Maximizing matching, equity and survival in kidney transplantation using molecular HLA immunogenicity quantitation.

HLA matching improves long-term outcomes of kidney transplantation, yet implementation challenges persist, particularly within the African American (Black) patient demographic due to donor scarcity. Consequently, kidney survival rates among Black patients significantly lag behind those of other racial groups. A refined matching scheme holds promise for improving kidney survival, with prioritized matching for Black patients potentially bolstering rates of HLA-matched transplants. To facilitate quantity, quality and equity in kidney transplants, we propose two matching algorithms based on quantification of HLA immunogenicity using the hydrophobic mismatch score (HMS) for prospective transplants. We mined the national transplant patient database (SRTR) for a diverse group of donors and recipients with known racial backgrounds. Additionally, we use novel methods to infer survival assessment in the simulated transplants generated by our matching algorithms, in the absence of actual target outcomes, utilizing modified unsupervised clustering techniques. Our allocation algorithms demonstrated the ability to match 87.7% of Black and 86.1% of White recipients under the HLA immunogenicity threshold of 10. Notably, at the lowest HMS threshold of 0, 4.4% of Black and 12.1% of White recipients were matched, a marked increase from the 1.8% and 6.6% matched under the prevailing allocation scheme. Furthermore, our allocation algorithms yielded similar or improved survival rates, as illustrated by Kaplan-Meier (KM) curves, and enhanced survival prediction accuracy, evidenced by C-indices and Integrated Brier Scores.

Electronic and Structural Disorder of the Epitaxial La0.67Sr0.33MnO3 Surface.

Understanding and tuning epitaxial complex oxide films are crucial in controlling the behavior of devices and catalytic processes. Substrate-induced strain, doping, and layer growth are known to influence the electronic and magnetic properties of the bulk of the film. In this study, we demonstrate a clear distinction between the bulk and surface of thin films of La0.67Sr0.33MnO3 in terms of chemical composition, electronic disorder, and surface morphology. We use a combined experimental approach of X-ray-based characterization methods and scanning probe microscopy. Using X-ray diffraction and resonant X-ray reflectivity, we uncover surface nonstoichiometry in the strontium and lanthanum alongside an accumulation of oxygen vacancies. With scanning tunneling microscopy, we observed an electronic phase separation (EPS) on the surface related to this nonstoichiometry. The EPS is likely driving the temperature-dependent resistivity transition and is a cause of proposed mixed-phase ferromagnetic and paramagnetic states near room temperature in these thin films.

Institutional practices for charitable medication access for uninsured patients.

OBJECTIVES: To identify the most frequently prescribed medications, the location where prescriptions were filled, and whether a voucher was utilized among patients enrolled in a charitable care program within an academic medical center. STUDY DESIGN: This was a retrospective cohort study analyzing electronic health record and pharmacy dispensing information at a medical center's outpatient pharmacies. METHODS: Patients included in this analysis were enrolled in a charitable care program and had at least 1 ambulatory encounter in a primary care clinic from March 1, 2019, to June 30, 2021. The study identified frequently prescribed medications, prescription payment methods, the overall cost of prescriptions if available, and the percentage of patients who filled their prescription at a medical center's outpatient pharmacies vs external outpatient pharmacies. Descriptive statistics were used to describe the results. RESULTS: This study included 511 patients, 87% of whom were Spanish speaking. A total of 8453 prescriptions were identified, and more than half of the prescriptions were sent to external outpatient pharmacies. The most common medications prescribed were for cardiovascular disease, diabetes, and pain treatment. Forty-seven percent of all prescriptions were sent to the medical center's outpatient pharmacies. The medical center's charitable care program covered the costs of 44% of the prescriptions sent to internal pharmacies, assisting 148 unique patients and incurring a cost of $111,052 for the medical center. CONCLUSIONS: Overall, this study was able to characterize patient demographics, historical costs related to charitable care coverage, and the utilization of health care services among this population. This information can be used to support the development and implementation of a charitable medication formulary, with the aims of improving quality of care for this population and reducing medical center costs.

Determining the characteristics of genetic disorders that predict inclusion in newborn genomic sequencing programs.

Over 30 international research studies and commercial laboratories are exploring the use of genomic sequencing to screen apparently healthy newborns for genetic disorders. These programs have individualized processes for determining which genes and genetic disorders are queried and reported in newborns. We compared lists of genes from 26 research and commercial newborn screening programs and found substantial heterogeneity among the genes included. A total of 1,750 genes were included in at least one newborn genome sequencing program, but only 74 genes were included on >80% of gene lists, 16 of which are not associated with conditions on the Recommended Uniform Screening Panel. We used a linear regression model to explore factors related to the inclusion of individual genes across programs, finding that a high evidence base as well as treatment efficacy were two of the most important factors for inclusion. We applied a machine learning model to predict how suitable a gene is for newborn sequencing. As knowledge about and treatments for genetic disorders expand, this model provides a dynamic tool to reassess genes for newborn screening implementation. This study highlights the complex landscape of gene list curation among genomic newborn screening programs and proposes an empirical path forward for determining the genes and disorders of highest priority for newborn screening programs.

Quantifying methane emissions from United States landfills.

Methane emissions from solid waste may represent a substantial fraction of the global anthropogenic budget, but few comprehensive studies exist to assess inventory assumptions. We quantified emissions at hundreds of large landfills across 18 states in the United States between 2016 and 2022 using airborne imaging spectrometers. Spanning 20% of open United States landfills, this represents the most systematic measurement-based study of methane point sources of the waste sector. We detected significant point source emissions at a majority (52%) of these sites, many with emissions persisting over multiple revisits (weeks to years). We compared these against independent contemporaneous in situ airborne observations at 15 landfills and established good agreement. Our findings indicate a need for long-term, synoptic-scale monitoring of landfill emissions in the context of climate change mitigation policy.

Effect of trauma quality improvement initiatives on outcomes and costs at community hospitals: A scoping review.

BACKGROUND: Due to complex geography and resource constraints, trauma patients are often initially transported to community or rural facilities rather than a larger Level I or II trauma center. The objective of this scoping review was to synthesize evidence on interventions that improved the quality of trauma care and/or reduced healthcare costs at non-Level I or II facilities. METHODS: A scoping review was performed to identify studies implementing a Quality Improvement (QI) initiative at a non-major trauma center (i.e., non-Level I or II trauma center [or equivalent]). We searched 3 electronic databases (MEDLINE, Embase, CINAHL) and the grey literature (relevant networks, organizations/associations). Methodological quality was evaluated using NIH and JBI study quality assessment tools. Studies were included if they evaluated the effect of implementing a trauma care QI initiative on one or more of the following: 1) trauma outcomes (mortality, morbidity); 2) system outcomes (e.g., length of stay [LOS], transfer times, provider factors); 3) provider knowledge or perception; or 4) healthcare costs. Pediatric trauma, pre-hospital and tele-trauma specific studies were excluded. RESULTS: Of 1046 data sources screened, 36 were included for full review (29 journal articles, 7 abstracts/posters without full text). Educational initiatives including the Rural Trauma Team Development Course and the Advanced Trauma Life Support course were the most common QI interventions investigated. Study outcomes included process metrics such as transfer time to tertiary care and hospital LOS, along with measures of provider perception and knowledge. Improvement in mortality was reported in a single study evaluating the impact of establishing a dedicated trauma service at a community hospital. CONCLUSIONS: Our review captured a broad spectrum of trauma QI projects implemented at non-major trauma centers. Educational interventions did result in process outcome improvements and high rates of self-reported improvements in trauma care. Given the heterogeneous capabilities of community and rural hospitals, there is no panacea for trauma QI at these facilities. Future research should focus on patient outcomes like mortality and morbidity, and locally relevant initiatives.

Epidemiology and factors associated with mortality among pediatric major trauma patients in Nova Scotia: A 17-year retrospective analysis.

BACKGROUND: Major traumatic injury in the pediatric population requires further evaluation to improve patient outcomes. Relatively few Canadian studies have investigated pediatric trauma using population-based data. Our objectives were to describe the epidemiology of pediatric major trauma in Nova Scotia and identify factors associated with in-hospital mortality. METHODS: Retrospective cohort study of pediatric major trauma patients (age <18 years) injured in Nova Scotia over a 17-year period (April 2001-March 2018). Data were collected from the Nova Scotia Trauma Registry. Characteristics were compared between patient subgroups using t-tests, chi-square analyses and Fisher's exact test. Temporal trends were evaluated using the Mann-Kendall test. Incidence and mortality rates were mapped using ArcGIS Pro. A multivariate logistic regression model was created to assess for factors associated with in-hospital mortality. RESULTS: A total of 1258 injuries were observed over the 17-year study period. The incidence of pediatric major trauma was 41.7 per 100,000 person-years. Most patients were male (819/1258; 65.1 %) and resided in urban areas (764/1258; 60.7 %). Blunt trauma accounted for 86.2 % (1084/1258) of injuries, and motor vehicle collisions were the most common cause (448/1258; 35.6 %). Incidence and mortality rates were highest in the 15-17 year age group, with a trend towards increasing incidence among females (p = 0.011). Mortality was 17.2 % (217/1258) of patients; 10.9 % (137/1258) died pre-hospital. No trends were detected in mortality rates. The regression model showed increased odds of in-hospital mortality for every point increase in the ISS (OR 1.05; 95 % CI 1.02 to 1.09) and for every unit decrease in scene GCS (OR 0.63; 95 % CI 0.56-0.71). Rural patients were 2 times more likely to die in-hospital versus urban patients (OR 2.40; 95 % CI 1.01-5.69), and patients injured at home were 6 times more likely to die compared to those injured in other locations (OR 6.19; 95 % CI 1.01-38.11). CONCLUSION: Pediatric trauma remains a major public health issue in Canada and beyond. Greater efforts are required to expand our understanding of trauma epidemiology and develop targeted injury prevention strategies, especially for rural inhabitants.

Clinical impact of preemptive pharmacogenomic testing on antiplatelet therapy in a real-world setting.

CYP2C19 genotyping to guide antiplatelet therapy after patients develop acute coronary syndromes (ACS) or require percutaneous coronary interventions (PCIs) reduces the likelihood of major adverse cardiovascular events (MACE). Evidence about the impact of preemptive testing, where genotyping occurs while patients are healthy, is lacking. In patients initiating antiplatelet therapy for ACS or PCI, we compared medical records data from 67 patients who received CYP2C19 genotyping preemptively (results >7 days before need), against medical records data from 67 propensity score-matched patients who received early genotyping (results within 7 days of need). We also examined data from 140 patients who received late genotyping (results >7 days after need). We compared the impact of genotyping approaches on medication selections, specialty visits, MACE and bleeding events over 1 year. Patients with CYP2C19 loss-of-function alleles were less likely to be initiated on clopidogrel if they received preemptive rather than early or late genotyping (18.2%, 66.7%, and 73.2% respectively, p = 0.001). No differences were observed by genotyping approach in the number of specialty visits or likelihood of MACE or bleeding events (all p > 0.21). Preemptive genotyping had a strong impact on initial antiplatelet selection and a comparable impact on patient outcomes and healthcare utilization, compared to genotyping ordered after a need for antiplatelet therapy had been identified.

Pre-hospital mortality among pediatric trauma patients in Nova Scotia.

OBJECTIVES: Limited data exist on pre-hospital pediatric trauma mortality in Canada. The Nova Scotia Trauma Registry is a provincial population-based registry that captures data from the Medical Examiner Service. This study examined the characteristics of pediatric trauma patient mortality in the pre-hospital and in-hospital settings. METHODS: We conducted a cohort study of major pediatric traumas recorded in our provincial database from April 1, 2001 to March 31, 2018. Characteristics of pre-hospital and in-hospital deaths were compared with t tests and Chi-square analyses. Multivariate regression modeling was used to identify predictors of pre-hospital mortality. The geographic distribution of pre-hospital trauma was assessed using choropleth maps. RESULTS: We identified 1,258 pediatric traumas, resulting in 217 deaths (137 pre-hospital, 80 in-hospital). Males accounted for 62.7% of fatalities. The 15-17 age group accounted for most deaths in both groups (pre-hospital 61.3%; in-hospital 41.3%). Injuries sustained in rural areas resulted in 74.7% of all deaths. For both groups, blunt trauma was the predominant injury type and motor vehicle collisions, the most prevalent injury mechanism. Patients who died pre-hospital had a higher mean age (13.3 vs. 10.7, p = 0.002) and a greater proportion were intentional injuries (23.4% vs. 15%; p = 0.02). Urban residency was more frequently observed in in-hospital deaths (57.5% vs. 36.5%, p < 0.001). Pre-hospital mortality was associated with increasing age (OR 1.1), higher injury severity score (OR 1.1), and intentional injury (OR 15.6). CONCLUSION: Over 10% of major pediatric traumas resulted in pre-hospital death, primarily from motor vehicle collisions in rural areas. Compared to in-hospital mortality, patients who died pre-hospital were older with more severe injuries and more likely to have intentionally injured themselves. These results underscore the importance for emergency physicians and EMS systems to consider geographic factors and injury patterns, advocate for improved injury prevention programs, mental health supports, and delivery of on-scene critical care services.

RéSUMé: OBJECTIFS: Il existe peu de données sur la mortalité liée aux traumatismes pédiatriques pré-hospitaliers au Canada. La Nouvelle-Écosse. Le registre des traumatismes est un registre provincial fondé sur la population qui saisit les données du Medical Examiner Service. Cette étude a examiné les caractéristiques des traumatismes pédiatriques la mortalité des patients en milieu pré-hospitalier et hospitalier. MéTHODES: Nous avons mené une étude de cohorte des traumatismes pédiatriques majeurs enregistrés dans notre province base de données du 1er avril 2001 au 31 mars 2018. Caractéristiques des services pré-hospitaliers et les décès hospitaliers ont été comparés aux tests-t et aux analyses du chi carré. La modélisation multivariée de régression a été utilisée pour identifier les prédicteurs de la mortalité pré-hospitalière. La répartition géographique des traumatismes pré-hospitaliers a été évaluée à l'aide de cartes choroplèthes. RéSULTATS: Nous avons identifié 1258 traumatismes pédiatriques, entraînant 217 décès (137 pré-hospitaliers, 80 hospitalier les hommes représentaient 62,7% des décès. Le groupe des 15 à 17 ans représentait la plupart des décès dans les deux groupes (avant l'hôpital 61,3%; à l'hôpital 41,3%). Blessures subies dans les régions rurales ont entraîné 74,7% de tous les décès. Pour les deux groupes, le traumatisme contondant était le type de blessure prédominant et les collisions de véhicules à moteur, les blessures les plus fréquentes. Les patients décédés avant l'hospitalisation avaient un âge moyen plus élevé (13,3 vs 10,7, p = 0,002) et une plus grande proportion étaient des blessures intentionnelles (23,4% contre 15%; p = 0,02). La résidence en milieu urbain était plus fréquemment observée dans les décès à l'hôpital (57,5% contre 36,5%, p < 0.001). La mortalité pré-hospitalière était associée à une augmentation de l'âge (CP 1.1) le score de gravité des blessures (CP 1.1) et les blessures intentionnelles (CP 15.6). CONCLUSIONS: Plus de 10% des traumatismes pédiatriques majeurs ont entraîné un décès avant l'hôpital, principalement à cause de troubles moteurs les collisions de véhicules dans les régions rurales. Comparativement à la mortalité à l'hôpital, les patients qui sont décédés avant. les établissements de soins palliatifs étaient plus âgés et plus susceptibles d'avoir intentionnellement subi des blessures plus graves. Ces résultats soulignent l'importance pour les médecins d'urgence et les systèmes de SMU pour tenir compte des facteurs géographiques et des tendances en matière de blessures, préconiser amélioration des programmes de prévention des blessures, du soutien en santé mentale et de la prestation sur place services de soins intensifs.

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co-pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI-4 aims to address by enrolling a diverse cohort.

Attribution of individual methane and carbon dioxide emission sources using EMIT observations from space.

Carbon dioxide and methane emissions are the two primary anthropogenic climate-forcing agents and an important source of uncertainty in the global carbon budget. Uncertainties are further magnified when emissions occur at fine spatial scales (<1 km), making attribution challenging. We present the first observations from NASA's Earth Surface Mineral Dust Source Investigation (EMIT) imaging spectrometer showing quantification and attribution of fine-scale methane (0.3 to 73 tonnes CH4 hour-1) and carbon dioxide sources (1571 to 3511 tonnes CO2 hour-1) spanning the oil and gas, waste, and energy sectors. For selected countries observed during the first 30 days of EMIT operations, methane emissions varied at a regional scale, with the largest total emissions observed for Turkmenistan (731 ± 148 tonnes CH4 hour-1). These results highlight the contributions of current and planned point source imagers in closing global carbon budgets.

Decoding Genetics, Ancestry, and Geospatial Context for Precision Health.

Mass General Brigham, an integrated healthcare system based in the Greater Boston area of Massachusetts, annually serves 1.5 million patients. We established the Mass General Brigham Biobank (MGBB), encompassing 142,238 participants, to unravel the intricate relationships among genomic profiles, environmental context, and disease manifestations within clinical practice. In this study, we highlight the impact of ancestral diversity in the MGBB by employing population genetics, geospatial assessment, and association analyses of rare and common genetic variants. The population structures captured by the genetics mirror the sequential immigration to the Greater Boston area throughout American history, highlighting communities tied to shared genetic and environmental factors. Our investigation underscores the potency of unbiased, large-scale analyses in a healthcare-affiliated biobank, elucidating the dynamic interplay across genetics, immigration, structural geospatial factors, and health outcomes in one of the earliest American sites of European colonization.

The GenoVA study: Equitable implementation of a pragmatic randomized trial of polygenic-risk scoring in primary care.

Polygenic risk scores (PRSs) hold promise for disease risk assessment and prevention. The Genomic Medicine at Veterans Affairs (GenoVA) Study is addressing three main challenges to the clinical implementation of PRSs in preventive care: defining and determining their clinical utility, implementing them in time-constrained primary care settings, and countering their potential to exacerbate healthcare disparities. The study processes used to test patients, report their PRS results to them and their primary care providers (PCPs), and promote the use of those results in clinical decision-making are modeled on common practices in primary care. The following diseases were chosen for their prevalence and familiarity to PCPs: coronary artery disease; type 2 diabetes; atrial fibrillation; and breast, colorectal, and prostate cancers. A randomized clinical trial (RCT) design and primary outcome of time-to-new-diagnosis of a target disease bring methodological rigor to the question of the clinical utility of PRS implementation. The study's pragmatic RCT design enhances its relevance to how PRS might reasonably be implemented in primary care. Steps the study has taken to promote health equity include the thoughtful handling of genetic ancestry in PRS construction and reporting and enhanced recruitment strategies to address underrepresentation in research participation. To date, enhanced recruitment efforts have been both necessary and successful: participants of underrepresented race and ethnicity groups have been less likely to enroll in the study than expected but ultimately achieved proportional representation through targeted efforts. The GenoVA Study experience to date offers insights for evaluating the clinical utility of equitable PRS implementation in adult primary care.

European gay fathers via surrogacy: Parenting, social support, anti-gay microaggressions, and child behavior problems.

The present study investigated child behavior problems, parenting styles, coparenting, and couple relationship satisfaction in 67 European gay father families via surrogacy and 67 European heterosexual parent families via unassisted conception, all with children aged 1.5-10 years (M = 3.57 years, SD = 2.09). The two family groups were matched for child age and gender. In the gay father group only, the associations between family anti-gay microaggressions, family/friend support, and other main variables also were explored. Children of gay fathers had fewer externalizing and internalizing problems compared to children of heterosexual parents. Also, gay fathers reported more effective parenting styles, greater coparenting quality, and higher couple relationship satisfaction compared to heterosexual parents. Overall, child externalizing problems (i.e., aggression, rule-breaking) and internalizing problems (i.e., anxiety, depression) were more strongly associated with being raised in a heterosexual parent family, more authoritarian parenting, and lower positive coparenting. Specific to the gay father sample, anti-gay microaggressions experienced by family members were associated with more child internalizing problems, lower positive coparenting, and lower social support from family and friends. These results refute concerns about possible detrimental effects on child development of surrogacy conception or of being raised by gay fathers. The results further suggest that family therapists treating child behavior problems should focus mainly on improving the coparenting relationship, reducing authoritarian/punitive parenting styles, and (for gay father families specifically) coping with anti-gay microaggressions and lack of social support outside the nuclear family.

An Ethical Framework for Research Using Genetic Ancestry.

A wide range of research uses patterns of genetic variation to infer genetic similarity between individuals, typically referred to as genetic ancestry. This research includes inference of human demographic history, understanding the genetic architecture of traits, and predicting disease risk. Researchers are not just structuring an intellectual inquiry when using genetic ancestry, they are also creating analytical frameworks with broader societal ramifications. This essay presents an ethics framework in the spirit of virtue ethics for these researchers: rather than focus on rule following, the framework is designed to build researchers' capacities to react to the ethical dimensions of their work. The authors identify one overarching principle of intellectual freedom and responsibility, noting that freedom in all its guises comes with responsibility, and they identify and define four principles that collectively uphold researchers' intellectual responsibility: truthfulness, justice and fairness, anti-racism, and public beneficence. Researchers should bring their practices into alignment with these principles, and to aid this, the authors name three common ways research practices infringe these principles, suggest a step-by-step process for aligning research choices with the principles, provide rules of thumb for achieving alignment, and give a worked case. The essay concludes by identifying support needed by researchers to act in accord with the proposed framework.

Development of LB244, an Irreversible STING Antagonist.

The cGMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway plays a critical role in sensing dsDNA localized to the cytosol, resulting in the activation of a robust inflammatory response. While cGAS-STING signaling is essential for antiviral immunity, aberrant STING activation is observed in amyotrophic lateral sclerosis (ALS), lupus, and autoinflammatory diseases such as Aicardi-Goutières syndrome (AGS) and STING associated vasculopathy with onset in infancy (SAVI). Significant efforts have therefore focused on the development of STING inhibitors. In a concurrent submission, we reported that BB-Cl-amidine inhibits STING-dependent signaling in the nanomolar range, both in vitro and in vivo. Considering this discovery, we sought to generate analogs with higher potency and proteome-wide selectivity. Herein, we report the development of LB244, which displays nanomolar potency and inhibits STING signaling with markedly enhanced proteome-wide selectivity. Moreover, LB244 mirrored the efficacy of BB-Cl-amidine in vivo. In summary, our data identify novel chemical entities that inhibit STING signaling and provide a scaffold for the development of therapeutics for treating STING-dependent inflammatory diseases.

Antithrombin III supplementation during neonatal and pediatric extracorporeal membrane oxygenation.

BACKGROUND: Bleeding and thrombosis are common extracorporeal membrane oxygenation (ECMO) complications associated with increased mortality. Heparin is the most commonly used ECMO anticoagulant, employed in 94% of cases. Reduced antithrombin III (AT3) levels could decrease heparin effectiveness. Neonates have inherently lower levels of AT3 than adults, and pediatric patients on ECMO can develop AT3 deficiency. One potential approach for patients on ECMO with AT3 deficiency is exogenous AT3 supplementation. However, there is conflicting data concerning the use of AT3 for pediatric and neonatal patients on ECMO. METHODS: We analyzed the Bleeding and Thrombosis during ECMO database of 514 neonatal and pediatric patients on ECMO. We constructed daily regression models to determine the association between AT3 supplementation and rates of bleeding and thrombosis. Given the physiological differences between pediatric patients and neonates, we constructed separate models for each. RESULTS: AT3 administration was associated with increased rates of daily bleeding among pediatric (adjusted odds ratio [aOR] 1.59, p < 0.01) and neonatal (aOR 1.37, p = 0.04) patients. AT3 supplementation did not reduce the rate of thrombosis for either pediatric or neonatal patients. CONCLUSION: AT3 administration was associated with increased rates of daily bleeding, a hypothesized potential complication of AT3 supplementation. In addition, AT3 supplementation did not result in lower rates of thrombosis. We recommend clinicians utilize caution when considering supplementing patients on ECMO with exogenous AT3.

Phenotypes of undiagnosed adults with actionable OTC and GLA variants.

Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMDs and can lead to protocols that improve clinical detection, counseling, and management. Using data from 57,340 participants in two hospital biobanks, we assessed the frequency and phenotypes of individuals with pathogenic/likely pathogenic variants (PLPVs) in two IMD genes: GLA, associated with Fabry disease, and OTC, associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in GLA or OTC. We identified three individuals (2 male, 1 female) with PLPVs in GLA, all of whom were undiagnosed, and three individuals (3 female) with PLPVs in OTC, two of whom were undiagnosed. All three individuals with PLPVs in GLA (100%) had symptoms suggestive of mild Fabry disease, and one individual (14.2%) had an ischemic stroke at age 33, likely indicating the presence of classic disease. No individuals with PLPVs in OTC had documented hyperammonemia despite exposure to catabolic states, but all (100%) had chronic symptoms suggestive of attenuated disease, including mood disorders and migraines. Our findings suggest that GLA and OTC variants identified via a genotype-first approach are of high penetrance and that population screening of these genes can be used to facilitate stepwise phenotyping and appropriate care.