Complex Regulation of Protocadherin Epigenetics on Aging-Related Brain Health.

Life expectancy continues to increase in the high-income world due to advances in medical care; however, quality of life declines with increasing age due to normal aging processes. Current research suggests that various aspects of aging are genetically modulated and thus may be slowed via genetic modification. Here, we show evidence for epigenetic modulation of the aging process in the brain from over 1800 individuals as part of the Framingham Heart Study. We investigated the methylation of genes in the protocadherin (PCDH) clusters, including the alpha (PCHDA), beta (PCDHB), and gamma (PCDHG) clusters. Reduced PCDHG, elevated PCDHA, and elevated PCDHB methylation levels were associated with substantial reductions in the rate of decline of regional white matter volume as well as certain cognitive skills, independent of overall accelerated or retarded aging as estimated by a DNA clock. These results are likely due to the different effects of the expression of genes in the alpha, beta, and gamma PCHD clusters and suggest that experience-based aging processes related to a decline in regional brain volume and select cognitive skills may be slowed via targeted epigenetic modifications.

Barriers and co-designed strategies for the implementation of negative pressure wound therapy in acute pediatric burn care in Australia: A mixed method study.

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.

Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network.

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.

Filaggrin loss-of-function variants are associated with atopic dermatitis phenotypes in a diverse, early-life prospective cohort.

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.

Systolic Blood Pressure and Survival to Very Old Age: Results From the Women's Health Initiative.

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.

The Role of Cytokines in Acute and Chronic Postsurgical Pain in Pediatric Patients after Major Musculoskeletal Surgeries.

Study Objective: To determine if baseline cytokines 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 after (up to two weeks) 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) pain were analyzed. After adjusting for covariates, univariate/multivariate regression analyses were conducted to associate baseline cytokine concentrations with postoperative pain, and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes. Main Results: Analyses included 3,164 measures of 16 cytokines 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 (ß=0.95, SE 0.31; p=.003), IL-1ß (ß=0.84, SE 0.36; p=.02), IL-2 (ß=0.78, SE 0.34; p=.03), and IL-12 p70 (ß=0.88, SE 0.40; p=.03) and longitudinal postoperative elevations in GM-CSF (ß=1.38, SE 0.57; p=.03), IFNγ (ß=1.36, SE 0.6; p=.03), IL-1ß (ß=1.25, SE 0.59; p=.03), IL-7 (ß=1.65, SE 0.7, p=.02), and IL-12 p70 (ß=1.17, SE 0.58; p=.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (ß= -0.39, SE 0.17; p=.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (ß= -0.57, SE 0.26; p=.03), IL-8 (ß= -0.68, SE 0.24; p=.006), and IL-13 (ß= -0.48, SE 0.22; p=.03). Furthermore, higher odds for CPSP were found for females (vs. males) for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNFα, and for pectus (vs. spine) surgery for IL-8 and IL-10. Conclusion: We identified pro-inflammatory cytokines associated with increased acute postoperative pain and anti-inflammatory cytokines associated with lower CPSP risk, with potential to serve as predictive and prognostic biomarkers.

Honoring our teachings: children's storybooks as indigenous public health practice.

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.

Inflammatory proteins and neutrophil extracellular traps increase in burn blister fluid 24h after burn.

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.

Quantifying the severity of sarcopenia in patients with cancer of the head and neck.

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 (cm2/m2) 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 (cm2/m2) 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.

Heart Failure Risk Among African-American Women With an ICAM1 Missense Variant.

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.

Trauma patient heterotopic ossification diagnosis is associated with increased hospital length of stay.

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.

Diagnostic yield after next-generation sequencing in pediatric cardiovascular disease.

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.

[Trained immunity : emerging strategies against antibiotic resistance]. / L'immunité entraînée - Une stratégie émergente contre l'antibiorésistance.

Title: L'immunité entraînée - Une stratégie émergente contre l'antibiorésistance. Abstract: Les étudiants de Polytech Nice Sophia (PNS) en Génie Biologique 5A ont exploré trois projets prometteurs. L'équipe pédagogique qui les a encadrés est composée de Cercina ONESTO et Nicole ARRIGHI, enseignants-chercheurs à PNS, et du trinome Céline PISIBON, Imène KROSSA et Juan GARCIA-SANCHEZ, doctorants et post-doctorants du Centre Méditerranéen de Médecine Moléculaire de Nice. Dès le début du cursus d'ingénieur, les étudiants suivent un cours d'introduction à la recherche. Plus ils avancent dans le cursus, plus ils se perfectionnent dans l'analyse de l'actualité scientifique de leur spécialité. Dans la mineure Pharmacologie et Biotechnologies, ils cernent les limites d'un traitement, puis ils réfléchissent en équipes à une nouvelle piste thérapeutique. Ainsi, ils anticipent l'innovation en santé, l'imaginent et la créent pour devenir les ingénieurs en santé de demain.

Progressive accumulation of hyperinflammatory NKG2Dlow NK cells in early childhood severe atopic dermatitis.

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.

Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults.

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/m2), 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.

Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations.

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.

A wellbeing program to promote mental health in paediatric burn patients: Study protocol.

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.

ADAM19 cleaves the PTH receptor and associates with brachydactyly type E.

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 Gq and decreased Gs 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.

Implementation of free-draft text messaging to enhance care retention and satisfaction for persons living with HIV infection.

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.

Local heating-induced cutaneous vasodilation in reinnervated and noninnervated deep inferior epigastric perforator flaps.

INTRODUCTION: Cutaneous vascular reactivity to local heating in free flaps has not been characterized. We aimed to assess local heating-induced cutaneous vasodilation in reinnervated and noninnervated deep inferior epigastric perforator (DIEP) flaps. METHODS: We conducted a cross-sectional study of 21 female patients with an uncomplicated unilateral delayed DIEP breast reconstruction at least 2 years after surgery. DIEP flaps and contralateral breasts were subjected to direct local heating, and skin blood flow was assessed using laser-Doppler flowmetry. To evaluate sensory-nerve-fiber function, touch perception thresholds were assessed using a 20-piece Touch-test™ Sensory Evaluator, and cutaneous warm detection and heat pain thresholds were measured using a TSA-II device. RESULTS: Of the participants, 10 had a reinnervated DIEP flap with a single coapted nerve (mean flap weight, 610 ± 296 g) and 11 had a noninnervated DIEP flap (mean flap weight, 613 ± 169 g). Mean age was 58 ± 11 years, mean follow-up time was 5 ± 1 years, and mean BMI was 24 ± 3 kg/m2 . DIEP flaps exhibited significantly weaker cutaneous vasodilation in response to local heating than contralateral breasts (median peak skin blood flow, 59 [25th-75th percentile, 36-71] a.u. for DIEP flaps versus 94 [74-141] a.u. for contralateral breasts; p < .001). The magnitude of the response was similar between reinnervated and noninnervated flaps (median peak skin blood flow, 55 [25th-75th percentile, 39-68] a.u. for reinnervated DIEP flaps versus 66 [36-77] a.u. for noninnervated DIEP flaps; p = .75). Of participants with reinnervated DIEP flaps, 90% perceived heat pain below the 50°C safety threshold, as compared to 36% of participants with noninnervated DIEP flaps (two-tailed p = .02). CONCLUSION: Our results suggest that free flap transfer causes longstanding impairment, yet not complete abolition, of both the sensory nerve-mediated and nitric oxide-dependent local heating-induced cutaneous vasodilatory systems. We found no statistical evidence that flap reinnervation improves the ability to raise skin blood flow in response to local heating.