Long-term ambient sulfur dioxide exposure during gestation and preterm birth in North Carolina, 2003-2015.

BACKGROUND: Coal-fired power plants are major contributors of ambient sulfur dioxide (SO2) air pollution. Epidemiological literature suggests an adverse association between SO2 exposure during gestation and preterm birth (PTB; <37 weeks completed gestation). PTB is strongly associated with infant mortality and increased risk for later life morbidities. OBJECTIVE: We investigated associations between SO2 and PTB in North Carolina and evaluated whether the associations were modified by race/ethnicity. METHODS: We assembled a retrospective, administrative cohort of singleton births in North Carolina from 2003-2015. We used US EPA EQUATES data to assign long-term SO2 gestational exposures to eligible births for the entire pregnancy and by trimester. We used multivariable generalized linear regression to estimate risk differences (RD (95%CI)) per 1-ppb increase in SO2, adjusted for gestational parent education, Medicaid status, marital status, and season of conception. Multi-pollutant models were additionally adjusted for other criteria air co-pollutants (O3, PM2.5, NO2). RESULTS: The median SO2 (24-hour average) across exposure windows was ~1.5 (IQR: 1.8) ppb. The overall baseline risk for PTB was 8,756 per 100,000 live births. When stratified by race/ethnicity, the baseline risk for PTB was 12215, 7824, and 7187 per 100,000 live births among non-Hispanic Black, non-Hispanic white, and Hispanic births, respectively. RDs per 1-ppb increase in SO2 averaged across the entire pregnancy were 317.0 (95%CI: 279.4, 354.5) and 568.2 (95%CI: 500.3, 636.1) per 100,000 live births for single- and multi-pollutant models, respectively. For the PTB multi-pollutant models, we observed similar RDs for non-Hispanic Black participants (669.6 [95%CI: 573.9, 765.2]) and non-Hispanic white participants (635.4 [95%CI: 557.2, 713.6]) with smaller RDs for Hispanic participants (336.8 [95%CI: 241.3, 432.2]). SIGNIFICANCE: The results for our adjusted single- and multi-pollutant models showed adverse associations between SO2 and PTB, with some evidence of effect measure modification by race/ethnicity within subcategories of PTB.

Voluntary wheel running access produces opposite effects in male and female rats on both palatable diet consumption and associated ventral striatal opioid- and dopamine-related gene expression.

The relationship between physical activity levels and feeding behaviors has been a focus of preclinical research for decades, yet this interaction has only recently been explored for potential sex differences. The aim of the present study was to isolate sex-dependent effects of voluntary wheel running (RUN) vs. sedentary locked wheel (SED) home cage conditions on palatability-driven feeding behavior using a 2-diet choice task between standard chow and a high-fat diet. The sex-dependent effects of physical activity on feeding behavior were examined following a within-subject novel reversal design of physical activity conditions (i.e., RUN > SED > RUN), to assess temporal sensitivity of the interaction. Following the final 2 weeks of reestablished and sustained RUN vs. SED conditions in separate groups of both males and females, reward-related opioid and dopamine gene expression within the nucleus accumbens (Acb) brain region were analyzed. Results demonstrated that the initial RUN > SED transition led to sex-dependent effects of SED condition, as males increased, and females decreased their high fat consumption, compared to their respective high fat consumption during previous RUN condition phase. Following reintroduction to the RUN condition, males decreased, and females increased their high fat consumption, compared to their separate SED control group. Last, sex-dependent shifts in ventral striatal opioid- and dopamine-related gene expression were observed to parallel the behavioral effects. The major findings of the study reveal that SED and RUN home cage conditions shift palatability-driven feeding in the opposite direction for males and females, these effects are sensitive to reversal, and these sex-dependent feeding behaviors track sex-dependent changes to critical reward-related gene expression patterns in the Acb. Considering the present high rates of sedentary behavior and obesity, furthering our understanding of the interaction between physical activity (or lack thereof) and feeding behavior should be a priority, especially in the context of these divergent sex-dependent outcomes.

High Above Knee Amputations for Femoral Osteosarcomas Treated with Free Microsurgical Tibial Reconstruction in the Pediatric Population.

SUMMARY: Improvements in the management of pediatric sarcoma including imaging, neo- and adjuvant therapy, and surgical technique has enhanced long-term survival of patients. Pediatric patients diagnosed with a femoral osteosarcoma undergoing oncologic resection who are ineligible for limb preservation reconstruction or rotationplasty are offered an above knee amputation (AKA). Limb amputations in the skeletally immature patient poses particular problems specific to endosteal bone overgrowth and spiking. Approximately half of these patients undergo revision of their amputation site. Furthermore, a high AKA often requires a hip-based prosthesis, which can be uncomfortable leading to poorer outcomes and higher energy expenditures.We have completed four 'spare parts' microvascular free tibial transfers for pediatric patients diagnosed with femoral osteosarcoma who were treated with an AKA. Two of these patients are currently ambulatory with their prosthetic and have not required long-term revision of their amputation site. One patient demonstrated radiographic evidence of bony union four months post-operatively, but subsequently succumbed to chemotherapy-resistant metastases. The fourth patient is in the process of prosthetic fitting and rehabilitation.This is a novel technique and the first series describing both proximal and distal free microvascular tibial bone transfers as a reconstructive option for pediatric patients with femoral osteosarcomas. It is a reliable flap with possible variations in vascular anatomy. Furthermore, it offers multiple benefits including the prevention of bony spiking, AKA stump augmentation, and facilitation of appropriate prosthetic fitting improving functional outcomes and decreased energy expenditure. However, the soft tissue coverage must be well planned.

Biodiversity in changing environments: An external-driver internal-topology framework to guide intervention.

Accompanying the climate crisis is the more enigmatic biodiversity crisis. Rapid reorganization of biodiversity due to global environmental change has defied prediction and tested the basic tenets of conservation and restoration. Conceptual and practical innovation is needed to support decision making in the face of these unprecedented shifts. Critical questions include: How can we generalize biodiversity change at the community level? When are systems able to reorganize and maintain integrity, and when does abiotic change result in collapse or restructuring? How does this understanding provide a template to guide when and how to intervene in conservation and restoration? To this end, we frame changes in community organization as the modulation of external abiotic drivers on the internal topology of species interactions, using plant-plant interactions in terrestrial communities as a starting point. We then explore how this framing can help translate available data on species abundance and trait distributions to corresponding decisions in management. Given the expectation that community response and reorganization are highly complex, the external-driver internal-topology (EDIT) framework offers a way to capture general patterns of biodiversity that can help guide resilience and adaptation in changing environments.

The mobile everyday cognition scale (mECog): development and pilot testing.

Objective: Subjective cognitive decline (SCD) is an important part of the aging process and may be a sign of neurodegenerative disease. Current measures of SCD are subject to the limits of retrospective recall of symptoms over a long span of time, which might be addressed by using ecological momentary assessment (EMA) methods. However, there are no currently available measures of SCD validated for use in EMA. Thus, our goal was to develop and pilot test the mobile Everyday Cognition Scale (mECog). Method: 31 community-dwelling older adults completed in lab measures of cognition and mental health symptoms, followed by daily mECog ratings on a smart phone for 28 days. Results: Most participants completed at least 75% of mECog assessments (n = 27, 87%), and the average number of assessments completed was 22. Further, respondents rated the mobile assessment platform and measures as easy to use and non-interfering with daily life. Test-retest reliability of mECog scores was very strong (RKRN = .99), and within-person reliability was moderate (RCN = .41). mECog scores demonstrated strong positive associations with scores from the original ECog (ρ = .62-69, p < .001) and short form ECog (ρ = .63-.69, p < .001) and non-significant associations with demographics (ρ = -0.25-.04, p = .21-.94) and mental health symptoms (ρ = -0.06-.34, p = .08-.99). mECog scores also exhibited small-to-moderate negative correlations with objective cognitive test scores, though these relationships did not reach statistical significance (ρ = -0.32 to -0.22, p = .10-.27). Conclusions: Results suggest that mobile assessment of SCD via the mECog is feasible and acceptable. Further, mECog scores demonstrated good psychometric properties, including evidence of strong reliability, convergent validity, and divergent validity.

Corrigendum: Sex differences in the genetics of sarcoidosis across European and African ancestry populations.

[This corrects the article DOI: 10.3389/fmed.2023.1132799.].

Sex-specific effects of injury and beta-adrenergic activation on metabolic and inflammatory mediators in a murine model of post-traumatic osteoarthritis.

OBJECTIVE: Metabolic processes are intricately linked to the resolution of innate inflammation and tissue repair, two critical steps for treating post-traumatic osteoarthritis (PTOA). Based on lipolytic and immunoregulatory actions of norepinephrine, we hypothesized that intra-articular ß-adrenergic receptor (ßAR) stimulation would suppress PTOA-associated inflammation in the infrapatellar fat pad (IFP) and synovium. DESIGN: We used the ßAR agonist isoproterenol to perturb intra-articular metabolism 3.5 weeks after applying a non-invasive single-load compression injury to knees of 12-week-old male and female mice. We examined the acute effects of intra-articular isoproterenol treatment relative to saline on IFP histology, multiplex gene expression of synovium-IFP tissue, synovial fluid metabolomics, and mechanical allodynia. RESULTS: Injured knees developed PTOA pathology characterized by heterotopic ossification, articular cartilage loss, and IFP atrophy and fibrosis. Isoproterenol suppressed the upregulation of pro-fibrotic genes and downregulated the expression of adipose genes and pro-inflammatory genes (Adam17, Cd14, Icam1, Csf1r, and Casp1) in injured joints of female (but not male) mice. Analysis of published single-cell RNA-seq data identified elevated catecholamine-associated gene expression in resident-like synovial-IFP macrophages after injury. Injury substantially altered synovial fluid metabolites by increasing amino acids, peptides, sphingolipids, phospholipids, bile acids, and dicarboxylic acids, but these changes were not appreciably altered by isoproterenol. Intra-articular injection of either isoproterenol or saline increased mechanical allodynia in female mice, whereas neither substance affected male mice. CONCLUSIONS: Acute ßAR activation altered synovial-IFP transcription in a sex and injury-dependent manner, suggesting that women with PTOA may be more sensitive than men to treatments targeting sympathetic neural signaling pathways.

Cell Cycle-Dependent TICRR/TRESLIN and MTBP Chromatin Binding Mechanisms and Patterns.

The selection of replication origins is a defining characteristic of DNA replication in eukaryotes, yet its mechanism in humans has not been well-defined. In this study, we use Cut&Run to examine genomic binding locations for TICRR/TRESLIN and MTBP, the human orthologs for the yeast DNA replication initiation factors Sld3 and Sld7. We mapped TRESLIN and MTBP binding in HCT116 colorectal cancer cells using asynchronous and G1 synchronized populations. Our data show that TRESLIN and MTBP binding patterns are more defined in a G1 synchronized population compared to asynchronously cycling cells. We also examined whether TRESLIN and MTBP are dependent on one another for binding. Our data suggest MTBP is dependent on TRESLIN for proper association with chromatin during G1 but not S phase. Finally, we asked whether TRESLIN and MTBP binding to chromatin requires licensed origins. Using cell lines with a non-degradable inducible Geminin to inhibit licensing, we show TRESLIN and MTBP binding does not require loaded MCMs. Altogether, our Cut&Run data provides evidence for a chromatin binding mechanism of TRESLIN-MTBP during G1 that is dependent on TRESLIN and does not require interactions with licensed origins.

Flowering time responses to warming drive reproductive fitness in a changing Arctic.

BACKGROUND AND AIMS: The Arctic is warming at an alarming rate, leading to earlier spring conditions and plant phenology. It is often unclear to what degree changes in reproductive fitness (flower, fruit, seed production) are a direct response to warming versus an indirect response through shifting phenology. This study aims to quantify the relative importance of these direct and indirect pathways and project the net effects of warming on plant phenology and reproductive fitness under current and future climate scenarios. METHODS: We used two long-term datasets on twelve tundra species in the Canadian Arctic as part of the International Tundra Experiment (ITEX). Phenology and reproductive fitness were recorded annually on tagged individual plants at both Daring Lake, Northwest Territories (64.87, -111.58) and Alexandra Fiord, Nunavut (78.83, -75.80). Plant species encompass a wide taxonomic diversity across a range of plant functional types with circumpolar/boreal distributions. We use Hierarchical Bayesian Structural Equation models to compare the direct and indirect effects of climate warming on phenology and reproductive fitness across species, sites and years. KEY RESULTS: We find that warming, both experimental and ambient, drives earlier flowering across species, which leads to higher numbers of flowers and fruits produced, reflecting directional phenotypic selection for earlier flowering phenology. Furthermore, this indirect effect of climate warming mediated through phenology was generally ~2-3x stronger than the direct effect of climate on reproductive fitness. Under future climate predictions, individual plants showed a ~2 to 4.5-fold increase in their reproductive fitness (flower counts) with advanced flowering phenology. CONCLUSIONS: Our results suggest that, on average, the benefits of early flowering, such as increased development time and subsequent enhanced reproductive fitness, may outweigh its risks. Overall, this work provides important insights into population-level consequences of phenological shifts in a warming Arctic over multi-decadal time scales.

Social barriers to safe sanitation access among housed populations in the United States: A systematic review.

BACKGROUND: Nearly six million people residing in the United States do not have access to safely managed sanitation. Housed populations may lack access to centralized wastewater treatment systems or functioning onsite wastewater treatment systems, which subsequently places them at higher risk for adverse health outcomes associated with unsafe sanitation. OBJECTIVES: We sought to understand the various social barriers that impact access to safe sanitation in the United States. METHODS: We included peer-reviewed studies published between January 2000 and March 2023. The publication search was conducted using Scopus, ProQuest Social Science Database, and HeinOnline. We extracted data on social barriers and physical factors associated with access to sanitation. RESULTS: Twenty publications met the inclusion criteria, and data relating to 11 social barriers and two physical factors were extracted. The social barriers to safe sanitation access mentioned most frequently were found to be socioeconomic status and race-based discrimination. Studies discussed sanitation in communities in five states. DISCUSSION: Barriers pertained to lack of access to centralized wastewater treatment system, inadequate repair or replacement of septic systems, and lack of safely managed onsite sanitation systems. We discuss the intersectionality of the barriers, the underlying policy and history that leads to them, and make recommendations to address inequitable access to safe sanitation. Legislation and policy must be critically reviewed at national, state, and local levels to limit or eliminate ability for utilities to be extended on the basis of a community's income and property values or racial makeup. Policy recommendations also include additional community engagement, onsite sanitation system monitoring, and knowledge dissemination and education of septic system users. More geographically diverse research and research on sanitation in specific communities such as those of migrant farmworkers, undocumented persons, and tenants are recommended.

Differences in transcription initiation directionality underlie distinctions between plants and animals in chromatin modification patterns at genes and cis-regulatory elements.

Transcriptional initiation is among the first regulated steps controlling eukaryotic gene expression. High-throughput profiling of fungal and animal genomes has revealed that RNA Polymerase II often initiates transcription in both directions at the promoter transcription start site, but generally only elongates productively into the gene body. Additionally, Pol II can initiate transcription in both directions at cis-regulatory elements such as enhancers. These bidirectional RNA Polymerase II initiation events can be observed directly with methods that capture nascent transcripts, and they are also revealed indirectly by the presence of transcription-associated histone modifications on both sides of the transcription start site or cis-regulatory elements. Previous studies have shown that nascent RNAs and transcription-associated histone modifications in the model plant Arabidopsis thaliana accumulate mainly in the gene body, suggesting that transcription does not initiate widely in the upstream direction from genes in this plant. We compared transcription-associated histone modifications and nascent transcripts at both transcription start sites and cis-regulatory elements in A. thaliana, Drosophila melanogaster, and Homo sapiens. Our results provide evidence for mostly unidirectional RNA Polymerase II initiation at both promoters and gene-proximal cis-regulatory elements of A. thaliana, whereas bidirectional transcription initiation is observed widely at promoters in both D. melanogaster and H. sapiens, as well as cis-regulatory elements in Drosophila. Furthermore, the distribution of transcription-associated histone modifications around transcription start sites in the Oryza sativa (rice) and Glycine max (soybean) genomes suggests that unidirectional transcription initiation is the norm in these genomes as well. These results suggest that there are fundamental differences in transcriptional initiation directionality between flowering plant and metazoan genomes, which are manifested as distinct patterns of chromatin modifications around RNA polymerase initiation sites.

Replacement of Arabidopsis H2A.Z with human H2A.Z orthologs reveals extensive functional conservation and limited importance of the N-terminal tail sequence for Arabidopsis development.

The incorporation of histone variants, distinct paralogs of core histones, into chromatin affects all DNA-templated processes in the cell, including the regulation of transcription. In recent years, much research has been focused on H2A.Z, an evolutionarily conserved H2A variant found in all eukaryotes. In order to investigate the functional conservation of H2A.Z histones during eukaryotic evolution we transformed h2a.z deficient plants with three human H2A.Z proteins to assess their ability to rescue the mutant defects. We discovered that human H2A.Z.1 and H2A.Z.2.1 fully complement the phenotypic abnormalities of h2a.z plants despite the fact that Arabidopsis and human H2A.Z N-terminal tail sequences are quite divergent. In contrast, the brain-specific splice variant H2A.Z.2.2 has a dominant-negative effect in wild-type plants. Furthermore, H2A.Z.1 almost completely re-establishes normal H2A.Z chromatin occupancy in h2a.z plants and restores the transcript levels of more than 84 % of misexpressed genes. Finally, our hypothesis that the N-terminal tail of Arabidopsis H2A.Z is not crucial for its developmental functions was supported by the ability of N-terminal end truncations of Arabidopsis HTA11 to largely rescue the defects of h2a.z mutants.

Differences in transcription initiation directionality underlie distinctions between plants and animals in chromatin modification patterns at genes and cis-regulatory elements.

Transcriptional initiation is among the first regulated steps controlling eukaryotic gene expression. High-throughput profiling of fungal and animal genomes has revealed that RNA Polymerase II (Pol II) often initiates transcription in both directions at the promoter transcription start site (TSS), but generally only elongates productively into the gene body. Additionally, Pol II can initiate transcription in both directions at cis-regulatory elements (CREs) such as enhancers. These bidirectional Pol II initiation events can be observed directly with methods that capture nascent transcripts, and they are also revealed indirectly by the presence of transcription-associated histone modifications on both sides of the TSS or CRE. Previous studies have shown that nascent RNAs and transcription-associated histone modifications in the model plant Arabidopsis thaliana accumulate mainly in the gene body, suggesting that transcription does not initiate widely in the upstream direction from genes in this plant. We compared transcription-associated histone modifications and nascent transcripts at both TSSs and CREs in Arabidopsis thaliana, Drosophila melanogaster, and Homo sapiens. Our results provide evidence for mostly unidirectional Pol II initiation at both promoters and gene-proximal CREs of Arabidopsis thaliana, whereas bidirectional transcription initiation is observed widely at promoters in both Drosophila melanogaster and Homo sapiens, as well as CREs in Drosophila. Furthermore, the distribution of transcription-associated histone modifications around TSSs in the Oryza sativa (rice) and Glycine max (soybean) genomes suggests that unidirectional transcription initiation is the norm in these genomes as well. These results suggest that there are fundamental differences in transcriptional initiation directionality between flowering plant and metazoan genomes, which are manifested as distinct patterns of chromatin modifications around RNA polymerase initiation sites.

Species-Specific Responses to Human Trampling Indicate Alpine Plant Size Is More Sensitive than Reproduction to Disturbance.

Human disturbance, such as trampling, is an integral component of global change, yet we lack a comprehensive understanding of its effects on alpine ecosystems. Many alpine systems are seeing a rapid increase in recreation and in understudied regions, such as the Coast Mountains of British Columbia, yet disturbance impacts on alpine plants remain unclear. We surveyed disturbed (trail-side) and undisturbed (off-trail) transects along elevational gradients of popular hiking trails in the T'ak't'ak'múy'in tl'a In'inyáxa7n region (Garibaldi Provincial Park), Canada, focusing on dominant shrubs (Phyllodoce empetriformis, Cassiope mertensiana, Vaccinium ovalifolium) and graminoids (Carex spp). We used a hierarchical Bayesian framework to test for disturbance by elevation effects on total plant percent cover, maximum plant height and diameter (growth proxies), and buds, flowers, and fruits (reproduction proxies). We found that trampling reduces plant cover and impacts all species, but that effects vary by species and trait, and disturbance effects only vary with elevation for one species' trait. Growth traits are more sensitive to trampling than reproductive traits, which may lead to differential impacts on population persistence and species-level fitness outcomes. Our study highlights that disturbance responses are species-specific, and this knowledge can help land managers minimize disturbance impacts on sensitive vegetation types.

COVID-19 Testing of United States-Bound Agricultural Workers in Mexico.

The COVID-19 pandemic presents global health, welfare, and economic concerns. The agricultural workforce has experienced adverse effects, placing the U.S. food supply at risk. Agricultural workers temporarily travel to the United States on H-2A visas to supplement the agricultural workforce. Approximately 300,000 agricultural workers enter the United States with H-2A visas each year; over 90.0% are from Mexico. During February-May 2021, a COVID-19 testing pilot was performed with Clínica Médica Internacional (CMI), a clinic that performs medical examinations for US-bound immigrants, to determine the SARS-CoV-2 infection status of H-2A agricultural workers in Mexico before entry to the US. The CerTest VIASURE Real Time PCR Detection Kit was used. Participants' demographic information, test results, and testing turnaround times were collected. Workers who tested positive for SARS-CoV-2 completed isolation before US entry. During the pilot, 1195 H-2A workers were tested; 15 (1.3%) tested positive. Average reporting time was 31 h after specimen collection. This pilot demonstrated there is interest from H-2A employers and agents in testing the H-2A community before US entry. Testing for SARS-CoV-2 can yield public health benefit, is feasible, and does not delay entry of temporary agricultural workers to the US.

Dissociative identity precipitated by emergence from general anesthesia: A case report and analytical framework.

Background: Dissociative identity disorder (DID) is a complex and controversial psychiatric condition in which one person maintains at least two separate and distinct personalities. Patients with DID often report a history of childhood abuse and may have other comorbid psychiatric conditions. Psychosocial stressors may be triggers for DID inception or recurrence. While anesthetic agents, in particular ketamine, may induce a temporary dissociative state, it has not yet been reported that anesthesia can precipitate a dissociative identity. Case report: We report a case of a woman with a history of childhood sexual abuse and past suicide attempt who experienced an episode of dissociative identity on emergence from anesthesia. The episode resolved within 90 minutes and the patient was discharged home safely on hospital day two. Conclusion: This case adds to the literature of potentially precipitating factors of DID and we provide a unifying mechanistic hypothesis linking anesthesia to functional brain connectivity.

Presence of Perfluoroalkyl Substances in Landfill Adjacent Surface Waters in North Carolina.

Landfills pose an important public health risk, especially in historically disenfranchised communities that are disproportionately sited for landfills and in rural areas where private wells may be impacted. Landfills are major sources of perfluoroalkyl substances (PFAS) that migrate into the surrounding environment. This study characterized PFAS in surface waters adjacent to two landfills, one in Sampson County (SC) and one in Orange County (OC) in North Carolina. In addition to municipal solid waste and construction and demolition waste, the landfill in SC accepts industrial sludge from a chemical plant that produces proprietary PFAS. Over four months, 35 surface water samples were collected at upstream, landfill-adjacent, and downstream/downgradient sites. Thirty-four PFAS were analyzed using liquid chromatography with tandem mass spectroscopy. Of those, six novel and six legacy PFAS were detected. Legacy PFAS were detected in surface water near both landfills, with the highest concentrations adjacent to the landfill. Novel PFAS were only detected in surface water near the SC landfill and showed the highest concentrations adjacent to the landfill, indicating offsite migration of PFAS. These findings support the need for more comprehensive and frequent monitoring of groundwater and surface water wells near landfills and stricter regulation regarding the landfilling of industrial materials.

Multiple Correspondence Analysis and HLA-Associations of Organ Involvement in a Large Cohort of African-American and European-American Patients with Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease with predominant pulmonary involvement and vast heterogeneity of clinical manifestations and disease outcomes. African American (AA) patients suffer greater morbidity and mortality. Using Multiple Correspondence Analysis, we identified seven clusters of organ involvement in European American (EA; n = 385) patients which were similar to those previously described in a Pan-European (GenPhenReSa) and a Spanish cohort (SARCOGEAS). In contrast, AA (n = 987) had six, less well-defined and overlapping clusters with little similarity to the cluster identified in the EA cohort evaluated at the same U.S. institutions. Association of cluster membership with two-digit HLA-DRB1 alleles demonstrated ancestry-specific patterns of association and replicated known HLA effects.These results further support the notion that genetically influenced immune risk profiles, which differ based on ancestry, play a role in phenotypic heterogeneity. Dissecting such risk profiles will move us closer to personalized medicine for this complex disease.

Sex differences in the genetics of sarcoidosis across European and African ancestry populations.

Background: Sex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren's syndrome (LS) and non-Löfgren's syndrome (non-LS). Methods: A meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by an SNP lookup in the UK Biobank (UKB, n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex. Results: We identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and ANXA11. Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified. Conclusion: Our findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis.