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Background: We studied whether increased systolic blood pressure (SBP), as determined by auscultatory SBP, ambulatory SBP, and the number of cardiovascular health risk indicators, are associated with neurocognition in adolescents., Methods: This cross-sectional study included 365 adolescents (mean age, 15.5 years) from 6 academic medical centers in the United States. The sample was 59.5% male, 52.6% White, with 23.9% of the caregivers having less than or equal to a high school degree. Primary exposures included the following: auscultatory SBP, ambulatory SBP, and the number of cardiovascular risk factors. Neurocognitive outcomes comprised nonverbal IQ, attention, and parent ratings of executive functions., Results: After examining the models for the effects of targeted covariates (eg, maternal education), higher auscultatory SBP was associated with lower nonverbal IQ (β=-1.39; P <0.001) and verbal attention (β=-2.39; P <0.05); higher ambulatory 24 hours. SBP (β=-21.39; P <0.05) and wake SBP (β=-21.62; P <0.05) were related to verbal attention; and all 3 ambulatory blood pressure measures were related to sustained attention accounting for small to medium amounts of variance (adjusted R 2 =0.08-0.09). Higher ambulatory blood pressure sleep SBP also was significantly associated with parent ratings of behavior regulation (β=12.61; P <0.05). These associations remained stable after a sensitivity analysis removed cases with hypertension. Number of cardiovascular risk factors performed similarly, with more risk factors being associated with lower nonverbal IQ (β=-1.35; P <0.01), verbal attention (β=-1.23; P <0.01), and all parent ratings of executive functions., Conclusions: Elevated SBP, even below the hypertension range, and general cardiovascular health are associated with neurocognitive outcomes in adolescents. How these findings might guide clinical care is worthy of additional study., Competing Interests: None.

Objectives: We tested abortion messaging to develop evidence-based communication recommendations for doctors who provide abortion care., Study Design: We conducted an online survey in a nationally representative sample of 1215 people, using National Opinion Research Center's Amerispeak Panel. We surveyed participants before and after viewing two brief videos featuring doctors who provide abortion care speaking about their work. Doctors' comments were grounded in strategic communications and applied psychology research, and emphasized caregiving roles, avoided political-sounding punditry, and acknowledged abortion's complexities. We assessed participants' characterizations of doctors, and how these characterizations impact support for abortion restrictions and views on abortion legality. We analyzed pre-post data using descriptive statistics, t tests, and multivariable regression., Results: Postmessaging more participants endorsed positive descriptors of doctors who provide abortion care (p < 0.001, t = 8.99); fewer endorsed negative descriptors (p < 0.001, t = 10.32). Increased postmessaging endorsement of positive descriptors predicted declines in support for abortion restrictions (adjusted odds ratio = 1.69, p < 0.01); decreased endorsement of negative descriptors did not. After messaging, 37% of respondents said their views of doctors who provide abortion care made them less likely to support abortion restrictions, compared to 14% before (p < 0.001, t = -6.9). After messaging, there was more overall support for legal abortion and less for abortion being mostly illegal (46% to 48% and 24% to 22%, p < 0.001; t = -4.11)., Conclusions: When doctors who provide abortion care use messaging recommendations that include speaking about abortion's complexities and avoiding political-sounding punditry, they generate more support for legal abortion and less for restrictions., Implications: The voices of doctors who provide abortion care shape public opinion. When doctors speak from caregiving perspectives, avoid punditry, and acknowledge abortion's complexities, they generate more support for legal abortion and less for restrictions. However, audiences may not be aware a priori that ideas of doctors shape their views., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Study Objective: To determine if baseline cytokines/chemokines and their changes over postoperative days 0-2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery., Design: Prospective, observational, longitudinal nested study., Setting: University-affiliated quaternary children's hospital., Patients: Subjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure., Measurements: Demographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and up to two weeks after surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score > 3/10 beyond 3 months post-surgery) post-surgical pain were analyzed using univariable and multivariable regression analyses with adjustment for covariates and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes., Main Results: Analyses included 3,164 repeated measures of 16 cytokines/chemokines from 112 subjects (median age 15.3, IQR 13.5-17.0, 54.5 % female, 59.8 % pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (β = 0.95, SE 0.31; p = 0.003), IL-1β (β = 0.84, SE 0.36; p = 0.02), IL-2 (β = 0.78, SE 0.34; p = 0.03), and IL-12 p70 (β = 0.88, SE 0.40; p = 0.03) and longitudinal postoperative elevations in GM-CSF (β = 1.38, SE 0.57; p = 0.03), IFNγ (β = 1.36, SE 0.6; p = 0.03), IL-1β (β = 1.25, SE 0.59; p = 0.03), IL-7 (β = 1.65, SE 0.7; p = 0.02), and IL-12 p70 (β = 1.17, SE 0.58; p = 0.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (β = -0.39, SE 0.17; p = 0.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (β = -0.57, SE 0.26; p = 0.03), IL-8 (β = -0.68, SE 0.24; p = 0.006), and IL-13 (β = -0.48, SE 0.22; p = 0.03). Covariates female (vs. male) sex and surgery type (pectus surgery vs. spine) were associated with higher odds for CPSP in baseline adjusted cytokine-CPSP association models for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNFα, and IL-8, IL-10, respectively., Conclusion: We identified pro-inflammatory cytokine profiles associated with higher risk of acute postoperative pain. Interestingly, pleiotropic cytokine IL-6, chemokine IL-8 (which promotes neutrophil infiltration and monocyte differentiation), and monocyte-released anti-inflammatory cytokine IL-13, were associated with lower CPSP risk. Our results suggest heterogenous outcomes of cytokine/chemokine signaling that can both promote and protect against post-surgical pain. These may serve as predictive and prognostic biomarkers of pain outcomes following surgery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Because young children cannot self-report symptoms, there is a need for parent surrogate reports. Although early work suggested parent-child alignment for eosinophil esophagitis (EoE) patient-reported outcomes (PROs), the longitudinal alignment is unclear., Objective: We sought to assess the agreement and longitudinal stability of PROs between children with EoE and their parents., Methods: A total of 292 parent-child respondents completed 723 questionnaires over 5 years in an observational trial in the Consortium of Eosinophilic Gastrointestinal Disease Researchers. The change in and agreement between parent and child Pediatric Eosinophilic Esophagitis Symptom Score version 2 (PEESSv2.0) and Pediatric Quality of Life Eosinophilic Esophagitis Module (PedsQL-EoE) PROs over time were assessed using Pearson correlation and Bland-Altman analyses. Clinical factors influencing PROs and their agreement were evaluated using linear mixed models., Results: The cohort had a median disease duration equaling 3.7 years and was predominantly male (73.6%) and White (85.3%). Child and parent PEESSv2.0 response groups were identified and were stable over time. There was strong correlation between child and parent reports (PEESSv2.0, 0.83;PedsQL-EoE, 0.74), with minimal pairwise differences for symptoms. Longitudinally, parent-reported PedsQL-EoE scores were stable (P ≥ .32), whereas child-reported PedsQL-EoE scores improved (P = .026). A larger difference in parent and child PedsQL-EoE reports was associated with younger age (P < .001), and differences were driven by psychosocial PRO domains., Conclusions: There is strong longitudinal alignment between child and parent reports using EoE PROs. These data provide evidence that parent report is a stable proxy for objective EoE symptoms in their children., Competing Interests: Disclosure statement CEGIR (U54 AI117804) is part of the Rare Disease Clinical Research Network, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS), and is funded through a collaboration between NIAID, the National Institute of Diabetes and Digestive and Kidney Diseases, and NCATS and funded in part by the Division of Intramural Research, NIAID. CEGIR is also supported by patient advocacy groups including the American Partnership for Eosinophilic Disorders, Campaign Urging Research for Eosinophilic Diseases, and Eosinophilic Family Coalition. As a member of the Rare Disease Clinical Research Network, CEGIR is supported by its Data Management and Coordinating Center (grant no. U2CTR002818). Funding support for the Data Management and Coordinating Center is provided by NCATS and the National Institute of Neurological Disorders and Stroke. G.S.H. is supported by a grant from the National Institutes of Health (NIH) (grant no. K23 DK131341). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Disclosure of potential conflict of interest: M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nexstone One, Santa Ana Bio, EnZen Therapeutics, Bristol Myers Squibb, AstraZeneca, Pfizer, GlaxoSmithKline, Regeneron/Sanofi, Revolo Biotherapeutics, and Guidepoint and has an equity interest in the first 9 listed; receives royalties from Teva Pharmaceuticals (reslizumab), Mapi Research Trust (PEESSv2.0), and UpToDate; and is an inventor of patents owned by Cincinnati Children’s Hospital. J. M. Spergel is a consultant for ReadySetfood, Regeneron/Sanofi, and ARS Pharma; has grant support from Novartis, Regeneron/Sanofi, Bristol Myers Squibb, Food Allergy Research and Education (FARE), and NIH; receives royalties from UpToDate; and serves on the Data Safety and Monitoring Board for Alladapt and NIAID. M. H. Collins is a consultant for Allakos, Arena/Pfizer, AstraZeneca, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene/Bristol Myers Squibb, Regeneron Pharmaceuticals, Robarts Clinical Trials, Inc/Alimentiv, Inc, and Shire/Takeda. S. S Aceves is a consultant and an educational speaker for Regeneron/Sanofi; has grant support from the NIH, Campaign Urging Research for Eosinophilic Diseases, Bristol Myers Squibb, and Implicit Biosciences; and is a coinventor of oral viscous budesonide patented by the University of California San Diego and licensed by Takeda. M. Pletneva is a consultant for Allakos. S. K. Gupta is a consultant and/or Data Safety and Monitoring Board member for Adare, Bristol Myers Squibb, QOL, Takeda, Medscape, PVI, ViaSkin, and UpToDate; and receives research support from Allakos, Ellodi, and AstraZeneca. J. B. Wechsler is a consultant for Bristol Myers Squibb, Ellodi, AstraZeneca, Allakos, and Regeneron/Sanofi; and receives research support from Regeneron. N. Gonsalves is a consultant for AstraZeneca, Allakos, Sanofi/Regeneron, AbbVie, Knopp, and Bristol Myers Squibb; is on the speaker bureau for Sanofi/Regeneron; and receives publication royalties from UpToDate. G. W. Falk is a consultant for Allakos, Bristol Myers Squibb/Celgene, Adare/Ellodi, Nexstone, Upstream Bio, and Sanofi/Regeneron; and receives research support from Allakos, Adare/Ellodi, Bristol Myers Squibb/Celgene, and Regeneron/Sanofi. I. Hirano has received research funding from Adare Pharmaceuticals/Ellodi Pharmaceuticals, Allakos, AstraZeneca, Meritage Pharma, Inc, Receptos/Celgene/Bristol Myers Squibb, Regeneron Pharmaceuticals, and Shire/Takeda; and is a consultant for Adare Pharmaceuticals/Ellodi Pharmaceuticals, Allakos, Arena Pharmaceuticals, Aslan Pharmaceuticals, AstraZeneca, Calyx/Parexel, Celldex Therapeutics, Inc, Dermavant, EsoCap Biotech, Gossamer Bio, Eli Lilly, Nexstone, Meritage Pharma, Inc, Phathom Pharmaceuticals, Receptos/Celgene/Bristol Myers Squibb, Sanofi/Regeneron Pharmaceuticals, and Shire/Takeda. M. Chehade has received consultant fees from Regeneron, Adare/Ellodi, AstraZeneca, Sanofi, Bristol Myers Squibb, Recludix Pharma, Allakos, Shire/Takeda, and Phathom; and has received research support from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, and Danone. C. M. Davis has received grant funding from DBV Technologies, Aimmune Therapeutics, Regeneron Pharmaceuticals, and Allergenis. E. S. Dellon is a consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GlaxoSmithKline, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; has received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, GlaxoSmithKline, Meritage, Miraca, Nutricia, Celgene/Receptos/Bristol Myers Squibb, Regeneron, Revolo, and Shire/Takeda; and has received an educational grant from Allakos, Aqilion, Holoclara, and Invea. G. T. Furuta is Chief Medical Officer for EnteroTrack; and receives research funding from Arena/Pfizer. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Genetic counseling is an important component of pediatric cardiac care. The financial costs and benefits of this care have yet to be defined in the literature. Downstream revenue (DSR) analysis can be used to assess the economic impact of genetic counselors (GCs) at their institution beyond the initial patient contact. Previous literature has reported DSR generated by oncology GCs, but there is no published DSR data from a cardiac GC setting. This study measured the DSR generated at a private hospital following a cardiac GC appointment. A chart review identified patients seen by a cardiac GC between 2018 and 2022. The study population included patients and their pediatric relatives who had not previously seen a cardiologist. Patients were included if they were affected with or at-risk for long QT syndrome, hypertrophic cardiomyopathy, dilated cardiomyopathy, or familial thoracic aortic aneurysm at the time of the GC visit. We recorded the frequency of common cardiac services and calculated the reimbursement for all cardiology services for 1 year following the initial GC appointment. The cohort included 121 participants from 61 families. Most individuals were at-risk for (n = 114, 94.3%) rather than affected by an inherited cardiac condition and presented for screening. The total DSR was $247,592.27, with an annual median of $1819.50 per patient (IQR $0, $3761.33). Revenue was similar among individuals who had undergone genetic testing and those who had not. Among participants, 72 (59.5%) had subsequent cardiology services. Most frequently, a patient who presented for subsequent care had an EKG, an echocardiogram, and a cardiology appointment. While the economic contributions of GC services do not speak to the broader value of GC involvement in patient care, they are important metrics for sustainability. This study outlines an approach to evaluating DSR and establishes a baseline understanding of DSR related to cardiac GC services., (© 2024 The Author(s). Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Atopic dermatitis (AD) is a chronic itchy inflammatory disease of the skin. Genetic studies have identified multiple risk factors linked to the disease; however, most of the studies have been derived from European and East Asian populations. The admixed African American (AA) genome may provide an opportunity to discovery ancestry-specific loci involved in AD susceptibility. Herein, we present joint analysis of ancestry and genotype effects followed by validation using differential gene expression analysis on AD using 726 AD-affected individuals and 999 non-AD control individuals from the AA population, genotyped using Multi-Ethnic Global Array (MEGA) followed by imputation using the Consortium on Asthma among African Ancestry Populations in the Americas (CAAPA) reference panel. The joint analysis identified two novel AD-susceptibility loci, rs2195989 in gene ANGPT1 (8q23.1) and rs62538818 in the intergenic region between genes LURAP1L and MPDZ (9p23). Admixture mapping (AM) results showed potential genomic inflation, and we implemented genomic control and identified five ancestry-of-origin loci with European ancestry effects. The multi-omics functional prioritization of variants in AM signals prioritized the loci SLAIN2, RNF39, and FOXA2. Genome-wide association study (GWAS) identified variants significantly associated with AD in the AA population, including SGK1 (rs113357522, odds ratio [OR] = 2.81), EFR3A (rs16904552, OR = 1.725), and MMP14 (rs911912, OR = 1.791). GWAS variants were common in the AA but rare in the European population, which suggests an African-ancestry-specific risk of AD. Four genes (ANGPT1, LURAP1L, EFR3A, and SGK1) were further validated using qPCR from AD and healthy skin. This study highlighted the importance of genetic studies on admixed populations, as well as local ancestry and genotype-ancestry joint effects to identify risk loci for AD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk., (© 2024. The Author(s).)

American Indian/Alaska Natives (AIAN) have some of the highest health disparities and poorest outcomes of all racial or ethnic minority groups in the United States. Across all age groups, suicide is 2.5 times higher in AIANs than the national average (National Indian Council on Aging, 2019). Cultural and institutional barriers prevent AIAN undergraduate and graduate college students from seeking mental health services, and many serious mental health problems remain untreated. While numerous barriers to mental health services exist for AIAN students, Indigenous faculty and support staff who share deep understanding of history, culture and traditional view of health and wellness can reduce the barriers and promote mental health and wellness for students. Shifting the focus to introduce a new narrative gives way to greater recognition of factors that create health and may help academic institutions provide holistic support for AIAN and other underrepresented students. The new narrative includes holistic strength-based support, social support, and fostering cultural identity and pride enhances mental health and success. Indigenization of the doctoral nursing curriculum supports faculty who are committed to decolonizing course content and institutionalized pedagogy. Improved health outcomes for Indigenous individuals and other underrepresented students will positively affect communities through increasing diversity of APRNs, nursing faculty, and nursing scholars., Competing Interests: Declaration of competing interest The authors have no known competing or conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Coronary heart disease (CHD) is one of the leading causes of mortality and morbidity in the United States. Accurate time-to-event CHD prediction models with high-dimensional DNA methylation and clinical features may assist with early prediction and intervention strategies. We developed a state-of-the-art deep learning autoencoder survival analysis model (AESurv) to effectively analyze high-dimensional blood DNA methylation features and traditional clinical risk factors by learning low-dimensional representation of participants for time-to-event CHD prediction. We demonstrated the utility of our model in two cohort studies: the Strong Heart Study cohort (SHS), a prospective cohort studying cardiovascular disease and its risk factors among American Indians adults; the Women's Health Initiative (WHI), a prospective cohort study including randomized clinical trials and observational study to improve postmenopausal women's health with one of the main focuses on cardiovascular disease. Our AESurv model effectively learned participant representations in low-dimensional latent space and achieved better model performance (concordance index-C index of 0.864 ± 0.009 and time-to-event mean area under the receiver operating characteristic curve-AUROC of 0.905 ± 0.009) than other survival analysis models (Cox proportional hazard, Cox proportional hazard deep neural network survival analysis, random survival forest, and gradient boosting survival analysis models) in the SHS. We further validated the AESurv model in WHI and also achieved the best model performance. The AESurv model can be used for accurate CHD prediction and assist health care professionals and patients to perform early intervention strategies. We suggest using AESurv model for future time-to-event CHD prediction based on DNA methylation features., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Radiomics refers to the extraction of quantitative information from medical images and is most commonly utilized in oncology to provide ancillary information for solid tumor diagnosis, prognosis, and treatment response. The traditional radiomic pipeline involves segmentation of volumes of interest with comparison to normal brain. In other neurologic disorders, such as epilepsy, lesion delineation may be difficult or impossible due to poor anatomic definition, small size, and multifocal or diffuse distribution. Tuberous sclerosis complex (TSC) is a rare genetic disease in which brain magnetic resonance imaging (MRI) demonstrates multifocal abnormalities with variable imaging and epileptogenic features., Purpose: The purpose of this study was to develop a radiomic workflow for identification of abnormal brain regions in TSC, using a whole-brain atlas-based approach with generation of heatmaps based on signal deviation from normal controls., Methods: This was a retrospective pilot study utilizing high-resolution whole-brain 3D FLAIR MRI datasets from retrospective enrollment of tuberous sclerosis complex (TSC) patients and normal controls. Subjects underwent MRI including high-resolution 3D FLAIR sequences. Preprocessing included skull stripping, coregistration, and intensity normalization. Using the Brainnetome and Harvard-Oxford atlases, brain regions were parcellated into 318 discrete regions. Expert neuroradiologists spatially labeled all tubers in TSC patients using ITK-SNAP. The pyradiomics toolbox was used to extract 88 radiomic features based on IBSI guidelines, comparing tuber-affected and non-tuber-affected parenchyma in TSC patients, as well as normal brain tissue in control patients. For model training and validation, regions with tubers from 20 TSC patients and 30 normal control subjects were randomly divided into two training sets (80%) and two validation sets (20%). Additional model testing was performed on a separate group of 20 healthy controls. LASSO (least absolute shrinkage and selection operator) was used to perform variable selection and regularization to identify regions containing tubers. Relevant radiomic features selected by LASSO were combined to produce a radiomic score ω, defined as the sum of squared differences from average control group values. Region-specific ω scores were converted to heat maps and spatially coregistered with brain MRI to reflect overall radiomic deviation from normal., Results: The proposed radiomic workflow allows for quantification of deviation from normal in 318 regions of the brain with the use of a summative radiomic score ω. This score can be used to generate spatially registered heatmaps to identify brain regions with radiomic abnormalities. The pilot study of TSC showed radiomic scores ω that were statistically different in regions containing tubers from regions without tubers/normal brain (p < 0.0001). Our model exhibits an AUC of 0.81 (95% confidence interval: 0.78-0.84) on the testing set, and the best threshold obtained on the training set, when applied to the testing set, allows us to identify regions with tubers with a specificity of 0.91 and a sensitivity of 0.60., Conclusion: We describe a whole-brain atlas-based radiomic approach to identify abnormal brain regions in TSC patients. This approach may be helpful for identifying specific regions of interest based on relatively greater signal deviation, particularly in clinical scenarios with numerous or poorly defined anatomic lesions., (© 2024 American Association of Physicists in Medicine.)

Rationale: Approximately 80% of patients with non-familial pulmonary arterial hypertension (PAH) lack identifiable pathogenic genetic variants. While most genetic studies of PAH have focused on predicted loss-of-function variants, recent approaches have identified ultra-rare missense variants associated with the disease. FOXF1 encodes a highly conserved transcription factor, essential for angiogenesis and vasculogenesis in human and mouse lungs., Objectives: We identified a rare FOXF1 missense coding variant in two unrelated probands with PAH. FOXF1 is an evolutionarily conserved transcription factor required for lung vascular development and vascular integrity. Our aims were to determine the frequency of FOXF1 variants in larger PAH cohorts compared to the general population, study FOXF1 expression in explanted lung tissue from PAH patients versus control (failed-donor) lungs, and define potential downstream targets linked to PAH development., Methods: Three independent, international, multicenter cohorts were analyzed to evaluate the frequency of FOXF1 rare variants. Various composite prediction models assessed the deleteriousness of individual variants. Bulk RNA sequencing datasets from human explanted lung tissues were compared to failed-donor controls to determine FOXF1 expression. Bioinformatic tools identified putative FOXF1 binding targets, which were orthogonally validated using mouse ChIP-seq datasets., Measurements and Main Results: Seven novel or ultra-rare missense coding variants were identified across three patient cohorts in different regions of the FOXF1 gene, including the DNA binding domain. FOXF1 expression was dysregulated in PAH lungs, correlating with disease severity. Histological analysis showed heterogeneous FOXF1 expression, with the lowest levels in phenotypically abnormal endothelial cells within complex vascular lesions in PAH samples. A hybrid bioinformatic approach identified FOXF1 downstream targets potentially involved in PAH pathogenesis, including BMPR2 ., Conclusions: Large genomic and transcriptomic datasets suggest that decreased FOXF1 expression or predicted dysfunction is associated with PAH.

Background: Patient-reported outcome measures have been associated with survival in oncology patients. Altered intake and malnutrition are common symptoms for patients treated for head and neck cancer and esophageal cancer (HNC/EC). The purpose of this study was to examine the relationship between patient-reported satisfaction with medical care and nutrition status., Methods: This prospective cohort study collected data from 11 international cancer care sites., Results: One hundred and sixtythree adult patients (n = 115 HNC; n = 48 EC) completed a patient satisfaction questionnaire (the Canadian Health Care Evaluation Project Lite) and were included. HNC/EC patient global satisfaction with medical care was 88.3/100 ± 15.3 at baseline and remained high at 86.6/100 ± 16.8 by 6 months (100 max satisfaction score). Poor nutrition status, as defined by the Patient-Generated Subjective Global Assessment Short Form, was associated with lower patient satisfaction with overall medical care, relationship with doctors, illness management, communication, and decision-making 6 months into treatment (P < 0.01). There was no difference in global satisfaction between patients who did and did not report swallowing difficulty (P = 0.99) and patients with and without feeding tube placement (P = 0.36). Patients who were seen by a dietitian for at least one nutrition assessment had global satisfaction with care that was 16.7 percentage points higher than those with no nutrition assessment (89.3 ± 13.8 vs 72.6 ± 23.6; P = 0.005) CONCLUSION: In HNC/EC patient-centered oncology care, decreasing malnutrition risk and providing access to dietitian-led nutrition assessments should be prioritized and supported to improve patient satisfaction and standard of care. Feeding tube placement did not decrease patient satisfaction with medical care., (© 2024 The Author(s). Nutrition in Clinical Practice published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic comorbidities remain ill-defined. Here, analysis of circulating NK cells in a longitudinal early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D, which was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aeroallergens, a risk factor for development of asthma. Individual-level longitudinal analysis in a subset of children revealed coincident reduction of NKG2D on NK cells with acquired or persistent sensitization, and this was associated with impaired skin barrier function assessed by transepidermal water loss. Low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine tumor necrosis factor-α. These observations provide important insights into a potential mechanism underlying the development of allergic comorbidity in early life in children with AD, which involves altered NK cell functional responses, and define an endotype of severe AD.

Background: Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven esophageal disorder. Connective tissue disorders (CTDs) and esophageal connective tissue alterations are associated with EoE. Therefore, angiotensin II type 1 receptor blockade with losartan, an accepted CTD treatment, is a potential EoE treatment., Objective: We evaluated losartan's effects on esophageal pathology, symptoms, and safety in patients with EoE with and without a CTD in an open-label, non-placebo controlled multisite study., Methods: Fifteen participants with EoE, aged 5 to 23 years, underwent treatment with per-protocol titrated doses of losartan in an open-label, 16-week pilot trial. Losartan was added to standard of care therapy and 14 patients completed the study. Eosinophil counts served as the primary end point, whereas we also assessed the EoE Histology Scoring System, Endoscopic Reference Scores, EoE Diagnostic Panel, and patient-reported outcomes., Results: Esophageal eosinophilia was not reduced after losartan. The peak eosinophil count was not reduced for the proximal (median [interquartile range]: -3 [-22 to 3]; P = .49) and distal esophagus (median [interquartile range]: -18 [-39 to -1]; P = .23). There were no differences in losartan response in EoE with or without CTD (n = 7 and 8, respectively). Regardless, in a small subset of four participants esophageal eosinophilia was resolved with a concomitant reduction in EoE Histology Scoring System score and Endoscopic Reference Score. Across all subjects, the Pediatric EoE Symptom Score, Pediatric Quality of Life Inventory EoE Module, and EoE Diagnostic Panel improved after losartan (P < .05)., Conclusions: Losartan treatment was associated with improved patient-reported outcome scores and EoE Diagnostic Panel biomarkers although without a reduction in esophageal eosinophilia overall. A subset of patients demonstrated improved histopathologic and endoscopic features that could not be tied to a specific feature predicting response to treatment., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

After burn injury there is considerable variation in scar outcome, partially due to genetic factors. Scar vascularity is one characteristic that varies between individuals, and this study aimed to identify genetic variants contributing to different scar vascularity outcomes. An exome-wide array association study and gene pathway analysis was performed on a prospective cohort of 665 patients of European ancestry treated for burn injury, using their scar vascularity (SV) sub-score, part of the modified Vancouver Scar Scale (mVSS), as an outcome measure. DNA was genotyped using the Infinium HumanCoreExome-24 BeadChip, imputed to the Haplotype Reference Consortium panel. Associations between genetic variants (single nucleotide polymorphisms) and SV were estimated using an additive genetic model adjusting for sex, age, % total body surface area and number of surgical procedures, utilising linear and multinomial logistic regression. No individual genetic variants achieved the cut-off threshold for significance. Gene sets were also analysed using the Functional Mapping and Annotation (FUMA) platform, in which biological processes indirectly related to angiogenesis were significantly represented. This study suggests that SNPs in genes associated with angiogenesis may influence SV, but further studies with larger datasets are essential to validate these findings., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to report., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background: A common genetic variant of ICAM1 among African-American individuals (rs5491; p.K56M) is associated with heart failure (HF) hospitalization, but whether this risk is specific to heart failure with preserved ejection fraction (HFpEF) remains unclear. Older women are at high risk for HFpEF, and the relationship between rs5491 and HFpEF across the age spectrum is unknown., Objectives: This study assessed risk of HF and its subtypes conferred by ICAM1 p.K56M (rs5491)., Methods: Associations of rs5491 with risk of HF and its subtypes were estimated among African American individuals in WHI (Women's Health Initiative). The study evaluated whether the association between rs5491 and HF hospitalizations was modified by baseline age. Subsequently, African-American women in WHI and MESA (Multi-Ethnic Study of Atherosclerosis) were pooled and analyses were repeated., Results: Among 8,401 women in WHI, the minor allele frequency of rs5491 was 20.7%, and 731 HF hospitalizations occurred over 19.2 years. The rs5491 variant was not associated with HF or its subtypes across WHI. Interaction analyses suggested that age as a continuous variable modified the association of rs5491 with HFpEF hospitalization (interaction P = 0.04). Upon categorizing women into age decades, rs5491 conferred increased risk of HFpEF among women ≥70 years (HR per additional rs5491 allele: 1.82 [95% CI: 1.25-2.65]; P = 0.002) but was not associated with HFpEF risk among women <70 years. Pooling African-American women in WHI (n = 8,401) and MESA (n = 856) demonstrated that the effect modification by age on the association of rs5491 with HFpEF became more significant (interaction P = 0.009), with consistent HFpEF risk effect estimates among women ≥70 years., Conclusions: ICAM1 p.K56M (rs5491) is associated with HFpEF among African-American women ≥70 years., Competing Interests: Funding Support and Author Disclosures This work was supported by grants KL2TR001424 from the National Center for Advancing Translational Sciences, U.S. NIH (National Institutes of Health). The WHI program is funded by the NHLBI (National Heart, Lung, and Blood Institute), NIH, U.S. Department of Health and Human Services through 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. The opinions expressed in this manuscript are those of the authors and do not necessarily reflect the views of the Department of Health and Human Services/NIH. MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. Dr Sanjiv Shah has received research grants from the NIH (U54 HL160]]273, R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer, and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Ravi B. Patel has received consulting fees from ICA, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Relationships between lifestyle risk factors and cardiovascular disease (CVD) risk in women with breast cancer (BC) are underexplored., Objectives: To evaluate the incidence of CVD in relation to the Life's Essential 8 (LE8) score among women with BC., Methods: Data from the Women's Health Initiative were utilized. The primary exposure was the LE8 score assessed prior to BC diagnosis. The LE8 score was stratified into low (0-59), moderate (60-79), and high (80-100) cardiovascular health (CVH). The primary endpoint was a composite of incident CVD events, which included coronary heart disease, defined as myocardial infarction along with coronary revascularization, CVD death, and stroke. We calculated the cumulative incidence of CVD and estimated hazard ratios., Results: Among 7,165 participants, the median age was 70.1 years at BC diagnosis. The mean LE8 score was 62.0 ± 12.2. Over a median follow-up period of 6 years, 490 composite CVD events occurred. The risk of CVD events was highest for low CVH compared with moderate and high CVH. Compared with low CVH, the hazard ratio for incident CVD was 0.57 (95% CI: 0.46-0.69) for moderate CVH and 0.34 (95% CI: 0.20-0.59) for high CVH. LE8, in conjunction with age, provided a C-statistic of 0.74 for the composite risk of CVD., Conclusions: Higher LE8 scores were associated with a lower risk of incident CVD among women with BC in the United States., Competing Interests: The WHI program is funded by National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This manuscript was partially funded by a grant from Alpha Phi. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Caspase recruitment domain family member 14 (CARD14) and its variants are associated with both atopic dermatitis (AD) and psoriasis, but their mechanistic impact on skin barrier homeostasis is largely unknown. CARD14 is known to signal via NF-κB; however, CARD14-NF-κB signaling does not fully explain the heterogeneity of CARD14-driven disease. Here, we describe a direct interaction between CARD14 and MYC and show that CARD14 signals through MYC in keratinocytes to coordinate skin barrier homeostasis. CARD14 directly binds MYC and influences barrier formation in an MYC-dependent fashion, and this mechanism is undermined by disease-associated CARD14 variants. These studies establish a paradigm that CARD14 activation regulates skin barrier function by two distinct mechanisms, including activating NF-κB to bolster the antimicrobial (chemical) barrier and stimulating MYC to bolster the physical barrier. Finally, we show that CARD14-dependent MYC signaling occurs in other epithelia, expanding the impact of our findings beyond the skin., Competing Interests: Declaration of interests Aspects of this manuscript have been included in a recent patent filing., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Risk assessment in pulmonary arterial hypertension (PAH) is fundamental to guiding treatment and improved outcomes. Clinical models are excellent at identifying high-risk patients, but leave uncertainty amongst moderate-risk patients., Research Question: Can a multiple blood biomarker model of PAH, using previously described biomarkers, improve risk discrimination over current models?, Study Design and Methods: Using a multiplex enzyme-linked immunosorbent assay, we measured N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), soluble suppressor of tumorigenicity, IL-6, endostatin, galectin 3, HDGF, and insulin-like growth factor binding proteins (IGFBP1-7) in training (n = 1,623), test (n = 696), and validation (n = 237) cohorts. Clinical variables and biomarkers were evaluated by principal component analysis. NT-proBNP was not included to develop a model independent of NT-proBNP. Unsupervised k-means clustering classified participants into clusters. Transplant-free survival by cluster was examined using Kaplan-Meier and Cox proportional hazard regressions. Hazard by cluster was compared with NT-proBNP, Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), and European Society of Cardiology (ESC) and European Respiratory Society (ERS) risk models alone and combined clinical and biomarker models., Results: The algorithm generated 5 clusters with good risk discrimination using 6 biomarkers, weight, height, and age at PAH diagnosis. In the test and validation cohorts, the biomarker model alone performed equivalent to REVEAL (area under the receiver operating characteristic curve, 0.74). Adding the biomarker model to the ESC and ERS score and REVEAL score improved the ESC and ERS score and REVEAL score. The best overall model was the biomarker model adjusted for NT-proBNP with the best C statistic, Akaike information criterion, and calibration for the adjusted model compared with either the biomarker or NT-proBNP model alone., Interpretation: A multibiomarker model alone was equivalent to current PAH clinical mortality risk prediction models and improved performance when combined and added to NT-proBNP. Clinical risk scores offer excellent predictive models, but require multiple tests; adding blood biomarkers to models can improve prediction or can enable more frequent, noninvasive monitoring of risk in PAH to support therapeutic decision-making., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Dengue fever (DF) is a mosquito-borne illness with substantial economic and societal impact. Understanding laboratory trends of hospitalized Dominican Republic (DR) pediatric patients could help develop screening procedures in low-resourced settings. We sought to describe laboratory findings over time in DR children with DF and DF severity from 2018 to 2020. Methods: Clinical information was obtained prospectively from recruited children with DF. Complete blood count (CBC) laboratory measures were assessed across Days 1-10 of fever. Participants were classified as DF-negative and DF-positive and grouped by severity. We assessed associations of DF severity with demographics, clinical characteristics, and peripheral blood studies. Using linear mixed-models, we assessed if hematologic values/trajectories differed by DF status/severity. Results: A total of 597 of 1101 with a DF clinical diagnosis were serologically evaluated, and 574 (471 DF-positive) met inclusion criteria. In DF, platelet count and hemoglobin were higher on earlier days of fever ( p < = 0.0017). Eighty had severe DF. Severe DF risk was associated with thrombocytopenia, intraillness anemia, and leukocytosis, differing by fever day ( p < = 0.001). Conclusions: In a pediatric hospitalized DR cohort, we found marked anemia in late stages of severe DF, unlike the typically seen hemoconcentration. These findings, paired with clinical symptom changes over time, may help guide risk-stratified screenings for resource-limited settings., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Melissa E. Day et al.)

Competing Interests: Conflict of interest Dr. Kubrak reported no conflicts of interest or financial disclosure. Dr. Martin reported no conflicts of interest or financial disclosure. Dr. Olson reported no conflicts of interest or financial disclosure. Dr. Grossberg reported serving as a consultant for Endevica Bio. No other disclosures were reported. Dr. Findlay reported receiving a Sydney Research PhD Scholarship (2018–2021) and Maridulu Budyari Gumal (SPHERE) Cancer Clinical Academic Group Senior Research Fellowship supported by a Cancer Institute NSW Research Capacity Building Grant (2021/CBG003). Dr. Bauer reported an honorarium from Nutricia. No other conflicts of interest or financial disclosure. Dr. Ottery reported affiliation with a consulting group Ottery and Associates LLC. No other disclosures were reported. Dr. Jha reported no conflicts of interest or financial disclosure. Dr. Scrimger reported no conflicts of interest or financial disclosure. Dr. Debenham reported no conflicts of interest or financial disclosure. Dr. Chua reported an honorarium from Merck and EMD Serono. No other conflicts of interest or financial disclosure. Dr. Walker reported serving as a consultant for Merck. No other conflicts of interest or financial disclosure. Dr. Baracos reported serving as a consultant for Pfizer Inc., Nestle Health Science and Baxter Health Sciences. No other disclosures were reported.

Sensing temperature is vitally important to adapt our body to environmental changes. Local warm detection is required to initiate regulation of cutaneous blood flow, which is part of the peripheral thermoregulatory mechanisms, and thus avoid damage to surrounding tissues. The mechanisms mediating cutaneous vasodilation during local heat stress are impaired with aging. However, the impact of aging on the ability of the skin to detect subtle thermal changes is unknown. Among heat-activated cation channels, transient receptor potential vanilloid 3 (TRPV3) is a thermo-sensor predominantly expressed on keratinocytes and involved in local vascular thermoregulatory mechanisms of the skin in young mice. In the present study, using a murine in vivo model of local heat exposure of the skin, we showed that heat-induced vasodilation was reduced in old mice associated with reduced expression of TRPV3 channels. We also found a decrease in expression and activity of TRPV3 channel, as well as reduced TRPV3-dependent adenosine tri-phosphate release in human primary keratinocytes from old donors. This study shows that aging alters the epidermal TRPV3 channels, which might delay the detection of changes in skin temperature, thereby limiting the mechanisms triggered for local vascular thermoregulation in the old skin., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Background & Aims: Exocrine pancreatic insufficiency (EPI) contributes to malnutrition, marked by muscle loss during chemotherapy for advanced pancreatic cancer (aPC). Pancreatic enzyme replacement therapy (PERT) is recommended for patients with EPI; however, it's efficacy for attenuating muscle loss has not been demonstrated. We aimed to delineate the impact of PERT dose on muscle loss using a 7-year population-based cohort with aPC who were provided PERT at the discretion of their oncologist or dietitian according to clinical indications of EPI., Methods: All patients treated with chemotherapy for aPC from 2013 to 2019 in Alberta, Canada (population ∼4.3 million) were included if they had computed tomography (CT) scans both prior to and 12 ± 4 weeks after chemotherapy initiation. Change in muscle area (cm 2 ) was measured at 3rd lumbar level on repeated CT scans. Muscle loss was defined by measurement error (loss >2.3 cm 2 ). Clinical and pharmaceutical data were retrieved from provincial registries. For patients who were dispensed PERT -8 to +6 weeks from chemo start (PERT users), estimated dose consumed per day was calculated as: (total dose dispensed) / (days, first to last dispensation). PERT users were categorized as high dose or low dose users according to the median estimated dose consumed. Non-users were classified as No PERT. Association between PERT use and muscle loss was analyzed with multivariable logistic regression., Results: Among 210 patients, 81 (39%) were PERT users. Median estimated dose consumed per day of 75 000 USP lipase units defined the cutoff between low dose and high dose uses. There were no significant differences in baseline characteristics between high dose and low dose groups. Muscle loss was more prevalent among low dose compared to both high dose and No PERT groups (88% vs. 58% and 67%, p < 0.05). In the multivariable model predicting muscle loss, low dose PERT was independently associated with greater odds of muscle loss (OR 5.4, p = 0.004) vs. high dose, independent of tumour response, disease stage, and chemotherapy regimen., Conclusion: In patients with clinical indications of EPI during chemotherapy for aPC, low doses of PERT were insufficient to prevent muscle loss. Patients with EPI consuming higher doses of PERT had similar odds of muscle maintenance to patients without clinical indications of EPI. Provider education for optimal PERT dosing in patients with EPI should be prioritized, and resources must be allocated to support dose titration., Competing Interests: Conflict of interest Vickie Baracos is a consultant for Pfizer and Nestle Health Science. Michael B. Sawyer and Jessica Kasnik have been engaged as speakers and advisors for Viatris Canada. These agencies had no role in the funding or design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The remaining authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Genetic testing with exome sequencing and genome sequencing is increasingly offered to infants and children with cardiovascular diseases. However, the rates of positive diagnoses after genetic testing within the different categories of cardiac disease and phenotypic subtypes of congenital heart disease (CHD) have been little studied. We report the diagnostic yield after next-generation sequencing in 500 patients with CHD from diverse population subgroups that were enrolled at three different sites in the Clinical Sequencing Evidence-Generating Research consortium. Patients were ascertained due to a primary cardiovascular issue comprising arrhythmia, cardiomyopathy, and/or CHD, and corresponding human phenotype ontology terms were selected to describe the cardiac and extracardiac findings. We examined the diagnostic yield for patients with arrhythmia, cardiomyopathy, and/or CHD and phenotypic subtypes of CHD comprising conotruncal defects, heterotaxy, left ventricular outflow tract obstruction, septal defects, and "other" heart defects. We found a significant increase in the frequency of positive findings for patients who underwent genome sequencing compared to exome sequencing and for syndromic cardiac defects compared to isolated cardiac defects. We also found significantly higher diagnostic rates for patients who presented with isolated cardiomyopathy compared to isolated CHD. For patients with syndromic presentations who underwent genome sequencing, there were significant differences in the numbers of positive diagnoses for phenotypic subcategories of CHD, ranging from 31.7% for septal defects to 60% for "other". Despite variation in the diagnostic yield at each site, our results support genetic testing in pediatric patients with syndromic and isolated cardiovascular issues and in all subtypes of CHD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Pediatric burn injuries are a global clinical issue causing significant morbidity. Early adjunctive negative pressure wound therapy improves re-epithelialization rates in children with burns, yet adoption in acute burn care is inconsistent. This investigation aimed to determine barriers to the implementation of adjunctive negative pressure wound therapy for the acute management of pediatric burns and co-design targeted implementation strategies., Methods: A sequential mixed methods design was used explore barriers to adjunctive negative pressure wound therapy implementation in acute pediatric burn care. An online questionnaire was disseminated to healthcare professionals within four major Australian pediatric hospitals, each with a dedicated burns service. Barriers were coded according to the Consolidated Framework for Implementation Research (CFIR). Semi-structured interviews with senior clinicians tailored implementation strategies to local contexts. A stakeholder consensus meeting consolidated implementation strategies and local processes., Results: Sixty-three healthcare professionals participated in the questionnaire, and semi-structured interviews involved nine senior burn clinicians. We identified eight implementation barriers across all five CFIR domains then co-designed targeted strategies to address identified barriers. Barriers included lack of available resources, limited access to knowledge and information, individual stage of change, patient needs and resources, limited knowledge and beliefs about the intervention, lack of external policies, intervention complexity, and poor implementation planning., Conclusion: Multiple contextual factors affect negative pressure wound therapy uptake in acute pediatric burn settings. Results will inform a multi-state stepped-wedge cluster randomized controlled trial. Additional resources, education, training, updated policies, and guidelines are required for successful implementation. It is anticipated that adjunctive negative pressure wound therapy, in conjunction with tailored implementation strategies, will enhance adoption and sustainability., Trial Registration: Australian and New Zealand Clinical Trials Registry: ACTRN12622000166774. Registered 1 February 2022., Competing Interests: Declaration of competing interest This project has been awarded funding from the National Health and Medical Research Council (NHMRC) Partnership Projects PRC2 Funding ID: 2006970. The authors declare that they have no competing interests., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Introduction: Developmental Delay (DD) is highly common in American Indian and Alaska Native (AI/AN; Indigenous) toddlers and leads to high numbers of AI/AN children who eventually need special education services. AI/AN children are 2.89 times more likely to receive special education compared to other children in the U.S., yet developmental disorders are more frequently under diagnosed and untreated in AI/AN infants and toddlers. DD, which can be identified as early as toddlerhood, can lead to negative impacts on developmental trajectories, school readiness, and long-term health. Signs of DD can be identified early with proper developmental screening and remediated with high quality early intervention that includes effective parent training. There are many evidence-based language facilitation interventions often used in Early Intervention programs. However, in communities in rural parts of the Navajo Nation where there are limited services and resources, infants and toddlers with early signs of DD are often missed and do not get the culturally responsive support and evidence-based intervention they deserve., Methods: The community-based +Language is Medicine (+LiM) study team partnered with tribal home visitors, community members, and a Diné linguist/elder using a collaborative virtual workgroup approach in 2021 and 2022 to present the +LiM pilot study aims and to discuss strategies for enhancing a language intervention for toddlers experiencing DD in their tribal community. This paper will detail the stages of community engagement, intervention enhancement and preparation for field testing of the +LiM intervention to address elevated rates of DD in toddlers in the Northern Agency of the Navajo Nation., Results: Two major outcomes from this collaborative workgroup included: (1) a team-initiated redefining of language nutrition to align with Indigenous values that center cultural connectedness and native language use and (2) a five-lesson caregiver-facilitated curriculum titled +Language is Medicine which includes caregiver lessons on language nutrition, language facilitation, shared book reading, pretend play, and incorporation of native language into home routines. These two workgroup outcomes were leveraged to develop a pilot pre-/post-intervention study to test the effectiveness of the +LiM intervention with caregiver-toddler dyads living on the Navajo Nation., Discussion: Delivering tailored child interventions through tribal home visiting are cost-effective and innovative methods for reaching reservation-based families who benefit from culturally responsive parent coaching and instruction. The +LiM team has applied a precision tribal home visiting approach to enhance methods of early intervention for children with DD. Our enhancement process was grounded in Indigenous community-based participatory research that centered culture and language., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Billey, Kushman, Meese, Martin, Jim, Austin-Garrison and Allison-Burbank.)

Background: Primary hypertension in childhood tracks into adulthood and may be associated with increased cardiovascular risk. Studies conducted in children and adolescents provide an opportunity to explore the early cardiovascular target organ injury (CV-TOI) in a population free from many of the comorbid cardiovascular disease risk factors that confound studies in adults., Methods: Youths (n=132, mean age 15.8 years) were stratified by blood pressure (BP) as low, elevated, and high-BP and by left ventricular mass index (LVMI) as low- and high-LVMI. Systemic circulating RNA, miRNA, and methylation profiles in peripheral blood mononuclear cells and deep proteome profiles in serum were determined using high-throughput sequencing techniques., Results: VASH1 gene expression was elevated in youths with high-BP with and without high-LVMI. VASH1 expression levels positively correlated with systolic BP (r=0.3143, p=0.0034). The expression of hsa-miR-335-5p, one of the VASH1- predicted miRNAs, was downregulated in high-BP with high-LVMI youths and was inversely correlated with systolic BP (r=-0.1891, p=0.0489). GSE1 hypermethylation, circulating PROZ upregulation (log 2 FC=0.61, p=0.0049 and log 2 FC=0.62, p=0.0064), and SOD3 downregulation (log 2 FC=-0.70, p=0.0042 and log 2 FC=-0.64, p=0.010) were observed in youths with elevated BP and high-BP with high-LVMI. Comparing the transcriptomic and proteomic profiles revealed elevated HYAL1 levels in youths displaying high-BP and high-LVMI., Conclusions: The findings are compatible with a novel blood pressure-associated mechanism that may occur through impaired angiogenesis and extracellular matrix degradation through dysregulation of Vasohibin-1 and Hyaluronidase1 was identified as a possible mediator of CV-TOI in youth with high-BP and suggests strategies for ameliorating TOI in adult-onset primary hypertension., Competing Interests: Conflicts of interest Dr. Sadayappan provides consulting and collaborative research studies to the Leducq Foundation (CURE-PLAN), Red Saree Inc., Alexion, Affinia Therapeutics Inc., and Cosmogene Skincare Private Limited, but such work is unrelated to the content of this article.

The differential performance of polygenic risk scores (PRSs) by group is one of the major ethical barriers to their clinical use. It is also one of the main practical challenges for any implementation effort. The social repercussions of how people are grouped in PRS research must be considered in communications with research participants, including return of results. Here, we outline the decisions faced and choices made by a large multi-site clinical implementation study returning PRSs to diverse participants in handling this issue of differential performance. Our approach to managing the complexities associated with the differential performance of PRSs serves as a case study that can help future implementers of PRSs to plot an anticipatory course in response to this issue., Competing Interests: Declaration of interests A.C.F.L. owns some stock in Fabric Genomics; E.D.E. is an employee and stockholder of Invitae, advisor and stockholder of Taproot Health, and advisor and stockholder of Exir; R.C.G. receives compensation for advising the following companies: Allelica, Atria, Fabric, Genomic Life, and Juniper Genomics; and is co-founder of Genome Medical and Nurture Genomics; E.E.K. has received personal fees from Regeneron Pharmaceuticals, 23&Me, Allelica, and Illumina; has received research funding from Allelica; and serves on the advisory boards for Encompass Biosciences, Overtone, and Galatea Bio; N.L. received personal fees from Illumina Inc; E.P. is a paid consultant for Allelica Inc.; M.S. is a member of the Institutional Review Board of the All of Us Research Program; J.W.S. is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity), has received grant support from Biogen, Inc., and is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Burn wound blister fluid is a valuable matrix for understanding the biological pathways associated with burn injury. In this study, 152 blister fluid samples collected from paediatric burn wounds at three different hospitals were analysed using mass spectrometry proteomic techniques. The protein abundance profile at different days after burn indicated more proteins were associated with cellular damage/repair in the first 24 h, whereas after this point more proteins were associated with antimicrobial defence. The inflammatory proteins persisted at a high level in the blister fluid for more than 7 days. This may indicate that removal of burn blisters prior to two days after burn is optimal to prevent excessive or prolonged inflammation in the wound environment. Additionally, many proteins associated with the neutrophil extracellular trap (NET) pathway were increased after burn, further implicating NETs in the post-burn inflammatory response. NET inhibitors may therefore be a potential treatment to reduce post-burn inflammation and coagulation pathology and enhance burn wound healing outcomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The relationship between systolic blood pressure (SBP) and longevity is not fully understood. We aimed to determine which SBP levels in women ≥65 years of age with or without blood pressure medication were associated with the highest probability of surviving to 90 years of age., Methods: The study population consisted of 16 570 participants enrolled in the Women's Health Initiative who were eligible to survive to 90 years of age by February 28, 2020, without a history of cardiovascular disease, diabetes, or cancer. Blood pressure was measured at baseline (1993 through 1998) and then annually through 2005. The outcome was defined as survival to 90 years of age with follow-up. Absolute probabilities of surviving to 90 years of age were estimated for all combinations of SBP and age using generalized additive logistic regression modeling. The SBP that maximized survival was estimated for each age, and a 95% CI was generated., Results: During a median follow-up of 19.8 years, 9723 of 16 570 women (59%) survived to 90 years of age. Women with an SBP between 110 and 130 mm Hg at attained ages of 65, 70, 75, and 80 years had a 38% (95% CI, 34%-48%), 54% (52%-56%), 66% (64%-67%), or 75% (73%-78%) absolute probability to survive to 90 years of age, respectively. The probability of surviving to 90 years of age was lower for greater SBP levels. Women at the attained age of 80 years with 0%, 20%, 40%, 60%, 80%, or 100% time in therapeutic range (defined as an SBP between 110 and 130 mm Hg) had a 66% (64%-69%), 68% (67%-70%), 71% (69%-72%), 73% (71%-74%), 75% (72%-77%), or 77% (74%-79%) absolute survival probability to 90 years of age., Conclusions: For women >65 years of age with low cardiovascular disease and other chronic disease risk, an SBP level <130 mm Hg was found to be associated with longevity. These findings reinforce current guidelines targeting an SBP target <130 mm Hg in older women., Competing Interests: Disclosures None.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Loss-of-function (LoF) variants in the filaggrin (FLG) gene are the strongest known genetic risk factor for atopic dermatitis (AD), but the impact of these variants on AD outcomes is poorly understood. We comprehensively identified genetic variants through targeted region sequencing of FLG in children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. Twenty FLG LoF variants were identified, including 1 novel variant and 9 variants not previously associated with AD. FLG LoF variants were found in the cohort. Among these children, the presence of 1 or more FLG LoF variants was associated with moderate/severe AD compared with those with mild AD. Children with FLG LoF variants had a higher SCORing for Atopic Dermatitis (SCORAD) and higher likelihood of food allergy within the first 2.5 years of life. LoF variants were associated with higher transepidermal water loss (TEWL) in both lesional and nonlesional skin. Collectively, our study identifies established and potentially novel AD-associated FLG LoF variants and associates FLG LoF variants with higher TEWL in lesional and nonlesional skin.

Background & Aims: Existing skeletal muscle index (SMI) thresholds for sarcopenia are inconsistent, and do not reflect severity of depletion. In this study we aimed to define criterion values for moderate and severe skeletal muscle depletion based on the risk of mortality in a population of patients with head and neck cancer (HNC). Additionally, we aimed to identify clinical and demographic predictors of skeletal muscle depletion, evaluate the survival impact of skeletal muscle depletion in patients with minimal nutritional risk or good performance status, and finally, benchmarking SMI values of patients with HNC against healthy young adults., Methods: Population cohort of 1231 consecutive patients and external validation cohorts with HNC had lumbar SMI measured by cross-sectional imaging. Optimal stratification determined sex-specific thresholds for 2-levels of SMI depletion (Class I and II) based on overall survival (OS). Adjusted multivariable regression analyses (tumor site, stage, performance status, age, sex, dietary intake, weight loss) determined relationships between 2-levels of SMI depletion and OS., Results: Mean SMI (cm 2 /m 2 ) was 51.7 ± 9.9 (males) and 39.8 ± 7.1 (females). The overall and sex-specific population demonstrated an increased risk of mortality associated with decreasing SMI. Sex-specific SMI (cm 2 /m 2 ) depletion thresholds for 2-levels of muscle depletion determined by optimal stratification for males and females, respectively (male: 45.2-37.5, and <37.5; female: 40.9-34.2, and <34.2). In the overall population, Normal SMI, Class I and II SMI depletion occurred in 65.0%, 24.0%, and 11.0%, respectively. Median OS was: Normal SMI (114 months, 95% CI, 97.1-130.8); Class I SMI Depletion (42 months, 95% CI, 28.5-55.4), and Class II SMI Depletion (15 months, 95% CI, 9.8-20.1). Adjusted multivariable analysis compared with Normal SMI (reference), Class I SMI Depletion (HR, 1.49; 95% CI, 1.18-1.88; P < .001), Class II SMI Depletion (HR, 1.91; 95% CI, 1.42-2.58; P < .001)., Conclusions: Moderate and severe SMI depletion demonstrate discrimination in OS in patients with HNC. Moderate and severe SMI depletion is prevalent in patients with minimal nutrition risk and good performance status. Benchmarking SMI values against healthy young adults exemplifies the magnitude of SMI depletion in patients with HNC and may be a useful method in standardizing SMI assessment., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Traumatic heterotopic ossification (tHO) refers to the development of extra-skeletal bone in muscle and soft tissues following tissue insult secondary to surgery or trauma. This presents a persistent clinical concern associated with significant patient morbidity and expense to diagnose and treat. Traumatic HO is a substantial barrier to rehabilitation for trauma-injured patients. As such, the development of tHO after burn and other trauma is hypothesised to prolong inpatient length of stay (LOS) and thus increase health care costs., Objective: To investigate the association between an inpatient tHO diagnosis and hospital LOS in trauma patients., Methods: A retrospective audit of trauma patients over a 14-year period was completed using data from four WA hospitals. Burn and neurological trauma patients diagnosed with tHO as an inpatient (tHO+) and control subjects (tHO-), matched (1:3) by age, gender, and injury severity factors, were identified using medical diagnostic codes. Data relating to patient and injury-related determinants of LOS from tHO+ and tHO- subjects were analysed to model the association of tHO on total hospital length of stay., Results: 188 identified patients were hospitalised due to traumatic injury; 47 patients with tHO following burn injury (n = 17), spinal cord injury (n = 13) and traumatic brain injury (n = 17), and 141 control patients. Those who developed tHO during hospitalisation had a significantly higher median LOS than matched trauma patients who did not develop tHO (142 days vs. 61 days). Multivariate regression analyses identified the following independent predictive factors of a prolonged hospital LOS: tHO diagnosis, mechanical ventilation hours, injury to the hip region and thigh area, other ossification disorder, pressure injury, admission to intensive care unit and deep vein thrombosis. Trauma patients diagnosed with tHO during their hospital admission stayed 1.6 times longer than trauma patients matched for injury severity without a tHO diagnosis (IRR 1.56, 95% CI 1.35-1.79, p<0.001)., Conclusion: Traumatic heterotopic ossification is an independent explanatory factor for increased hospital LOS in patients following burns, spinal cord, and traumatic brain injury. Early diagnosis may assist in reducing the impact of tHO on acute hospital stay after trauma., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Background: There is a need to adopt valid techniques to assess skeletal muscle (SM) in clinical practice. SM can be precisely quantified from computed tomography (CT) images. This study describes how registered dietitians (RDs), trained to quantify SM from CT images, implemented this technique in clinical practice., Methods: This was an explanatory sequential mixed-methods design with a quantitative and a qualitative phase. RDs collected data describing how they implemented CT SM assessments in clinical practice, followed by a focus group exploring barriers and enablers to using CT SM assessments., Results: RDs (N = 4) completed 96 CT SM assessments, with most (94%, N = 90/96) taking <15 min to complete. RDs identified reduced muscle mass in 63% (N = 45/72) of men and 71% (N = 17/24) of women. RDs used results of CT SM assessments to increase protein composition of the diet/nutrition support, advocate for initiation or longer duration of nutrition support, coordinate nutrition care, and provide nutrition education to patients and other health service providers. The main barriers to implementing CT SM assessments in clinical practice related to cumbersome health system processes (ie, CT image acquisition) and challenges integrating CT image analysis software into the health system computing environment., Conclusion: Preliminary results suggest RDs found CT SM assessments positively contributed to their nutrition care practice, particularly in completing nutrition assessments and in planning, advocating for, and implementing nutrition interventions. Use of CT SM assessments in clinical practice requires innovative IT solutions and strategies to support skill development and use in clinical nutrition care., (© 2023 The Authors. Nutrition in Clinical Practice published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Eligible persons with HIV infection can receive client-centered case management to coordinate medical and social services. Novel mobile health interventions could improve effective case management and retention in care, an important goal to help end the HIV epidemic. Using a hybrid type I effectiveness-implementation design, we assessed whether access to bidirectional, free-draft secure text messaging with a case manager and clinic pharmacist could improve client satisfaction and care retention in a Southern academic HIV clinic. Sixty-four clients enrolled between November 2019 and March 2020, had a median age of 39 years, and were mostly male, single, and African-American. Heavy app users texted over 100 times ( n  = 6) over the course of the 12-month intervention while others never texted ( n  = 12). App usage peaked during months of clinic closure due to COVID-19. Most participants reported high satisfaction with the app and planned continued usage after study completion. Changes in clinic retention and virologic suppression rates were not observed, a result confounded by practice changes due to COVID-19. High usage and satisfaction of free-draft text messaging in case-managed HIV clients supports inclusion of this communication option in routine HIV clinical care.

Parents' emotions after their child's burn might be influenced by the injury circumstances or demographic characteristics of the patient and family. Parents' post-traumatic stress symptoms and their child's distress may interact and affect emotional states. The psychosocial outcomes of parents were measured using the Impact of Event Scale-Revised, the CARe Burn Scale, and the Post-traumatic Growth Inventory-Brief. The psychosocial quality of life outcomes of the pediatric burn patients were measured using the Pediatric Quality of Life Inventory (PedsQL). Regression analysis was used to assess the relationship between patient psychosocial quality of life and the related parent scores. A total of 48 patients and parents participated, with 36 giving full data at 12 months. Parental post-traumatic stress symptoms were initially high, settling by six months, although outliers remained. Parents reported higher IESR scores if their child was female, if they felt helpless at the time of the incident, and if a language other than English was spoken in the home. Parents' scores of their child's psychosocial function were similar to their child's self-scores. Parents who perceived poorer emotional functioning in their child reported higher IESR scores.

Purpose: Psychosexual distress is known to be a common complication of treatment for gynaecological cancer (GC), affecting the sexual quality of life (SQoL) for an increasing number of young gynaecological cancer survivors (YGCS). The SQoL in YGCS study aimed to identify strategies that are acceptable and helpful to YGCS in protecting and improving SQoL, using a salutogenic approach., Methods: A qualitative study was undertaken with young women aged 18-45 and pre- or perimenopausal at diagnosis. Semi-structured interviews were conducted on Zoom and a thematic analysis of transcripts was completed in NVivo., Results: Fifteen interviews with YGCS revealed three themes for strategy development: psychosexual education, psychosocial support, and healthcare policy and strategy to establish SQoL as standard care in gynaecologic oncology., Conclusion: The strategies put forward by YGCS showed the need for a holistic, patient-centric, and multidisciplinary approach to SQoL. A better understanding of the strategies acceptable to YGCS, including the importance of using a trauma-informed approach to communication and care, can help healthcare providers play a vital role in protecting and improving SQoL., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: American Indian and Alaska Native (AIAN) communities continue to flourish and innovate in the face of the COVID-19 pandemic. Storytelling is an important tradition for AIAN communities that can function as an intervention modality. To support the needs of AIAN children and caregivers, we (a collaborative workgroup of Indigenous health researchers) developed a culturally grounded storybook that provides pandemic-related public health guidance and mental health coping strategies woven with Inter-Tribal values and teachings., Methods: A collaborative workgroup, representing diverse tribal affiliations, met via four virtual meetings in early 2021 to discuss evolving COVID-19 pandemic public health guidance, community experiences and responses to emerging challenges, and how to ground the story in shared AIAN cultural strengths. We developed and distributed a brief survey for caregivers to evaluate the resulting book., Results: The workgroup iteratively reviewed versions of the storyline until reaching a consensus on the final text. An AI artist from the workgroup created illustrations to accompany the text. The resulting book, titled Our Smallest Warriors, Our Strongest Medicine: Honoring Our Teachings during COVID-19 contains 46 pages of text and full-color illustrations. An online toolkit including coloring pages, traditional language activities, and caregiver resources accompanies the book. We printed and distributed 50,024 physical copies of the book and a free online version remains available. An online survey completed by N  = 34 caregivers who read the book with their child(ren) showed strong satisfaction with the book and interest in future books., Discussion: The development of this storybook provides insights for creative dissemination of future public health initiatives, especially those geared toward AIAN communities. The positive reception and widespread interest in the storybook illustrate how braiding AIAN cultural teachings with public health guidance can be an effective way to disseminate health information. This storybook highlights the importance of storytelling as an immersive learning experience through which caregivers and children connect to family, community, culture, and public health guidance. Culturally grounded public health interventions can be effective and powerful in uplifting AIAN cultural values and promoting health and well-being for present and future generations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Maudrie, Grubin, Conrad, Velasquez Baez, Saniguq Ullrich, Allison-Burbank, Martin, Austin, Joyner, Ronyak, Masten, Ingalls, Haroz and O’Keefe.)

Background: One of the most traumatic injuries a child can experience is a severe burn. Despite improvements in medical treatments which have led to better physical outcomes and reduced mortality rates for paediatric burns patients, the psychological impact associated with experiencing such a traumatic injury has mostly been overlooked. This is concerning given the high incidence of psychopathology amongst paediatric burn survivors., Objectives: This project will aim to pilot test and evaluate a co-designed trauma-focused intervention to support resilience and promote positive mental health in children and adolescents who have sustained an acute burn injury. Our first objective is to collect pilot data to evaluate the efficacy of the intervention and to inform the design of future trauma-focussed interventions. Our second objective is to collect pilot data to determine the appropriateness of the developed intervention by investigating the changes in mental health indicators pre- and post-intervention. This will inform the design of future interventions., Methods: This pilot intervention study will recruit 40 children aged between 6-17 years who have sustained an acute burn injury and their respective caregivers. These participants will have attended the Stan Perron Centre of Excellence for Childhood Burns at Perth Children's Hospital. Participants will attend a 45-minute weekly or fortnightly session for six weeks that involves building skills around information gathering, managing reactions (behaviours and thoughts), identifying, and bolstering coping skills, problem solving and preventing setbacks. The potential effects and feasibility of our intervention will be assessed through a range of age-appropriate screening measures which will assess social behaviours, personal qualities, mental health and/or resilience. Assessments will be administered at baseline, immediately post-intervention, at 6- and 12-months post-intervention., Conclusion: The results of this study will lay the foundation for an evidence-based, trauma-informed approach to clinical care for paediatric burn survivors and their families in Western Australia. This will have important implications for the design of future support offered to children with and beyond burn injuries, and other medical trauma populations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wickens et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64-65. ADAM-19 cleavage increased G q and decreased G s activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions., (© 2024 Aydin et al.)

Background: Despite the medical and surgical improvements of paediatric burn injuries, burn injuries can be a painful and traumatic experience for the child and their family. It is therefore important to explore the experiences of caregivers who support their child throughout the burn journey. Thus, the purpose of this study was to explore the traumatic nature of paediatric burns on the family from a caregiver's perspective., Methods: This study used a descriptive qualitative approach to conduct online semi-structured interviews with caregivers (18 years and older) of children (aged four to 17 years) that had previously been admitted with an unintentional acute burn injury to a paediatric burns unit in Western Australia. Interviews explored the child's and caregiver's experiences throughout the burn journey from the perspective of the caregiver and were digitally recorded and transcribed verbatim. Transcripts were analysed using Braun and Clarke's six stages of reflexive thematic analysis., Results: Eleven mothers participated in the interviews and identified a range of poor psychological and psychosocial outcomes that themselves and their child experienced. Three overarching themes were elaborated from the interviews: Child and caregiver mental health difficulties during and after the burn (including medical trauma, mental health outcomes and caregiver guilt); Lifestyle and physical changes following the burn (including disruptions to routine, appearance concerns and puberty); and factors supporting or inhibiting the recovery journey (including personality factors, coping strategies, family dynamics and support)., Final Considerations: This study has presented the difficulties that children, young people, and their family face throughout a paediatric burn injury, which makes the implementation of timely and effective family centred interventions imperative. Meeting the needs and supporting these families with their mental health throughout this traumatic recovery journey, can ensure positive psychosocial outcomes and adaptive coping strategies are adopted early on., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults., Methods: We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.6±4.9 kg/m 2 ), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women's Health Initiative)., Results: In 184 proteins in >2000 young adults in CARDIA, we identified 2 proteotypes of diabetes susceptibility-a proinflammatory fat proteotype (visceral fat, liver fat, inflammatory biomarkers) and a muscularity proteotype (muscle mass), linked to diabetes in CARDIA and WHI/FHS. These proteotypes specified broad mechanisms of early diabetes pathogenesis, including transorgan communication, hepatic and skeletal muscle stress responses, vascular inflammation and hemostasis, fibrosis, and renal injury. Using human adipose tissue single cell/nuclear RNA-seq, we demonstrate expression at transcriptional level for implicated proteins across adipocytes and nonadipocyte cell types (eg, fibroadipogenic precursors, immune and vascular cells). Using functional assays in human adipose tissue, we demonstrate the association of expression of genes encoding these implicated proteins with adipose tissue metabolism, inflammation, and insulin resistance., Conclusions: A multifaceted discovery effort uniting proteomics, underlying clinical susceptibility phenotypes, and tissue expression patterns may uncover potentially novel functional biomarkers of early diabetes susceptibility in young adults for future mechanistic evaluation., Competing Interests: Disclosures Dr Murthy owns stock or stock options in General Electric, Cardinal Health, Ionetix, Boston Scientific, Merck, Eli Lilly, Johnson and Johnson, Pfizer, Intel, and nVidia. He has received research grants and speaking honoraria from Siemens Medical Imaging and expert testimony fees on behalf of Jubilant Draximage. He has served on medical advisory boards for Ionetix and Curium. Dr Wilkins reports consulting for 3M. Dr Shah has served as a consultant for Cytokinetics and Amgen and is a co-inventor on a patent for ex-RNAs signatures of cardiac remodeling. The other authors report no conflicts.

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings., (© 2024. The Author(s).)

The split-thickness skin graft (STSG) donor site is the commonest used during burn surgery which has its own complications and as such the focus should be on minimizing it. Modifications to practice in our unit which we believe aid this include limiting the amount of STSG taken and the harvest of super-thin STSGs, with 0.003-0.005 in. (0.08-0.13 mm) being the commonest dermatome settings used. A patient-reported survey via a mobile phone link to a questionnaire was sent to 250 patients who had a STSG for an acute burn between 1st August 2020 and 31st July 2021. Patient demographics were collected from electronic records including the thickness of the FTSG taken when recorded. Patient responses were statistically analyzed and logistic regression with backwards elimination was performed to explore which contributing factors led to an improved experience of the donor site. Questionnaire responses were obtained from 107 patients (43%). These were between one and two and a half years after the injury. Concerning early donor site issues, itch was a problem for 52% of patients, pain was a problem for 48% of patients. Less common problems (fewer than 25% of patients) were leaking donor sites, wound breakdown, and over-granulation. Regarding long-term outcomes, increased, decreased or mixed pigmentation at the donor site was reported by 32% patients at the time of the survey. Hyper-vascular donor sites were reported by 24% patients. Raised or uneven feeling donor sites were reported by 19% patients, firm or stiff donor sites by 13% patients, and altered sensation by 10% patients. At the time of the survey, 70% responders reported their donor site looked "the same or about the same as my normal skin". Of these, 62 reported how long it took for this to happen, and it equates to a third looking normal at 6 months and half looking normal at a year. For the 32 patients who reported their donor site looking abnormal, 72% were "not bothered" by it. Patients with super-thin grafts (0.003-0.005 in.) were significantly more likely to have normal sensation, normal stiffness, and be less raised at their donor sites than those who had thin grafts (0.006-0.008 in.). This survey gives important information on patients' experiences of donor site morbidity that may form part of an informed consent process and allow tailored advice. Furthermore, it suggests that super-thin grafts may provide a superior donor site experience for patients., Competing Interests: Declaration of Competing Interest All authors declare no financial or personal associations that could inappropriately influence this work., (Copyright © 2023 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

The Human Exposome Project aims to revolutionize our understanding of how environmental exposures affect human health by systematically cataloging and analyzing the myriad exposures individuals encounter throughout their lives. This initiative draws a parallel with the Human Genome Project, expanding the focus from genetic factors to the dynamic and complex nature of environ-mental interactions. The project leverages advanced methodologies such as omics technologies, biomonitoring, microphysiological systems (MPS), and artificial intelligence (AI), forming the foun-dation of exposome intelligence (EI) to integrate and interpret vast datasets. Key objectives include identifying exposure-disease links, prioritizing hazardous chemicals, enhancing public health and regulatory policies, and reducing reliance on animal testing. The Implementation Moonshot Project for Alternative Chemical Testing (IMPACT), spearheaded by the Center for Alternatives to Animal Testing (CAAT), is a new element in this endeavor, driving the creation of a public-private part-nership toward a Human Exposome Project with a stakeholder forum in 2025. Establishing robust infrastructure, fostering interdisciplinary collaborations, and ensuring quality assurance through sys-tematic reviews and evidence-based frameworks are crucial for the project's success. The expected outcomes promise transformative advancements in precision public health, disease prevention, and a more ethical approach to toxicology. This paper outlines the strategic imperatives, challenges, and opportunities that lie ahead, calling on stakeholders to support and participate in this landmark initiative for a healthier, more sustainable future.