The subcutaneous adipose transcriptome identifies a molecular signature of insulin resistance shared with visceral adipose.

OBJECTIVE: The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity. METHODS: We used SAT RNA sequencing in 220 individuals with metabolic phenotyping. RESULTS: We identified a 35-gene signature with high predictive accuracy for homeostatic model of IR that was expressed across a variety of non-immune cell populations. We observed primarily "protective" IR associations for adipocyte transcripts and "deleterious" associations for macrophage transcripts, as well as a high concordance between SAT and visceral adipose tissue (VAT). Multiple SAT genes exhibited dynamic expression 5 years after weight loss surgery and with insulin stimulation. Using available expression quantitative trait loci in SAT and/or VAT, we demonstrated similar genetic effect sizes of SAT and VAT on type 2 diabetes and BMI. CONCLUSIONS: SAT is conventionally viewed as a metabolic buffer for lipid deposition during positive energy balance, whereas VAT is viewed as a dominant contributor to and prime mediator of IR and cardiometabolic disease risk. Our results implicate a dynamic transcriptional architecture of IR that resides in both immune and non-immune populations in SAT and is shared with VAT, nuancing the current VAT-centric concept of IR in humans.

Evaluating the Shock Index, Revised Assessment of Bleeding and Transfusion (RABT), Assessment of Blood Consumption (ABC) and novel PTTrauma score to predict critical transfusion threshold (CAT) in penetrating thoracic trauma.

The shock index (SI) has been associated with predicting transfusion needs in trauma patients. However, its utility in penetrating thoracic trauma (PTTrauma) for predicting the Critical Administration Threshold (CAT) has not been well-studied. This study aimed to evaluate the prognostic value of SI in predicting CAT in PTTrauma patients and compare its performance with the Assessment of Blood Consumption (ABC) and Revised Assessment of Bleeding and Transfusion (RABT) scores. We conducted a prognostic type 2, single-center retrospective observational cohort study on patients with PTTrauma and an Injury Severity Score (ISS) > 9. The primary exposure was SI at admission, and the primary outcome was CAT. Logistic regression and decision curve analysis were used to assess the predictive performance of SI and the PTTrauma score, a novel model incorporating clinical variables. Of the 620 participants, 53 (8.5%) had more than one CAT. An SI > 0.9 was associated with CAT (adjusted OR 4.89, 95% CI 1.64-14.60). The PTTrauma score outperformed SI, ABC, and RABT scores in predicting CAT (AUC 0.867, 95% CI 0.826-0.908). SI is a valuable predictor of CAT in PTTrauma patients. The novel PTTrauma score demonstrates superior performance compared to existing scores, highlighting the importance of developing targeted predictive models for specific injury patterns. These findings can guide clinical decision-making and resource allocation in the management of PTTrauma.

Sustained Human Outbreak of a New MPXV Clade I Lineage in the Eastern Democratic Republic of the Congo.

Outbreaks of mpox have historically resulted from zoonotic spillover of clade I monkeypox virus (MPXV) in Central Africa and clade II MPXV in West Africa. In 2022, subclade IIb caused a global epidemic linked to transmission through sexual contact. Here, we describe the epidemiological and genomic features of an mpox outbreak in a mining region in the Eastern Democratic Republic of the Congo (DRC), caused by clade I MPXV. Surveillance data collected between September 2023 and January 2024 identified 241 suspected cases. Genomic analysis demonstrates a distinct clade I lineage divergent from previously circulating strains in the DRC. Of the 108 PCR-confirmed mpox cases, the median age of individuals was 22 years, 51.9% were female, and 29% were sex workers, suggesting a potential role for sexual transmission. The predominance of APOBEC3-type mutations and the estimated emergence time around mid-September 2023 imply recent sustained human-to-human transmission.

Development of a population-level dichotomous indicator of minimum dietary diversity as a proxy for micronutrient adequacy in U.S. adolescents aged 10-19 years.

BACKGROUND: Diversity is a key component of diet quality and health, but no indicator exists for adolescents under the age of 15 years. OBJECTIVE: To establish a dichotomous indicator for population-level assessment of adolescent dietary diversity as a proxy for micronutrient adequacy. METHODS: We used the probability approach to construct mean probability of adequacy (MPA) of 11 micronutrients from 2 days of 24-hour dietary recall data from NHANES, 2007-2018. For each micronutrient, probability of adequacy was calculated using the best linear unbiased predictor of usual intake. Adolescent dietary diversity score (ADDS) was derived with a maximum score of 10 food groups. Generalized linear mixed models were used to examine associations between ADDS and MPA. Receiver operating characteristic analysis was used to establish a cutoff for minimum dietary diversity for adolescents (MDD-A), using an energy-adjusted logistic model with ADDS predicting MPA > 0.6. RESULTS: Probability of adequacy was greater than 80% for all nutrients except vitamin C (42.1%), folate (65.7%), and calcium (23.8%). Population MPA was 79.4%, and nearly 92% of adolescents had an MPA > 0.6. ADDS was positively associated with MPA, and energy was a significant confounder. Area under the curve was > 0.8 on both days with sensitivity and specificity ranging from 0.71-0.80. The MDD-A cutoff was calculated as 5.12 and 5.10 food groups on day 1 and 2, respectively. CONCLUSIONS: In U.S. adolescents, the best cutoff for a dichotomous indicator of dietary diversity as a proxy for micronutrient adequacy is 6 food groups in a given day. Future research could validate MDD-A and its associated cutoff for use across country contexts.

Introduction to the Emerging Cognitive Science of Distributed Human-Autonomy Teams.

Teams are a fundamental aspect of life-from sports to business, to defense, to science, to education. While the cognitive sciences tend to focus on information processing within individuals, others have argued that teams are also capable of demonstrating cognitive capacities similar to humans, such as skill acquisition and forgetting (cf., Cooke, Gorman, Myers, & Duran, 2013; Fiore et al., 2010). As artificially intelligent and autonomous systems improve in their ability to learn, reason, interact, and coordinate with human teammates combined with the observation that teams can express cognitive capacities typically seen in individuals, a cognitive science of teams is emerging. Consequently, new questions are being asked about teams regarding teamness, trust, the introduction and effects of autonomous systems on teams, and how best to measure team behavior and phenomena. In this topic, four facets of human-autonomy team cognition are introduced with leaders in the field providing in-depth articles associated with one or more of the facets: (1) defining teams; (2) how trust is established, maintained, and repaired when broken; (3) autonomous systems operating as teammates; and (4) metrics for evaluating team cognition across communication, coordination, and performance.

Reassessing retinal pigment epithelial ketogenesis: Enzymatic assays for ketone body levels provide inaccurate results.

The retinal pigment epithelium (RPE) is omnivorous and can utilize a wide range of substrates for oxidative phosphorylation. Certain tissues with high mitochondrial metabolic load are capable of ketogenesis, a biochemical pathway that consolidates acetyl-CoA into ketone bodies. Earlier work demonstrated that the RPE expresses the rate-limiting enzyme for ketogenesis, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), and that the RPE indeed produces ketone bodies, including beta-hydroxybutyrate (ß-HB). Prior work, based on detecting ß-HB via enzymatic assays, suggested that differentiated cultures of primary RPE preferentially export ß-HB across the apical membrane. Here, we compare the accuracy of measuring ß-HB by enzymatic assay kits to mass spectrometry analysis. We found that commercial kits lack the sensitivity to accurately measure the levels of ß-HB in RPE cultures and are prone to artifact. Using mass spectrometry, we found that while RPE cultures secrete ß-HB, they do so equally to both apical and basal sides. We also find RPE is capable of consuming ß-HB as levels rise. Using isotopically labeled glucose, amino acid, and fatty acid tracers, we found that carbons from both fatty acids and ketogenic amino acids, but not from glucose, produce ß-HB. Altogether, we substantiate ß-HB secretion in RPE but find that the secretion is equal apically and basally, RPE ß-HB can derive from ketogenic amino acids or fatty acids, and accurate ß-HB assessment requires mass spectrometric analysis.

EndoPRS: Incorporating Endophenotype Information to Improve Polygenic Risk Scores for Clinical Endpoints.

Polygenic risk score (PRS) prediction of complex diseases can be improved by leveraging related phenotypes. This has motivated the development of several multi-trait PRS methods that jointly model information from genetically correlated traits. However, these methods do not account for vertical pleiotropy between traits, in which one trait acts as a mediator for another. Here, we introduce endoPRS, a weighted lasso model that incorporates information from relevant endophenotypes to improve disease risk prediction without making assumptions about the genetic architecture underlying the endophenotype-disease relationship. Through extensive simulation analysis, we demonstrate the robustness of endoPRS in a variety of complex genetic frameworks. We also apply endoPRS to predict the risk of childhood onset asthma in UK Biobank by leveraging a paired GWAS of eosinophil count, a relevant endophenotype. We find that endoPRS significantly improves prediction compared to many existing PRS methods, including multi-trait PRS methods, MTAG and wMT-BLUP, which suggests advantages of endoPRS in real-life clinical settings.

Guideline for reporting systematic reviews of outcome measurement instruments (OMIs): PRISMA-COSMIN for OMIs 2024.

PURPOSE: Although comprehensive and widespread guidelines on how to conduct systematic reviews of outcome measurement instruments (OMIs) exist, for example from the COSMIN (COnsensus-based Standards for the selection of health Measure- ment INstruments) initiative, key information is often missing in published reports. This article describes the development of an extension of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline: PRISMA-COSMIN for OMIs 2024. METHODS: The development process followed the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) guidelines and included a literature search, expert consultations, a Delphi study, a hybrid workgroup meeting, pilot testing, and an end-of-project meeting, with integrated patient/public involvement. RESULTS: From the literature and expert consultation, 49 potentially relevant reporting items were identified. Round 1 of the Delphi study was completed by 103 panelists, whereas round 2 and 3 were completed by 78 panelists. After 3 rounds, agreement (≥ 67%) on inclusion and wording was reached for 44 items. Eleven items without consensus for inclusion and/or wording were discussed at a workgroup meeting attended by 24 participants. Agreement was reached for the inclusion and wording of 10 items, and the deletion of 1 item. Pilot testing with 65 authors of OMI systematic reviews further improved the guideline through minor changes in wording and structure, finalized during the end-of-project meeting. The final check- list to facilitate the reporting of full systematic review reports contains 54 (sub)items addressing the review's title, abstract, plain language summary, open science, introduction, methods, results, and discussion. Thirteen items pertaining to the title and abstract are also included in a separate abstract checklist, guiding authors in reporting for example conference abstracts. CONCLUSION: PRISMA-COSMIN for OMIs 2024 consists of two checklists (full reports; abstracts), their corresponding expla- nation and elaboration documents detailing the rationale and examples for each item, and a data flow diagram. PRISMA- COSMIN for OMIs 2024 can improve the reporting of systematic reviews of OMIs, fostering their reproducibility and allowing end-users to appraise the quality of OMIs and select the most appropriate OMI for a specific application.

The impact of enhanced Milieu teaching with phonological emphasis (EMT + PE) on the speech and language outcomes for toddlers with cleft palate in Brazil and the United States of America.

PURPOSE: The purpose of this study was to compare the speech and language outcomes of children with cleft palate with or without cleft lip (CP+/-L) in the USA to children with CP+/-L in Brazil who underwent intervention with enhanced Milieu teaching with phonological emphasis (EMT + PE), as there are few cross-country intervention comparisons for children with CP+/-L. METHOD: This is a retrospective analysis of 29 participants from the USA and 24 participants from Brazil who were matched on age. The US participants were between the ages of 13-35 months (M = 23.76), spoke Standard American English in the home, and were recruited from East Tennessee State University and Vanderbilt University. The Brazilian participants were between the ages of 20-34 months (M = 25.04), spoke Brazilian Portuguese in the home, and were recruited from the Hospital de Reabilitação de Anomalias Craniofaciais-Universidade de São Paulo. All treatment participants received EMT + PE from trained speech-language pathologists in hospital-university clinics. RESULT: The treatment groups demonstrated greater gains than comparison groups in percent consonants correct, number of different words, and expressive/receptive vocabulary. There was no main effect nor interaction by country. CONCLUSION: The application of EMT + PE in a second culture and language is a viable early intervention option for participants with CP+/-L.

Sensitivity of Magnetic Resonance Imaging in Detection of Choroidal Metastases.

Introduction: The objective of this study was to determine the sensitivity of brain magnetic resonance imaging (MRI) in the detection of choroidal metastasis (CM) from systemic primary cancers. Methods: A retrospective chart review identified patients with clinically confirmed CM seen on the Oncology Service (Byers Eye Institute) between January 2018 and March 2022. Patients had an MRI brain and/or orbits performed within 3 months of CM diagnosis. Evaluation of CM detection by MRI was then divided into two parts: an initial "standard read," where determination of CM detection was based solely on the original radiology report, to reflect real-world performance, and a subsequent "dedicated read," for which a board-certified neuroradiologist, blinded to the laterality and location of the CM, reevaluated the studies to provide an objective "gold standard" interpretation regarding the radiographic detection of CM. Results: The study included 42 eyes of 40 patients with confirmed CM. On standard read, MRI detection of CM occurred in 21 of 42 eyes (50%), with no significant difference between MRI brain and orbit protocols (p = 0.249). Features associated with improved detection were increased tumor basal diameter (p < 0.001) and ultrasonographic tumor thickness (p = 0.003). On dedicated read, MRI detection of CM improved to 26 of 33 eyes (76%; limited to eyes with full complement of pre- and post-gadolinium sequences). Post-gadolinium 3D fluid-attenuated inversion recovery (FLAIR) sequence with fat suppression was the most sensitive (88%) for CM detection. 42% and 58% of lesions were visualized using conventional pre-gadolinium T1- and T2-weighted imaging, respectively. Conclusions: MRI sensitivity to detect CM improved from 50% to 76% with focused reinterpretation. Increased utilization of the post-gadolinium 3D FLAIR sequence and increased ocular scrutiny in cancer patients undergoing brain imaging may facilitate earlier diagnosis of CM.

Characterizing genetic profiles for high triglyceride levels in U.S. patients of African ancestry.

Hypertriglyceridemia (HTG) is a common cardiovascular risk factor characterized by elevated triglyceride (TG) levels. Researchers have assessed the genetic factors that influence HTG in studies focused predominantly on individuals of European ancestry. However, relatively little is known about the contribution of genetic variation of HTG in people of African ancestry (AA), potentially constraining research and treatment opportunities. Our objective was to characterize genetic profiles among individuals of AA with mild-to-moderate HTG and severe HTG versus those with normal TGs by leveraging whole-genome sequencing data and longitudinal electronic health records available in the All of Us program. We compared the enrichment of functional variants within five canonical TG metabolism genes, an AA-specific polygenic risk score for TGs, and frequencies of 145 known potentially causal TG variants between HTG patients and normal TG among a cohort of AA patients (N = 15,373). Those with mild-to-moderate HTG (N = 342) and severe HTG (N ≤ 20) were more likely to carry APOA5 p.S19W (odds ratio = 1.94, 95% confidence interval = [1.48-2.54], P = 1.63 × 10-6 and OR = 3.65, 95% confidence interval: [1.22-10.93], P = 0.02, respectively) than those with normal TG. They were also more likely to have an elevated (top 10%) polygenic risk score, elevated carriage of potentially causal variant alleles, and carry any genetic risk factor. Alternative definitions of HTG yielded comparable results. In conclusion, individuals of AA with HTG were enriched for genetic risk factors compared to individuals with normal TGs.

Dynamic measurements of geographical accessibility considering traffic congestion using open data: a cross-sectional assessment for haemodialysis services in Cali, Colombia.

Background: Many cities with traffic congestion lack accessibility assessments accounting for traffic congestion and equity considerations but have disaggregated georeferenced municipal-level open data on health services, populations, and travel times big data. We convened a multistakeholder intersectoral collaborative group that developed a digital, web-based platform integrating open and big data to derive dynamic spatial-temporal accessibility measurements (DSTAM) for haemodialysis services. We worked with stakeholders and data scientists and considered people's places of residence, service locations, and travel time to the service with the shortest travel time. Additionally, we predicted the impacts of strategically introducing haemodialysis services where they optimise accessibility. Methods: Cross-sectional analyses of DSTAM, accounting for traffic congestion, were conducted using a web-based platform. This platform integrated traffic analysis zones, public census and health services datasets, and Google Distance Matrix API travel-time data. Predictive and prescriptive analytics identified optimal locations for new haemodialysis services and estimated improvements. Primary outcomes included the percentage of residents within a 20-min car drive of a haemodialysis service during peak and free-flow traffic congestion. Secondary outcomes focused on optimal locations to maximise accessibility with new services and potential improvements. Findings were disaggregated by sociodemographic characteristics, providing an equity perspective. The study in Cali, Colombia, used geographic and disaggregated sociodemographic data from the adjusted 2018 Colombian census. Predicted travel times were obtained for two weeks in 2020. Findings: There were substantial traffic variations. Congestion reduced accessibility, especially among marginalised groups. For 6-12 July, free-flow and peak-traffic accessibility rates were 95.2% and 45.0%, respectively. For 23-29 November, free-flow and peak traffic accessibility rates were 89.1% and 69.7%. The locations where new services would optimise accessibility had slight variation and would notably enhance accessibility and health equity. Interpretation: Establishing haemodialysis services in targeted areas has significant potential benefits. By increasing accessibility, it would enhance urban health and equity. Funding: No external or institutional funding was received.

The global relevance of locally grounded ethnobiology.

While ethnobiology is a discipline that focuses on the local, it has an outstanding, but not yet fully realized potential to address global issues. Part of this unrealized potential is that universalistic approaches often do not fully recognize culturally grounded perspectives and there are multiple challenges with scaling up place-based research. However, scalability is paramount to ensure that the intimate and context-specific diversity of human-environmental relationships and understandings are recognized in global-scale planning and policy development. Here, we identify four pathways to enable the scalability of place-based ethnobiological research from the ground up: local-to-global dialogues, aggregation of published data, multi-sited studies, and geospatial analyses. We also discuss some major challenges and consideration to encourage continuous reflexivity in these endeavours and to ensure that scalability does not contribute to unnecessarily decontextualizing, co-opting, or overwriting the epistemologies of Indigenous Peoples and local communities. As ethnobiology navigates multiple scales of time and space and seeks to increase its breadth, this study shows that the use of deliberately global approaches, when carefully nested within rich field-based and ecological and ethnographically grounded data, can contribute to: (1) upscaling case-specific insights to unveil global patterns and dynamics in the biocultural contexts of Indigenous Peoples and local communities; (2) bringing ethnobiological knowledge into resolutions that can influence global environmental research and policy agendas; and (3) enriching ethnobiology's field-based ethos with a deliberate global analytical focus.

Acceptability and Feasibility of Survivorship Group Medical Visits for Breast Cancer Survivors in a Safety Net Hospital.

Providing cost-effective, comprehensive survivorship care remains a significant challenge. Breast cancer survivors (BCS) who have limited income and are from marginalized racial and ethnic groups experience a worse quality of life and report higher distress. Thus, innovative care models are required to address the needs of BCS in low resource settings. Group medical visits (GMV), utilized in chronic disease management, are an excellent model for education and building skills. This single-arm intervention study was conducted at a public hospital in California. GMVs consisted of five 2-h weekly sessions focused on survivorship care planning, side effects of treatment and prevention, emotional health, sexual health, physical activity, and diet. The patient navigators recruited three consecutive GMV groups of six English-speaking BCS (N = 17). A multidisciplinary team delivered GMVs, and a patient navigator facilitated all the sessions. We used attendance rates, pre- and post-surveys, and debriefing interviews to assess the feasibility and acceptability of the intervention. We enrolled 18 BCS. One participant dropped out before the intervention started, 17 BCS consistently attended and actively participated in the GMV, and 76% (13) attended all planned sessions. Participants rated GMVs in the post-survey and shared their support for GMVs in debriefing interviews. The BCS who completed the post-survey reported that GMVs increased their awareness, confidence, and knowledge of survivorship care. GMVs were explicitly designed to address unmet needs for services necessary for survivorship care but not readily available in safety net settings. Our pilot data suggest that patient-navigator-facilitated GMVs are a feasible and acceptable model for integrating survivorship care in public hospitals.

Exome sequencing implicates ancestry-related Mendelian variation at SYNE1 in childhood-onset essential hypertension.

Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope protein 1 (SYNE1), a cardiovascular candidate gene, in 3 of 16 families with early-onset COEH without an antecedent family history. By leveraging exome sequence data from an additional 48 COEH families, 1,700 in-house trios, and publicly available data sets, we demonstrate that compound heterozygous SYNE1 variation in these COEH individuals occurred more often than expected by chance and that this class of biallelic rare variation was significantly enriched among individuals of African genetic ancestry. Using in vitro shRNA knockdown of SYNE1, we show that reduced SYNE1 expression resulted in a substantial decrease in the elasticity of smooth muscle vascular cells that could be rescued by pharmacological inhibition of the downstream RhoA/Rho-associated protein kinase pathway. These results provide insights into the molecular genetics and underlying pathophysiology of COEH and suggest a role for precision therapeutics in the future.

Local Anesthetic Systemic Toxicity (LAST): More Common Than You Think.

The number of anesthetic body procedures in the United States is rapidly increasing, with many being performed on an outpatient basis. These procedures are advertised as being safe, and many times the serious complications may not be discussed. Although local anesthetic systemic toxicity is a rare complication, it is associated with an increase in morbidity. The emergency department staff should be aware of the possibility of this rare complication, as well as the variety of resulting symptoms (from minor to severe), potential sequelae, and appropriate management for patients who have undergone an outpatient anesthetic body procedure. Multiple factors contribute to the development of local anesthetic systemic toxicity, resulting in life-threatening effects on the neurologic and cardiovascular systems. Also, the site of administration, along with the local anesthetic agent used, can impact the risk of the development of local anesthetic systemic toxicity. To minimize the risk and ensure the best possible outcome for these patients, emergency department staff must be highly aware of the mechanisms, risk factors, prevention, and management/treatment of local anesthetic systemic toxicity.

The Loss of an Orphan Nuclear Receptor NR2E3 Augments Wnt/ß-catenin Signaling via Epigenetic Dysregulation that Enhances Sp1-ß catenin-p300 Interactions in Hepatocellular Carcinoma.

The orphan nuclear receptor NR2E3 (Nuclear receptor subfamily 2 group E, Member 3) is an epigenetic player that modulates chromatin accessibility to activate p53 during liver injury. Nonetheless, a precise tumor suppressive and epigenetic role of NR2E3 in hepatocellular carcinoma (HCC) development remains unclear. HCC patients expressing low NR2E3 exhibit unfavorable clinical outcomes, aligning with heightened activation of the Wnt/ß-catenin signaling pathway. The murine HCC models utilizing NR2E3 knockout mice consistently exhibits accelerated liver tumor formation accompanied by enhanced activation of Wnt/ß-catenin signaling pathway and inactivation of p53 signaling. At cellular level, the loss of NR2E3 increases the acquisition of aggressive cancer cell phenotype and tumorigenicity and upregulates key genes in the WNT/ß-catenin pathway with increased chromatin accessibility. This event is mediated through increased formation of active transcription complex involving Sp1, ß-catenin, and p300, a histone acetyltransferase, on the promoters of target genes. These findings demonstrate that the loss of NR2E3 activates Wnt/ß-catenin signaling at cellular and organism levels and this dysregulation is associated with aggressive HCC development and poor clinical outcomes. In summary, NR2E3 is a novel tumor suppressor with a significant prognostic value, maintaining epigenetic homeostasis to suppress the Wnt/ß-catenin signaling pathway that promotes HCC development.