that malaria may have been underreported in 2019, likely again a function of decreased access to healthcare.

Abstract Background Natural HbA1c levels in GCK Maturity-onset diabetes of the young (GCK-MODY) patients often sit above the diagnostic threshold for type 2 diabetes (T2D). Treatments to lower HbA1c levels show reduced effectiveness in these individuals, yet in case studies to date, GCK-MODY patients often evade secondary T2D complications. Given these deviations, genetic screening of GCK may be clinically useful, but population studies are needed to more broadly understand T2D-related complications in GCK variant carriers. Methods To identify GCK variant carriers at the population level, we used both ACMG/AMP variant interpretation for GCK-MODY pathogenicity and a state-of-the-art variant interpretation strategy based on functional and statistical evidence to predict glucose elevations. Presence of pathogenic and glucose-elevating GCK variants was assessed in two cohorts (n~535,000). We identified 442 individuals with GCK variants predicted to increase glucose (~1/1200), with 150 (34%) of these individuals harboring variants reaching a pathogenic interpretation. Results In a retrospective analysis, we show that in addition to elevated HbA1c, pathogenic variant carriers are 10x as likely, and all other glucose-elevating GCK variant carriers are 3x as likely, to receive a T2D diagnosis compared to non-GCK carriers. Surprisingly, carriers of pathogenic and glucose-elevating GCK variants with T2D develop T2D-related complications at rates more than double that of individuals without T2D, comparable to non-GCK individuals with T2D. Conclusions This population-level assessment shows secondary complications in individuals with pathogenic and glucose-elevating GCK variants and T2D and suggests that genotyping for these variants should be considered in a precision medicine approach for T2D treatment and prevention.

Abstract Spinal projection neurons (PNs) are defined by long axons that travel from their origin in the spinal cord to the brain where they relay sensory information from the body. The existence and function of a substantial axon collateral network, also arising from PNs and remaining within the spinal cord, is less well appreciated. Here we use a retrograde viral transduction strategy to characterise a novel subpopulation of deep dorsal horn spinoparabrachial neurons. Brainbow assisted analysis confirmed that virally labelled PN cell bodies formed a discrete cell column in the lateral part of Lamina V (LVlat) and the adjoining white matter. These PNs exhibited large dendritic territories biased to regions lateral and ventral to the cell body column and extending considerable rostrocaudal distances. Optogenetic activation of LVLat PNs confirmed this population mediates widespread signalling within spinal cord circuits, including activation in the superficial dorsal horn. This signalling was also demonstrated with patch clamp recordings during LVLat PN photostimulation, with a range of direct and indirect connections identified and evidence of a postsynaptic population of inhibitory interneurons. Together, these findings confirm a substantial role for PNs in local spinal sensory processing, as well as relay of sensory signals to the brain.

Abstract Background Whether including additional environmental risk factors improves cardiovascular disease (CVD) prediction is unclear. We attempted to improve CVD mortality prediction performance beyond traditional CVD risk factors by additionally using metals measured in the urine and blood and with statistical machine learning methods. Methods Our sample included 7,085 U.S. adults aged 40 years or older from the National Health and Nutrition Examination Survey 2003–2004 through 2015–2016, linked with the National Death Index through December 31, 2019. Data were randomly split into a 50/50 training dataset used to construct CVD mortality prediction models (n = 3542) and testing dataset used as validation to assess prediction performance (n = 3543). Relative to the traditional risk factors (age, sex, race/ethnicity, smoking status, systolic blood pressure, total and high-density lipoprotein cholesterol, hypertension, and diabetes), we compared models with an additional 17 blood and urinary metal concentrations. To build the prediction models, we used Cox proportional hazards, elastic-net (ENET) penalized Cox, and random survival forest methods. Results 420 participants died from CVD with 8.8 mean years of follow-up. Blood lead, cadmium, and mercury were associated (p

Abstract Purpose Developing personal goals beyond weight and shape, and promoting the agency to pursue those goals, could aid in treatment and recovery from anorexia nervosa (AN). This research explores the strengths, interests and goals of individuals currently receiving treatment for AN and evaluates how treatment services are supporting them to work towards personal goals across all areas of everyday life. Method A total of 58 community-dwelling adults currently receiving treatment for anorexia nervosa at any stage of recovery completed the Client Assessment of Strengths, Interests and Goals Self-Report (CASIG-SR). Participants reported their goals for accommodation, work and study, interpersonal relationships, recreational activities, spirituality, religion or life purpose, physical health and mental health, and the personal strengths and supports needed to achieve those goals. Concordance scores were calculated between importance of personal goals and level of support from current services regarding these goals. Results Themes identified across goals, strengths and supports were Connection, Independence & Confidence, Meaning & Self: The Real Me, and Stability & Balance. Work and study goals and strengths were identified strongly. The key support needed was stability from the current treatment team to provide a stable base for change. Concordance scores indicate support provided for personal goals was less than the importance of the goal to the individual. Conclusion Results suggest goals for everyday living are critical to recovery in anorexia nervosa. Specific clinical considerations to increase motivation and hope are increased access to peer support, a focus on increasing positive affect, supporting safe exercise and promoting outdoor experiences and connection with nature. Level III Evidence obtained from well-designed cohort or case–control analytic studies.

Abstract BamA is the central component of the essential β-barrel assembly machine (BAM), a conserved multi-subunit complex that dynamically inserts and folds β-barrel proteins into the outer membrane of Gram-negative bacteria. Despite recent advances in our mechanistic and structural understanding of BamA, there are few potent and selective tool molecules that can bind to and modulate BamA activity. Here, we explored in vitro selection methods and different BamA/BAM protein formulations to discover peptide macrocycles that kill Escherichia coli by targeting extreme conformational states of BamA. Our studies show that Peptide Targeting BamA-1 (PTB1) targets an extracellular divalent cation-dependent binding site and locks BamA into a closed lateral gate conformation. By contrast, PTB2 targets a luminal binding site and traps BamA into an open lateral gate conformation. Our results will inform future antibiotic discovery efforts targeting BamA and provide a template to prospectively discover modulators of other dynamic integral membrane proteins.

Abstract Background Intense pyrethroid resistance threatens the effectiveness of the primary vector control intervention, insecticide-treated nets (ITNs), in Nigeria, the country with the largest malaria burden globally. In this study, the epidemiological and entomological impact of a new type of ITN (piperonyl-butoxide [PBO] ITNs) distributed in Ebonyi State were evaluated. The epidemiological impact was also compared to the impact of standard pyrethroid-only ITNs in Cross River State. Methods A controlled interrupted time series analysis was conducted on monthly malaria incidence data collected at the health facility level, using a multilevel mixed-effects negative binomial model. Data were analysed two years before and after the PBO ITN campaign in Ebonyi State (December 2017 to November 2021). A pre-post analysis, with no comparison group, was used to assess the impact of PBO ITNs on human biting rates and indoor resting density in Ebonyi during the high transmission season immediately before and after the PBO ITN campaign. Results In Ebonyi, PBO ITNs were associated with a 46.7% decrease (95%CI: -51.5, -40.8%; p

Abstract Background Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) are a promising therapeutic for neuroinflammation. MSC-EVs can interact with microglia, the resident immune cells of the brain, to exert their immunomodulatory effects. In response to inflammatory cues, such as cytokines, microglia undergo phenotypic changes indicative of their function e.g. morphology and secretion. However, these changes in response to MSC-EVs are not well understood. Additionally, no disease-relevant screening tools to assess MSC-EV bioactivity exist, which has further impeded clinical translation. Here, we developed a quantitative, high throughput morphological profiling approach to assess the response of microglia to neuroinflammation- relevant signals and whether this morphological response can be used to indicate the bioactivity of MSC-EVs. Results Using an immortalized human microglia cell-line, we observed increased size (perimeter, major axis length) and complexity (form factor) upon stimulation with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Upon treatment with MSC-EVs, the overall morphological score (determined using principal component analysis) shifted towards the unstimulated morphology, indicating that MSC-EVs are bioactive and modulate microglia. The morphological effects of MSC-EVs in TNF-α /IFN-γ stimulated cells were concomitant with reduced secretion of 14 chemokines/cytokines (e.g. CXCL6, CXCL9) and increased secretion of 12 chemokines/cytokines (e.g. CXCL8, CXCL10). Proteomic analysis of cell lysates revealed significant increases in 192 proteins (e.g. HIBADH, MEAK7, LAMC1) and decreases in 257 proteins (e.g. PTEN, TOM1, MFF) with MSC-EV treatment. Of note, many of these proteins are involved in regulation of cell morphology and migration. Gene Set Variation Analysis revealed upregulation of pathways associated with immune response, such as regulation of cytokine production, immune cell infiltration (e.g. T cells, NK cells) and morphological changes (e.g. Semaphorin, RHO/Rac signaling). Additionally, changes in microglia mitochondrial morphology were measured suggesting that MSC-EV modulate mitochondrial metabolism. Conclusion This study comprehensively demonstrates the effects of MSC-EVs on human microglial morphology, cytokine secretion, cellular proteome, and mitochondrial content. Our high-throughput, rapid, low-cost morphometric approach enables screening of MSC-EV batches and manufacturing conditions to enhance EV function and mitigate EV functional heterogeneity in a disease relevant manner. This approach is highly generalizable and can be further adapted and refined based on selection of the disease-relevant signal, target cell, and therapeutic product.

Abstract Background Veterans of the 1990–1991 Gulf War have experienced excess health problems, most prominently the multisymptom condition Gulf War illness (GWI). The Department of Veterans Affairs (VA) Cooperative Studies Program #2006 “Genomics of Gulf War Illness in Veterans” project was established to address important questions concerning pathobiological and genetic aspects of GWI. The current study evaluated patterns of chronic ill health/GWI in the VA Million Veteran Program (MVP) Gulf War veteran cohort in relation to wartime exposures and key features of deployment, 27–30 years after Gulf War service. Methods MVP participants who served in the 1990–1991 Gulf War completed the MVP Gulf War Era Survey in 2018–2020. Survey responses provided detailed information on veterans’ health, Gulf War exposures, and deployment time periods and locations. Analyses determined associations of three defined GWI/ill health outcomes with Gulf War deployment characteristics and exposures. Results The final cohort included 14,103 veterans; demographic and military characteristics of the sample were similar to the full population of U.S. 1990–1991 Gulf War veterans. Overall, a substantial number of veterans experienced chronic ill health, as indicated by three defined outcomes: 49% reported their health as fair or poor, 31% met Centers for Disease Control and Prevention criteria for severe GWI, and 20% had been diagnosed with GWI by a healthcare provider. Health outcomes varied consistently with veterans’ demographic and military characteristics, and with exposures during deployment. All outcomes were most prevalent among youngest veterans (

Abstract Increasing anthropogenic emissions of nitrogen (N) and carbon (C) are major threats to ecosystems globally. Although atmospheric N deposition is likely affecting N cycling and community composition in California's serpentine ecosystems, a historical record of N inputs to vegetation has yet to be reconstructed for these nutrient‐limited biodiversity hotspots. For leather oak (Quercus durata var. durata), a foundational, serpentine‐endemic species, we investigated leaf N and C isotopic composition (δ15N and δ13C) and leaf %N of herbarium and modern leaf samples collected from 1899 to 2009 from serpentine ecosystems in two study areas in California: Santa Clara County, and Lake and Napa Counties combined. We also evaluated tree ring growth over a similar time period in long‐lived leather oak individuals. Leaf δ15N and δ13C values decreased over time in both study areas, likely reflecting changes in the regional and local atmospheric N and C pools caused by human perturbation. However, leaf %N values and stem growth did not change over time with increasing N deposition, indicating that increasing atmospheric N deposition and CO2 concentration may not translate to increased N uptake or productivity in plants with conservative growth strategies, even in ecosystems thought to be N‐limited. In serpentine systems, this could competitively advantage nitrophilic invasive annual grasses and accelerate trends toward native species loss. While the rates of decline in leaf δ15N values were similar between study areas, rates of decline in leaf δ13C values were steeper in Santa Clara County, possibly reflecting its more urban environment. Herbarium samples combined with tree ring data can provide a valuable opportunity to explore the historical record of human‐induced changes in N and C cycling and their biotic impacts.

Background: The number of breast cancer survivors increases, but information about long-term adverse health effects in breast cancer survivors is sparse. We aimed to get an overview of the health effects for which survivors visit their general practitioner up to 14 years after diagnosis. Methods: We retrieved data on 11,495 women diagnosed with breast cancer in 2000–2016 and 23,242 age and sex matched controls from the PSCCR-Breast Cancer, a database containing data about cancer diagnosis, treatment and primary healthcare. We built Cox regression models for 685 health effects, with time until the health effect as the outcome and survivor/control and cancer treatment as predictors. Models were built separately for four age groups (aged 18/44, 45/59, 60/74 and 75/89) and two follow-up periods (1/4 and 5/14 years after diagnosis). Results: 148 health effects occurred statistically significantly more often in survivors than in controls (p

Summary: Background: Perivascular spaces (PVS) on brain MRI are surrogates for small parenchymal blood vessels and their perivascular compartment, and may relate to brain health. However, it is unknown whether PVS can predict dementia risk and brain atrophy trajectories in participants without dementia, as longitudinal studies on PVS are scarce and current methods for PVS assessment lack robustness and inter-scanner reproducibility. Methods: We developed a robust algorithm to automatically assess PVS count and size on clinical MRI, and investigated 1) their relationship with dementia risk and brain atrophy in participants without dementia, 2) their longitudinal evolution, and 3) their potential use as a screening tool in simulated clinical trials. We analysed 46,478 clinical measurements of cognitive functioning and 20,845 brain MRI scans from 10,004 participants (71.1 ± 9.7 years-old, 56.6% women) from three publicly available observational studies on ageing and dementia (the Alzheimer’s Disease Neuroimaging Initiative, the National Alzheimer’s Coordinating Centre database, and the Open Access Series of Imaging Studies). Clinical and MRI data collected between 2004 and 2022 were analysed with consistent methods, controlling for confounding factors, and combined using mixed-effects models. Findings: Our fully-automated method for PVS assessment showed excellent inter-scanner reproducibility (intraclass correlation coefficients >0.8). Fewer PVS and larger PVS diameter at baseline predicted higher dementia risk and accelerated brain atrophy. Longitudinal trajectories of PVS markers differed significantly in participants without dementia who converted to dementia compared with non-converters. In simulated placebo-controlled trials for treatments targeting cognitive decline, screening out participants at low risk of dementia based on our PVS markers enhanced the power of the trial independently of Alzheimer’s disease biomarkers. Interpretation: These robust cerebrovascular markers predict dementia risk and brain atrophy and may improve risk-stratification of patients, potentially reducing cost and increasing throughput of clinical trials to combat dementia. Funding: US National Institutes of Health.

BackgroundCollege students significantly decrease physical activity (PA) over the course of a four-year degree, increasing the risk for chronic disease. Research shows that psychological constructs impact behavior and goal attainment. However, little is known regarding the effect of psychological variables on PA levels in students. This study examined the association of psychological factors, PA, and exercise goals in college students.MethodsStudents completed two questionnaires within one semester approximately 8 weeks apart. The first (Time 1) included the Adult Hope Scale, Life Orientation Test-Revised, Self-Efficacy to Regulate Exercise, International Physical Activity Questionnaire (IPAQ), and goal assessments. The second (Time 2) included the IPAQ, and scales for goal progress and success. One-hundred seven participants completed both surveys and included an exercise goal.ResultsPredictors of exercise goal attainment included moderate PA at Time 1, goal importance, hope-agency, and the hope-agency by major interaction. Predictors of vigorous PA at Time 2 included hope-agency and moderate PA. The only predictor of moderate PA at Time 2 was moderate PA at Time 1. The only predictor of total PA at Time 2 was moderate PA at Time 1.ConclusionHigher hope-agency scores predicted self-reported vigorous PA. We also provide evidence that trait hope influences perceived exercise goal achievement over time.

Background/Objective: Caregivers from the Millennial generation are an emerging and understudied group of unpaid care providers in America who may benefit from digitally delivered support. To inform the design/tailoring of interventions for this group, we aimed to understand how Millennials may differ from other generations of caregivers regarding digital health-related technology use. Methods: Using the Health Information National Trends Survey (HINTS), Version 6, we conducted a cross-sectional study comparing health technology access and use across four generations of unpaid caregivers (n = 545; Millennials, Gen X, Baby Boomers, and Silent Generation) of adults with chronic conditions using chi-square and Kruskal–Wallis non-parametric tests. Results: Compared to Baby Boomer and Silent Generation caregivers, Millennial caregivers more frequently reported having a cellular internet connection, using a wearable activity device, a health/wellness mobile application, choosing telehealth appointments for convenience, and most frequently used social media in general and to view health-related videos (ps < 0.005). Additionally, Millennials were more likely to report possessing a smartphone (compared to Gen X and Silent Generation) and more frequently used social media for peer interaction about health (compared to all older generations; ps < 0.005). Conclusion: Millennials differ from older generations of caregivers regarding health-related technology access and use, which may have implications for intervention design and tailoring.

Abstract Background Patients with persistent critical illness experience prolonged multi-system morbidity, functional impairments, and chronic conditions. As a result, these patients have prolonged intensive care unit admissions. If discharged, they return home with long-term medical dependencies. Care partners take on a variety of physical, mental health, cognitive, and social roles to support the provision of care for these patients. There is limited evidence, however, of the impact of being a care partner for this patient population during hospitalization. Methods A qualitative descriptive study was conducted to explore the impact care provision on care partners for patients experiencing persistent critical illness. Patients who have or have had persistent critical illness and care partners were recruited from two inpatient units in a single community academic hospital in Toronto, Canada to participate in semi-structured interviews. Data was analyzed using a team-based inductive content analysis. Results Seven (43.8%) participants were patient survivors, and nine (56.3%) were care partners. Patients and care partners reported physical, socio-emotional, and social stress as impacts of care provision during persistent critical illness hospitalization. Care partners identified several protective strategies that they used to mitigate the impacts of care provision on them such as seeking external mental health support and boundary setting. Features of formalized and care partner programs were also identified and suggest that these programs can be protective of care partner values, mitigate feelings of helplessness and stress, and may improve relationships between the family members who are in the care partner role and the healthcare team. Conclusions This study identified physical, socio-emotional, and social stress related impacts of care provision on care partners of patients with persistent critical illness during hospitalization. Additionally, this study identified protective factors initiated by care partners to mitigate the reported stresses of the role, as well as protective features of a care partner program. The results provide a better understanding supportive features of care partner programs that are specific to the experiences and needs of persistent critical illness and add to the growing body of evidence about how to provide equitable access to care during and post hospitalization.

Abstract Background Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. Methods We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. Results Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. Limitations. The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. Conclusions We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits.

Evidence supporting a link between gait and cognition is accumulating. However, the relation between executive functioning and spatiotemporal gait parameters has received little attention. This is surprising since these gait variables are related to falls. The goal of this preliminary study was to determine whether performance on measures of inhibition, reasoning, and fluency is related to variability in stride length and step width during dual-task treadmill walking in a sample of healthy adults. Nineteen healthy adults averaging 40 years of age were evaluated. Results indicated that processing speed was reduced, t(18) = 6.31, p = 0.0001, step width increased, t(18) = −8.00, p = 0.0001, and stride length decreased, t(18) = 3.06, p = 0.007, while dual tasking, but variability in gait parameters did not significantly change, consistent with a gait/posture-first approach. As hypothesized, better performance on a visual design fluency task which assesses cognitive flexibility was associated with less dual-task stride length variability, rs(17) = −0.43, p = 0.034, and step width variability, r = −0.56, p = 0.006. The results extend previous findings with older adults walking over ground and additionally suggest that cognitive flexibility may be important for gait maintenance while dual tasking.

Abstract Background Early reports showed that patients with COVID-19 had recrudescence of previously resolved coccidioidomycosis (Valley fever, VF), and there were indications that coinfection had more severe outcomes. We therefore investigated serial infection of Coccidioides posadasii and SARS-CoV-2 in a K18-hACE2 mouse model to assess disease outcomes. Methods In our model, we challenged K18-hACE2 mice sequentially with a sub-lethal dose of SARS-CoV-2 and 24 hours later with low virulence strain of Coccidioides posadasii, and vice versa, compared to mice that only received a single infection challenge. We performed survival and pathogenesis mouse studies as well as looked at the systemic immune response differences between treatment groups. Results Here we show that co-infected groups have a more severe disease progression as well as a decrease in survival. Importantly, results differ depending on the SARS-CoV-2 variant (WA-1, Delta, or Omicron) and infection timing (SARS-CoV-2 first, C. posadasii second or vice versa). We find that groups that are infected with the virus first had a decrease in survival, increased morbidity and weight loss, increased fungal and viral burdens, differences in immune responses, and the amount and size of fungal spherules. We also find that groups coinfected with C. posadasii first have a decrease fungal burden and inflammatory responses. Conclusions This is the first in vivo model investigation of a coinfection of SARS-CoV-2 and Coccidioides. Because of the potential for increased severity of disease in a coinfection, we suggest populations that live in areas of high coccidioidomycosis endemicity may experience higher incidence of complicated disease progression with COVID-19.

Due to their immunomodulatory function, mesenchymal stromal cells (MSCs) are a promising therapeutic with the potential to treat neuroinflammation associated with neurodegenerative diseases. This function is mediated by secreted extracellular vesicles (MSC-EVs). Despite established safety, MSC clinical translation has been unsuccessful due to inconsistent clinical outcomes resulting from functional heterogeneity. Current approaches to mitigate functional heterogeneity include ‘priming’ MSCs with inflammatory signals to enhance function. However, comprehensive evaluation of priming and its effects on MSC-EV function has not been performed. Furthermore, clinical translation of MSC-EV therapies requires significant manufacturing scale-up, yet few studies have investigated the effects of priming in bioreactors. As MSC morphology has been shown to predict their immunomodulatory function, we screened MSC morphological response to an array of priming signals and evaluated MSC-EV identity and potency in response to priming in flasks and bioreactors. We identified unique priming conditions corresponding to distinct morphologies. These conditions demonstrated a range of MSC-EV preparation quality and lipidome, allowing us to discover a novel MSC-EV manufacturing condition, as well as gain insight into potential mechanisms of MSC-EV microglia modulation. Our novel screening approach and application of priming to MSC-EV bioreactor manufacturing informs refinement of larger-scale manufacturing and enhancement of MSC-EV function.

Abstract Background Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized. Methods In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (

Abstract Background Exposure to systemic racism is linked to increased dementia burden. To assess systemic inflammation as a potential pathway linking exposure to racism and dementia disparities, we investigated the mediating role of C-reactive protein (CRP), a systemic inflammation marker, and the moderating role of the racialization process in incident dementia. Methods In the US Health and Retirement Study (n = 6,908), serum CRP was measured at baseline (2006, 2008 waves). Incident dementia was classified by cognitive tests over a six-year follow-up. Self-reported racialized categories were a proxy for exposure to the racialization process. We decomposed racialized disparities in dementia incidence (non-Hispanic Black and/or Hispanic vs. non-Hispanic white) into 1) the mediated effect of CRP, 2) the moderated portion attributable to the interaction between racialized group membership and CRP, and 3) the controlled direct effect (other pathways through which racism operates). Results The 6-year cumulative incidence of dementia is 12%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP levels ( ≥ 75th percentile or 4.73μg/mL) are associated with 1.26 (95%CI: 0.98, 1.62) times greater risk of incident dementia than low CRP (

Abstract Immune thrombocytopenia (ITP) is the most common acquired primary hemostatic disorder in dogs. Immune thrombocytopenia less commonly affects cats but is an important cause of mortality and treatment‐associated morbidity in both species. Immune thrombocytopenia remains a diagnosis of exclusion for which diagnostic guidelines are lacking. Primary, or non‐associative, ITP refers to autoimmune platelet destruction. Secondary, or associative, ITP arises in response to an underlying disease trigger. However, evidence for which comorbidities serve as ITP triggers has not been systematically evaluated. To identify key diagnostic steps for ITP and important comorbidities associated with secondary ITP, we developed 12 Population Evaluation/Exposure Comparison Outcome (PECO) format questions. These questions were addressed by evidence evaluators utilizing a literature pool of 287 articles identified by the panelists using a structured search strategy. Evidence evaluators, using panel‐designed templates and data extraction tools, summarized evidence and created guideline recommendations that then were integrated by diagnosis and comorbidity domain chairs. The revised PECO responses underwent a Delphi survey process to reach consensus on final guidelines. A combination of panel expertise and PECO responses were employed to develop algorithms for diagnosis of ITP in dogs and cats, which also underwent 4 iterations of Delphi review. Comorbidity evidence evaluators employed an integrated measure of evidence (IME) tool to determine evidence quality for each comorbidity; IME values combined with evidence summaries for each comorbidity were integrated to develop ITP screening recommendations, which also were subjected to Delphi review. Commentary was solicited from multiple relevant professional organizations before finalizing the consensus. The final consensus statement provides clinical guidelines for the diagnosis of, and underlying disease screening for, ITP in dogs and cats. The systematic consensus process identified numerous knowledge gaps that should guide future studies. This statement is a companion manuscript to the ACVIM Consensus Statement on the Treatment of Immune Thrombocytopenia.

To distinguish DNA methylation (DNAm) from cell proportion changes in whole placental villous tissue research, we developed a robust cell type-specific DNAm reference to estimate cell composition. We collated new and existing cell type DNAm profiles quantified via Illumina EPIC or 450k microarrays. To estimate cell composition, we deconvoluted whole placental samples (n = 36) with robust partial correlation based on the top 30 hyper- and hypomethylated sites identified per cell type. To test deconvolution performance, we evaluated root mean square error in predicting principal components of DNAm variation in 204 external placental samples. We analyzed DNAm profiles (n = 368,435 sites) from 12 cell types: cytotrophoblasts (n = 18), endothelial cells (n = 19), Hofbauer cells (n = 26), stromal cells (n = 21), syncytiotrophoblasts (n = 4), six lymphocyte types (n = 36), and nucleated red blood cells (n = 11). Median cell composition was consistent with placental biology: 60.9% syncytiotrophoblast, 17.3% stromal, 8.8% endothelial, 3.7% cytotrophoblast, 3.7% Hofbauer, 1.7% nucleated red blood cells, and 1.2% neutrophils. Our expanded reference outperformed an existing reference in predicting DNAm variation (PC1, 15.4% variance explained, IQR = 21.61) with cell composition estimates (mean square error of prediction: 8.62 vs. 10.79, p-value < 0.001). This cell type reference can robustly estimate cell composition from whole placental DNAm data to detect important cell types, reveal biological mechanisms, and improve causal inference.

Loneliness is a complex human trait that is highly polygenic and found to affect gene expression related to inflammatory and immunological functioning. To date, no epigenome-wide association studies of loneliness have tested whether differentially methylated sites are annotated to genes associated with inflammatory and immunological processes. Using 281 individual adult twins’ DNA methylation data from the Louisville Twin Study, we performed an epigenome-wide analysis of loneliness to address this gap in the literature. In the discovery analysis, 169 twins were used to prioritize probes and test associations with DNA methylation age acceleration, and 56 independent monozygotic (MZ) twin pairs (112 individuals) were used in a within-family replication analysis. Among the 837,274 sites analyzed, no probe sites were statistically significant at the genome-wide level (p

Background Orofacial pain is a specialty of dentistry that often encounters complex symptoms beyond the scope of dental practice, indicating a role for interprofessional teams in treating chronic orofacial pain.Discussion Interprofessional teams often include specialists from neurology, physical therapy, sleep medicine, and behavioral medicine, among others. Interprofessional practices can be difficult to achieve and require a commitment of communication, collaboration, co-location, and organizational support. A complex chronic orofacial pain case exemplifies the challenges for patients receiving sequential or siloed care, including delays in diagnosis, invasive procedures, and worsened disability. Common barriers to collaborative care and possible steps to close these gaps are discussed..

Chronic pain, which is described as pain lasting for greater than 3 months, accounts for a large percentage of economic debt in the United States, with approximately 20% of Americans experiencing a form of chronic pain. Despite the current pharmacologic recommendations for pain treatment, there are differences in how medications are prescribed to patients. Gender and sex are common variables when discussing biases in both pain perception and treatment. Pain perception can differ amongst the sexes based on a myriad of reasons such as differences in gonadal hormones or chronic pain syndromes. The purpose of this narrative literature review is to report physiologic and pharmacokinetic differences between the sexes and highlight the possible biases in pain treatment amongst men and women. By bringing awareness to differences in pain perception and treatment experienced by men and women, clinically, we can increase the efficacy of pain management amongst the sexes.

Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition. Akkermansia, Ruminococcaceae UCG-002, Subdoligranulum, and Lachnospiraceae UCG-004 were more abundant, while Veillonella, Tyzzerella 4, Clostridium innocuum group, Ruminococcus gnavus group, Escherichia-Shigella, and an uncultured Ruminococcaceae family genus were less abundant in women compared to men. In women, only baseline Eubacterium ventriosum group abundance correlated with EGCG+RES-induced changes in SkM-Ox. In men, low Dorea, Barnsiella, Anaerotruncus, Ruminococcus, Subdoligranulum, Coprococcus, Eubacterium ventriosum group, Ruminococcaceae UCG-003, and a Ruminococcaceae family genus abundance, and high Blautia abundance at baseline were associated with improvements in SkM-Ox. Changes in whole-body fat oxidation were not associated with gut microbiota features. We conclude that baseline microbiota composition predicts changes in SkM-Ox as a result of EGCG+RES supplementation in men but not in women. Men may be more prone to diet-induced, gut microbiota-related improvements in cardiometabolic health. These sex-differences should be further investigated in future precision-based intervention studies.

Background: The anterior and posterior bellies of digastric muscle act to facilitate components of phonation, jaw opening, and hyoid bone stabilization during swallowing. Variations in the digastric muscle within the submental triangle are well-documented in the literature. Ongoing and up-to-date reporting and knowledge of these variations is important from a clinical perspective. Method: Routine human anatomical dissection of the anterior neck in a male donor revealed bilateral pairs of accessory muscles (n = 4) attached to and within the depth plane of right and left anterior bellies of digastric muscles. Results: The case presented here is of a bilateral, tripartite digastric muscle variation within the submental triangle of an anatomical donor. Attachments and relationships were noted. Variant digastric muscles were found to be innervated by the nerve to the mylohyoid muscle and supplied by the submental artery, consistent with supply to the anterior belly of the digastric muscle. Conclusion: The clinical relevance of these additional muscles primarily pertains to radiological evaluation and reconstructive surgical procedures in the submental region, as digastric muscle bellies serve as essential landmarks and potential targets. Describing anatomical variations is crucial for appropriate planning of interventions in this region.

Summary: Background: Amyotrophic lateral sclerosis (ALS) is linked to ageing and genetic and environmental risk factors, yet underlying mechanisms are incompletely understood. We aimed to evaluate epigenetic age acceleration (EAA), i.e., DNA methylation (DNAm) age acceleration, and its association with ALS case status and survival. Methods: In this study, we included 428 ALS and 288 control samples collected between 2011 and 2021. We calculated EAA using the GrimAge residual method from ALS and control blood samples and grouped participants with ALS into three ageing groups (fast, normal, slow). We associated EAA with ALS case status and survival, stratified by sex, and correlated it with environmental and biological factors through occupational exposure assessments, immune cell proportions, and transcriptome changes. Findings: Participants with ALS had higher average EAA by 1.80 ± 0.30 years (p

The type of algorithm employed to predict drug release from liposomes plays an important role in affecting the accuracy. In recent years, Machine Learning (ML) has shown potential for modeling complex drug delivery systems and predicting drug release dynamics with a greater degree of precision. In this regard, Random Forest (RF) and Support Vector Machine (SVM) are two ML algorithms that have been extensively applied in various biomedical and drug delivery contexts. Yet, direct comparisons of their predictive accuracy in modeling ultrasound-triggered drug release from liposomes remain limited. Existing studies predominantly focus on drug release under static conditions or with limited external stimuli rather than the dynamic, nonlinear responses observed under ultrasound exposure. Objective This study presents a comparative analysis of RF and SVM for predicting calcein release from ultrasound-triggered, targeted liposomes under varied low-frequency ultrasound (LFUS) power densities (6.2, 9, and 10 mW/cm 2 ). Methods Liposomes loaded with calcein and targeted with seven different moieties (cRGD, estrone, folate, Herceptin, hyaluronic acid, lactobionic acid, and transferrin) were synthesized using the thin-film hydration method. The liposomes were characterized using Dynamic Light Scattering and Bicinchoninic Acid assays. Extensive data collection and preprocessing were performed. RF and SVM models were trained and evaluated using mean absolute error (MAE), mean squared error (MSE), coefficient of determination (R²), and the a20 index as performance metrics. Results RF consistently outperformed SVM, achieving R 2 scores above 0.96 across all power densities, particularly excelling at higher power densities and indicating a strong correlation with the actual data. Conclusion RF outperforms SVM in drug release prediction, though both show strengths and apply based on specific prediction needs.

ABSTRACT Overnight inpatient monitoring is common following balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH). We describe our institutional experience in same‐day discharge (SDD) after BPA. Across 78 BPA sessions, there were only 2 (2.6%) admissions for hemoptysis with no reperfusion lung injury or deaths at 30 days.

One of the world’s largest “blue carbon” ecosystems, Louisiana’s tidal wetlands on the US Gulf of Mexico coast, is rapidly being lost. Louisiana’s strong legal, regulatory, and monitoring framework, developed for one of the world’s largest tidal wetland systems, provides an opportunity for a programmatic approach to blue carbon accreditation to support restoration of these ecologically and economically important tidal wetlands. Louisiana’s coastal wetlands span ∼1.4 million ha and accumulate 5.5–7.3 Tg yr−1 of blue carbon (organic carbon), ∼6%–8% of tidal marsh blue carbon accumulation globally. Louisiana has a favorable governance framework to advance blue carbon accreditation, due to centralized restoration planning, long term coastal monitoring, and strong legal and regulatory frameworks around carbon. Additional restoration efforts, planned through Louisiana’s Coastal Master Plan, over 50 years are projected to create, or avoid loss of, up to 81,000 ha of wetland. Current restoration funding, primarily from Deepwater Horizon oil spill settlements, will be fully committed by the early 2030s and additional funding sources are required. Existing accreditation methodologies have not been successfully applied to coastal Louisiana’s ecosystem restoration approaches or herbaceous tidal wetland types. Achieving financial viability for accreditation of these restoration and wetland types will require expanded application of existing blue carbon crediting methodologies. It will also require expanded approaches for predicting the future landscape without restoration, such as numerical modeling, to be validated. Additional methodologies (and/or standards) would have many common elements with those currently available but may be beneficial, depending on the goals and needs of both the state of Louisiana and potential purchasers of Louisiana tidal wetland carbon credits. This study identified twenty targeted needs that will address data and knowledge gaps to maximize financial viability of blue carbon accreditation for Louisiana’s tidal wetlands. Knowledge needs were identified in five categories: legislative and policy, accreditation methodologies and standards, soil carbon flux, methane flux, and lateral carbon flux. Due to the large spatial scale and diversity of tidal wetlands, it is expected that progress in coastal Louisiana has high potential to be generalized to similar wetland ecosystems across the northern Gulf of Mexico and globally.

Objective: Congenital heart disease is a risk factor for mortality after orthotopic heart transplantation; however, the impact of preoperative circulation type and primary congenital heart disease diagnosis remains poorly delineated. Methods: We retrospectively reviewed patients with adult congenital heart disease aged 16 years or more who underwent orthotopic heart transplantation at our institution between 2008 and 2022. Patients were categorized as having single-ventricle or biventricular circulation. The primary end point was 5-year post-transplant survival. Results: Sixty-one patients with adult congenital heart disease (single-ventricle: n = 26 [42.6%], biventricular: n = 35 [57.4%]) underwent orthotopic heart transplantation at 33.7 [interquartile range, 19.1-48.7] years. The most common congenital heart disease diagnosis was hypoplastic left heart syndrome (n = 11, 42.3%) in the single-ventricle group and congenitally corrected transposition of the great arteries (n = 7, 20.0%) in the biventricular group. Twenty-four patients previously underwent Fontan palliation. At transplant, patients in the single-ventricle group were younger (18.5 [interquartile range, 17.6-32.3] years vs 45.0 [interquartile range, 33.0-52.2] years, P

Abstract Background Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer’s disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups. Methods Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older. Results PTSD symptoms (B = 0.50–0.52, p

Abstract Objective Tuberous sclerosis complex (TSC) results from overactivity of the mechanistic target of rapamycin (mTOR). Sirolimus and everolimus are mTOR inhibitors that treat most facets of TSC but are understudied in infants. We sought to understand the safety and potential efficacy of preventative sirolimus in infants with TSC. Methods We conducted a phase 1 clinical trial of sirolimus, treating five patients until 12 months of age. Enrolled infants had to be younger than 6 months of age with no history of seizures and no clinical indication for sirolimus treatment. Adverse events (AEs), tolerability, and blood concentrations of sirolimus measured by tandem mass spectrometry were tracked through 12 months of age, and clinical outcomes (seizure characteristics and developmental profiles) were tracked through 24 months of age. Results There were 92 AEs, with 34 possibly, probably, or definitely related to treatment. Of those, only two were grade 3 (both elevated lipids) and all AEs were resolved by the age of 24 months. During the trial, 94% of blood sirolimus trough levels were in the target range (5–15 ng/mL). Treatment was well tolerated, with less than 8% of doses held because of an AE (241 of 2941). Of the five patients, three developed seizures (but were well controlled on medications) at 24 months of age. Of the five patients, four had normal cognitive development for age. One was diagnosed with possible autism spectrum disorder. Interpretation These results suggest that sirolimus is both safe and well tolerated by infants with TSC in the first year of life. Additionally, the preliminary work suggests a favorable efficacy profile compared with previous TSC cohorts not exposed to early sirolimus treatment. Results support sirolimus being studied as preventive treatment in TSC, which is now underway in a prospective phase 2 clinical trial (TSC‐STEPS).

Abstract Background Body composition and body fat distribution are important predictors of cardiometabolic diseases. The etiology of cardiometabolic diseases is heterogenous, and partly driven by inter-individual differences in tissue-specific insulin sensitivity. Objectives To investigate (1) the associations between body composition and whole-body, liver and muscle insulin sensitivity, and (2) changes in body composition and insulin sensitivity and their relationship after a 12-week isocaloric diet high in mono-unsaturated fatty acids (HMUFA) or a low-fat, high-protein, high-fiber (LFHP) diet. Methods This subcohort analysis of the PERSON study includes 93 individuals (53% women, BMI 25–40 kg/m2, 40–75 years) who participated in this randomized intervention study. At baseline and after 12 weeks of following the LFHP, or HMUFA diet, we performed a 7-point oral glucose tolerance test to assess whole-body, liver, and muscle insulin sensitivity, and whole-body magnetic resonance imaging to determine body composition and body fat distribution. Both diets are within the guidelines of healthy nutrition. Results At baseline, liver fat content was associated with worse liver insulin sensitivity (β [95%CI]; 0.12 [0.01; 0.22]). Only in women, thigh muscle fat content was inversely related to muscle insulin sensitivity (-0.27 [-0.48; -0.05]). Visceral adipose tissue (VAT) was inversely associated with whole-body, liver, and muscle insulin sensitivity. Both diets decreased VAT, abdominal subcutaneous adipose tissue (aSAT), and liver fat, but not whole-body and tissue-specific insulin sensitivity with no differences between diets. Waist circumference, however, decreased more following the LFHP diet as compared to the HMUFA diet (-3.0 vs. -0.5 cm, respectively). After the LFHP but not HMUFA diet, improvements in body composition were positively associated with improvements in whole-body and liver insulin sensitivity. Conclusions Liver and muscle insulin sensitivity are distinctly associated with liver and muscle fat accumulation. Although both LFHP and HMUFA diets improved in body fat, VAT, aSAT, and liver fat, only LFHP-induced improvements in body composition are associated with improved insulin sensitivity. Trial registration NCT03708419 (clinicaltrials.gov).

Abstract Continuous glucose monitoring (CGM) is a promising, minimally invasive alternative to plasma glucose measurements for calibrating physiology-based mathematical models of insulin-regulated glucose metabolism, reducing the reliance on in-clinic measurements. However, the use of CGM glucose, particularly in combination with insulin measurements, to develop personalized models of glucose regulation remains unexplored. Here, we simultaneously measured interstitial glucose concentrations using CGM as well as plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT) in individuals with overweight or obesity to calibrate personalized models of glucose-insulin dynamics. We compared the use of interstitial glucose with plasma glucose in model calibration, and evaluated the effects on model fit, identifiability, and model parameters’ association with clinically relevant metabolic indicators. Models calibrated on both plasma and interstitial glucose resulted in good model fit, and the parameter estimates associated with metabolic indicators such as insulin sensitivity measures in both cases. Moreover, practical identifiability of model parameters was improved in models estimated on CGM glucose compared to plasma glucose. Together these results suggest that CGM glucose may be considered as a minimally invasive alternative to plasma glucose measurements in model calibration to quantify the dynamics of glucose regulation.

Although “BDSM” (i.e., bondage, discipline, dominance, submission, sadism, and masochism) has become increasingly present in popular media in recent years, much remains unknown about the etiology and correlates of BDSM. Research has demonstrated a relationship between religion and sexual behaviours/attitudes; therefore, religion could also be associated with sadism and masochism. To address gaps in existing knowledge, we conducted an online survey of 515 participants who answered a questionnaire on sexual life and behaviour, including questions on arousal in response to sadism and masochism scenarios, associated negative impacts, and religion. We found a higher prevalence of arousal in response to sadism scenarios amongst non-religious participants (64.6%; n = 228/353) than religious participants (54.7%; n = 88/161) with a small, but potentially meaningful effect size (Φ = -.095, p = .032). Increased impact of religious beliefs on sex life was associated with slightly lower sadism arousal, r(499) = -.080, p = .075. This association was strong enough to be considered a potentially meaningful factor but was not statistically significant. There was also a small negative correlation between masochism arousal and impact of religious beliefs on sex life and behaviour, r(500) = -.129, p = .004. Based on these findings, we conclude that there could be a limited but meaningful relationship between religion and sadism/masochism arousal. Further research should explore specific religious affiliations and beliefs as potentially associated with sadism and masochism arousal.

Background: Relatives of probands diagnosed with familial hypercholesterolemia (FH) should undergo cascade testing for FH. Objectives: The purpose of this study was to evaluate probands’ choices of innovative strategies to communicate their FH result with relatives and facilitate cascade testing uptake. Methods: Probands with an FH genetic result from the MyCode Community Health Initiative could choose to share their FH result with adult blood relatives via the Family and Healthcare Professional Packet (packet), family sharing and cascade chatbots (chatbot), and/or FH Outreach and Support Program (direct contact). Cascade testing uptake was measured as reported completion of genetic or cholesterol testing. Generalized estimating equations models were used to identify factors associated with testing. Results: One hundred seventy five probands received an FH result, median age was 58.9 (IQR: 44.9-69.3), and 58.9% were female. Probands shared information about 1,915 adult and 163 minor relatives (11.9 relatives per proband). Seventy percent of probands (121/175) selected at least one strategy for at least one adult relative. An average of 1.2 strategies was selected per adult relative. Cascade testing was completed for 26.6% (144/541) of adults with at least one strategy selected, 2.4% (33/1,374) of adults without a strategy selected, and 25.2% (41/163) of minor relatives. Factors associated with increased cascade testing uptake were selection of at least one strategy (6.32 higher odds), specifically, selection of direct contact (16.78 higher odds). Conclusions: Strategies implemented improved FH cascade testing uptake compared to previous estimates and in families where no strategy was selected. Overall uptake remains insufficient, which can be attributed to probands reluctance to select a strategy for many relatives.

Background: Little is known regarding the characteristics, treatment patterns, and outcomes in patients with adult congenital heart disease (ACHD) admitted to cardiac intensive care units (CICUs). Objectives: The authors sought to better define the contemporary epidemiology, treatment patterns, and outcomes of ACHD admissions in the CICU. Methods: The Critical Care Cardiology Trials Network is a multicenter network of CICUs in North America. Participating centers contributed prospective data from consecutive admissions during 2-month annual snapshots from 2017 to 2022. We analyzed characteristics and outcomes of admissions with ACHD compared with those without ACHD. Multivariable logistic regression was used to assess mortality in ACHD vs non-ACHD admissions. Results: Of 23,299 CICU admissions across 42 sites, there were 441 (1.9%) ACHD admissions. Shunt lesions were most common (46.1%), followed by right-sided lesions (29.5%) and complex lesions (28.7%). ACHD admissions were younger (median age 46 vs 67 years) than non-ACHD admissions. ACHD admissions were more commonly for heart failure (21.3% vs 15.7%, P

Background: Previous studies that suggest a shorter time from cervical ripening balloon placement to delivery with shorter total balloon placement time have excluded patients with prior cesarean deliveries. Objective: To evaluate, in patients with a prior history of cesarean delivery undergoing cervical ripening with a double-balloon catheter, whether planned removal of device after 6 vs 12 hours would result in shorter time to vaginal delivery. Study Design: A before-and-after study was performed after a practice change occurred November 2020, shortening the planned time of double-balloon catheter placement for cervical ripening from 12 to 6 hours. Data were collected via retrospective electronic chart review. Primary outcome was time from balloon placement to vaginal delivery. Secondary outcomes included rates of cesarean delivery, maternal intraamniotic infection, and uterine rupture. Kaplan–Meier curves compared median times to delivery between the groups. A Cox proportional-hazards model was used to adjust for time of balloon placement, number of previous vaginal deliveries, and co-medications used. Results: From November 2018 to November 2022, 189 analyzable patients with a prior history of cesarean delivery received a double-balloon catheter for cervical ripening during their trial of labor. Patients were separated into pre- and postpolicy change groups (n=91 and 98, respectively). The median time to vaginal delivery for the pregroup was 28 hours (95% CI: 26, 35) and 25 hours (95% CI: 23, 29) for those in the postgroup (P value .052). After adjusting for dilation at time of balloon placement, number of previous vaginal deliveries, and co-medication, the estimated hazard ratio for successful vaginal delivery postpolicy change was 1.89 (95% CI: 1.27, 2.81). There were no differences in rates of secondary outcomes. Conclusion: In patients with prior cesarean delivery undergoing mechanical cervical ripening with a double-balloon catheter, planned removal at 6 hours compared to 12 hours may result in higher chances of successful vaginal delivery and possibly a shorter time to delivery, without increasing rates of cesarean delivery and intraamniotic infection.