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Jennifer Vandooren,1 Nele Berghmans,1 Chris Dillen,1 Ilse Van Aelst,1 Isabelle Ronsse,1 Liron Limor Israel,2 Ina Rosenberger,3 Jörg Kreuter,3 Jean-Paul Lellouche,2 Shulamit Michaeli,4 Erica Locatelli,5 Mauro Comes Franchini,5 Miren K Aiertza,6 Laura Sánchez-Abella,6 Iraida Loinaz,6 Dylan R Edwards,7 Louis Shenkman,8 Ghislain Opdenakker1 1Rega Institute for Medical Research, University of Leuven, Leuven, Belgium; 2Department of Chemistry and Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan, Tel Aviv, Israel; 3Institut für Pharmazeutische Technologie, Johann Wolfgang Goethe-Universität, Frankfurt, Germany; 4The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat Gan, Tel Aviv, Israel; 5Department of Industrial Chemistry Toso Montanari, University of Bologna, Bologna, Italy; 6New Materials Department, Fundación CIDETEC, San Sebastián, Spain; 7School of Biological Sciences, University of East Anglia, Norwich, UK; 8Tel Aviv University, Ramat Aviv, Tel Aviv, Israel Abstract: The need for test systems for nanoparticle biocompatibility, toxicity, and inflammatory or adaptive immunological responses is paramount. Nanoparticles should be free of microbiological and chemical contaminants, and devoid of toxicity. Nevertheless, in the absence of contamination, these particles may still induce undesired immunological effects in vivo, such as enhanced autoimmunity, hypersensitivity reactions, and fibrosis. Here we show that artificial particles of specific sizes affect immune cell recruitment as tested in a dermal air pouch model in mice. In addition, we demonstrate that the composition of nanoparticles may influence immune cell recruitment in vivo. Aside from biophysical characterizations in terms of hydrodynamic diameter, zeta potential, concentration, and atomic concentration of metals, we show that – after first-line in vitro assays – characterization of cellular and molecular effects by dermal air pouch analysis is straightforward and should be included in the quality control of nanoparticles. We demonstrate this for innate immunological effects such as neutrophil recruitment and the production of immune-modulating matrix metalloproteases such as MMP-9; we propose the use of air pouch leukocytosis analysis as a future standard assay. Keywords: nanoparticles, biocompatibility, toxicity, air pouch, immunologyA Letter to the Editor has been received and published for this article.

Lymphatic malformations [LM] are benign hamartomatous growths that reflect abnormal development of lymphatic channels. They primarily affect children & young adults but may occur at any age and in any location. 75% of all LM are diagnosed in the H&N. This research was performed with multi-institutional collaboration when the demographics of 23 cases of H&N lymphangiomas/LM were retrospectively reviewed, including one case from the max. sinus which is considered rare. 9 [39.1%] and 14 [60.8%] occurred in males & females respectively, with an age range of "6-88" y.o. Lesions ranged from 1.5 mm to 40 mm in size. One LM involved each of the max. sinus, submand. space, neck, and cervicothoracic region. 19 [82.6%] cases occurred intraorally; tongue [8]: 4-R&L lateral, 3-dorsal, 1-base], followed by gingiva [6], buccal mucosa [2], soft palate [2], and labial mucosa [1 case]. All cases were surgically excised except one managed with IMRT. Post-management follow-up was documented in 9 [39.13%] showing no recurrence but was not available in [52.1%] of cases. Lesions were clinically interpreted as various entities. The diagnosis was histologically confirmed in all cases. As in hemangiomas, it is a dilemma to classify lymphangiomas as true neoplasms, hamartomas, or lymphangiectasias. For practical purposes, the distinction is of little value knowing all lesions are benign and management is related to location and clinical extent. The (ISSVA) in 2018, separated vascular anomalies into tumors and malformations, where the latter included lymphatic malformations (LM). LM may be divided into congenital and acquired, clinically separated into superficial and deeply seated, or macrocytic, microcystic, or an admixture of both types based on size, respectively. Little or no difference exists in the histomorphologic features between these categories. We present the demographics in a series of H&N LM, imaging characteristics, and updated review of the entity. [ABSTRACT FROM AUTHOR]

This article addresses some of the issues arising from the continuing research and debate on open access (OA) publishing, primarily from the perspective of an academic in the field of humanities. As an academic, the author feels it is essential that scholars embrace the responsibility of being part of the process that reconsiders how to publish their research, and that they recognize they have a key role to play amongst a variety of stakeholders. The launch of the Open Library of Humanities (OLH) in early 2013 and its growing momentum as a scholarly-led movement over the last 12 months demonstrates that there is an increasing awareness amongst the academic community in the humanities of what is required to build a new kind of publishing model. Aspects of this 'do-it-yourself' culture are considered along with various funding options, concluding with a look at international challenges facing the transformation towards open access and where the OLH fits into the picture. [ABSTRACT FROM AUTHOR]

Objective: We systematically reviewed the effectiveness of progestogens for prevention of preterm birth among women with prior spontaneous preterm birth, multiple gestations, preterm labor, short cervix, or other indications.Data Sources: We searched MEDLINE and EMBASE databases for English language articles published from January 1966 to October 2011.Methods Of Study Selection: We excluded publications that were not randomized controlled trials or had fewer than 20 participants, identifying 34 publications, of which 19 contained data for Bayesian meta-analysis.Tabulation, Integration, and Results: Two reviewers independently extracted data and assigned overall quality ratings based on predetermined criteria. Among women with prior preterm birth and a singleton pregnancy (five randomized controlled trials), progestogen treatment decreased the median risk of preterm birth by 22% (relative risk [RR] 0.78, 95% Bayesian credible interval 0.68-0.88) and neonatal death by 42% (RR 0.58, 95% Bayesian credible interval 0.27-0.98). The evidence suggests progestogen treatment does not prevent prematurity (RR 1.02, 95% Bayesian credible interval 0.87-1.17) or neonatal death (RR 1.44, 95% Bayesian credible interval 0.46-3.18) in multiple gestations. Limited evidence suggests progestogen treatment may prevent prematurity in women with preterm labor (RR 0.62, 95% Bayesian credible interval 0.47-0.79) and short cervix (RR 0.52, 95% Bayesian credible interval 0.36-0.70). Across indications, evidence about maternal, fetal, or neonatal health outcomes, other than reducing preterm birth and neonatal mortality, is inconsistent, insufficient, or absent.Conclusion: Progestogens prevent preterm birth when used in singleton pregnancies for women with a prior preterm birth. In contrast, evidence suggests lack of effectiveness for multiple gestations. Evidence supporting all other uses is insufficient to guide clinical care. Overall, clinicians and patients lack longer-term information to understand whether intervention has the ultimately desired outcome of preventing morbidity and promoting normal childhood development. [ABSTRACT FROM AUTHOR]

Objective: To estimate the association between over-the-counter nonsteroidal anti-inflammatory drug (NSAID) exposure during the early first trimester and risk for spontaneous abortion (gestation before 20 weeks of gestation) in a prospective cohort.Methods: Women were enrolled in the Right from the Start study (2004-2010). Exposure data regarding over-the-counter NSAID use from the last menstrual period (LMP) through the sixth week of pregnancy were obtained from intake and first-trimester interviews. Pregnancy outcomes were self-reported and verified by medical records. Gestational age was determined from the LMP. Stage of development before loss was determined from study ultrasonography. Cox proportional hazards regression models were used to estimate the association between NSAID exposure and pregnancy outcome taking into account candidate confounders.Results: Among 2,780 pregnancies, 367 women (13%) experienced a spontaneous abortion. NSAID exposure was reported by 1,185 (43%) women. NSAID exposure was not associated with spontaneous abortion risk in unadjusted models (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.82-1.24) or models adjusted for maternal age (adjusted HR 1.00, 95% CI 0.81-1.23).Conclusion: Our findings suggest that use of nonprescription over-the-counter NSAIDs in early pregnancy does not put women at increased risk of spontaneous abortion. [ABSTRACT FROM AUTHOR]

The field of molecular biology is an important part of research into neoplastic conditions. Much of this research requires access to human tissue samples, which may need to be collected and stored in a specific way, according to the type of study for which they are intended. Anonymous clinical information about the samples enables researchers to apply results to different patient groups. Access to stored tissues is particularly important in head and neck disease research as many neoplastic conditions affecting this area have a relatively low incidence. Consequently, it may take a long time to build up enough individual cases to make a study worthwhile.We describe here the current legal, ethical and practical issues of research tissue banking, with regard to head and neck disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE. To profile the messenger RNA (mRNA) expression for the 23 known genes of matrix metalloproteinases (MMPs), 19 genes of ADAMTS, 4 genes of tissue inhibitors of metalloproteinases (TIMPs), and ADAM genes 8, 10, 12, and 17 in normal, painful, and ruptured Achilles tendons. METHODS: Tendon samples were obtained from cadavers or from patients undergoing surgical procedures to treat chronic painful tendinopathy or ruptured tendon. Total RNA was extracted and mRNA expression was analyzed by quantitative real-time reverse transcription-polymerase chain reaction, normalized to 18S ribosomal RNA. RESULTS: In comparing expression of all genes, the normal, painful, and ruptured Achilles tendon groups each had a distinct mRNA expression signature. Three mRNA were not detected and 14 showed no significant difference in expression levels between the groups. Statistically significant (P < 0.05) differences in mRNA expression, when adjusted for age, included lower levels of MMPs 3 and 10 and TIMP-3 and higher levels of ADAM-12 and MMP-23 in painful compared with normal tendons, and lower levels of MMPs 3 and 7 and TIMPs 2, 3, and 4 and higher levels of ADAMs 8 and 12, MMPs 1, 9, 19, and 25, and TIMP-1 in ruptured compared with normal tendons. CONCLUSION: The distinct mRNA profile of each tendon group suggests differences in extracellular proteolytic activity, which would affect the production and remodeling of the tendon extracellular matrix. Some proteolytic activities are implicated in the maintenance of normal tendon, while chronically painful tendons and ruptured tendons are shown to be distinct groups. These data will provide a foundation for further study of the role and activity of many of these enzymes that underlie the pathologic processes in the tendon. [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary cavitation is fundamental to the global success of Mycobacterium tuberculosis. However, the mechanisms of this lung destruction are poorly understood. The biochemistry of lung matrix predicts matrix metalloproteinase (MMP) involvement in immunopathology.Methods: We investigated gene expression of all MMPs, proteins with a disintegrin and metalloproteinase domain, and tissue inhibitors of metalloproteinases in M. tuberculosis-infected human macrophages by real-time polymerase chain reaction. MMP secretion was measured by zymography and Western analysis, and expression in patients with pulmonary tuberculosis was localized by immunohistochemistry.Results: MMP-1 and MMP-7 gene expression and secretion are potently upregulated by M. tuberculosis, and no increase in tissue inhibitor of metalloproteinase expression occurs to oppose their activity. Dexamethasone completely suppresses MMP-1 but not MMP-7 gene expression and secretion. In patients with active tuberculosis, macrophages express MMP-1 and MMP-7 adjacent to areas of tissue destruction. MMP-1 but not MMP-7 expression and secretion are relatively M. tuberculosis specific, are not upregulated by tuberculosis- associated cytokines, and are prostaglandin dependent. In contrast, the vaccine M. bovis bacillus Calmette-Guérin (BCG) does not stimulate MMP-1 secretion from human macrophages, although M. tuberculosis and BCG do upregulate MMP-7 equally. BCG-infected macrophages secrete reduced prostaglandin E[2] concentrations compared with M. tuberculosis-infected macrophages, and prostaglandin pathway supplementation augments MMP-1 secretion from BCG-infected cells.Conclusions: M. tuberculosis specifically upregulates MMP-1 in a cellular model of human infection and in patients with tuberculosis. In contrast, vaccine BCG, which does not cause lung cavitation, does not upregulate prostaglandin E[2]-dependent MMP-1 secretion. [ABSTRACT FROM AUTHOR]

To report 4 pediatric RMS in Guatemala [age range 8-13 years] exhibiting aggressive clinical behavior. 2 cases involved sinonasal & paranasal sinuses; one the anterior mandibular facial area & another affecting paraorbital and mid facial region, with previous additional history of radiation therapy & R. ocular exenteration at 2 years of age for retinoblastoma. Rapid, massive growth with nasal obstruction was observed in all 3 cases, leading to gross. R. ocular displacement and facial deformity was noted in one case, while facial and mandibular swelling was reported in another. The period of tumor growth ranged from 2 -6 months. 3/ 4 patients were treated with Rad. & chemoth. & 1 patient (post radiation) also underwent surgical intervention as chemoth. & Rad. showed no response. Follow-up period ranged from 2 months to 3 years, where 2 patients were alive & disease free while the other 2 expired of wide spread disease, including CNS invasion & both patients within that cohort had evidence of regional lymph node metastasis and one of the 2 also exhibited CNS involvement. Histomor-morphologic subtypes included 3 embryonal and 1 post radiation subtypes. All cases reacted positively with IHC to desmin & myogenin. Ki67 labeling was 75% to 90 % in 3 cases and was not performed in the 4th. One of the cases which encompassed small round cell morphology also reacted positively with CD99, albeit with co-expression of desmin and myogenin. Our cases highlight the aggressive nature of RMS, with distant metastasis in 3 cases and high Ki-67 labeling. Positive expression of CD99 should not deter from the diagnosis of RMS provided co-expression of myogenin and desmin is confirmed. Considering its aggressiveness and failure to respond to any form of current treatment, post-radiation RMS should be classified as an unspecific variant of RMS. [ABSTRACT FROM AUTHOR]

Objectives: To address the need for interactive visualization tools and databases in characterizing multimorbidity patterns across different populations, we developed the Phenome-wide Multi-Institutional Multimorbidity Explorer (PheMIME). This tool leverages three large-scale EHR systems to facilitate efficient analysis and visualization of disease multimorbidity, aiming to reveal both robust and novel disease associations that are consistent across different systems and to provide insight for enhancing personalized healthcare strategies., Materials and Methods: PheMIME integrates summary statistics from phenome-wide analyses of disease multimorbidities, utilizing data from Vanderbilt University Medical Center, Mass General Brigham, and the UK Biobank. It offers interactive and multifaceted visualizations for exploring multimorbidity. Incorporating an enhanced version of associationSubgraphs, PheMIME also enables dynamic analysis and inference of disease clusters, promoting the discovery of complex multimorbidity patterns. A case study on schizophrenia demonstrates its capability for generating interactive visualizations of multimorbidity networks within and across multiple systems. Additionally, PheMIME supports diverse multimorbidity-based discoveries, detailed further in online case studies., Results: The PheMIME is accessible at https://prod.tbilab.org/PheMIME/. A comprehensive tutorial and multiple case studies for demonstration are available at https://prod.tbilab.org/PheMIME&#95;supplementary&#95;materials/. The source code can be downloaded from https://github.com/tbilab/PheMIME., Discussion: PheMIME represents a significant advancement in medical informatics, offering an efficient solution for accessing, analyzing, and interpreting the complex and noisy real-world patient data in electronic health records., Conclusion: PheMIME provides an extensive multimorbidity knowledge base that consolidates data from three EHR systems, and it is a novel interactive tool designed to analyze and visualize multimorbidities across multiple EHR datasets. It stands out as the first of its kind to offer extensive multimorbidity knowledge integration with substantial support for efficient online analysis and interactive visualization., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: Genetic polymorphisms have been associated with risk of antituberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil., Methods: Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015 and 2019, and who were eligible for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24-month follow-up. Analyses included 43 polymorphisms in 20 genes related to antituberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset., Results: Among 903 participants in multivariable genetic association analyses, NAT2 slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely among NAT2 rapid acetylators, but not statistically significant at the 5% level. A GSTM1 polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. SLCO1B1 polymorphisms were associated with increased risk of treatment-related hepatoxicity and treatment failure/recurrence. Polymorphisms in NR1/2 were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism in VTI1A, and the genes METTL17 and PRSS57, but none achieved genome-wide significance., Conclusion: In a clinical cohort representing three regions of Brazil, NAT2 acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations, particularly regarding risk of treatment failure/recurrence., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Black women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive., Objective: The aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women., Study Design: We conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5-12), western blot (sample size range=5-6), and immunohistochemistry techniques (sample size range=9-16)., Results: The transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix-related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of Tenascin C, type I collagen alpha 1 chain, fibronectin, and phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women., Conclusion: These findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is a common and devastating complication of hospitalization. Here, we identified genetic loci associated with AKI in patients hospitalized between 2002-2019 in the Million Veteran Program and data from Vanderbilt University Medical Center's BioVU. AKI was defined as meeting a modified KDIGO Stage 1 or more for two or more consecutive days or kidney replacement therapy. Control individuals were required to have one or more qualifying hospitalizations without AKI and no evidence of AKI during any other observed hospitalizations. Genome-wide association studies (GWAS), stratified by race, adjusting for sex, age, baseline estimated glomerular filtration rate (eGFR), and the top ten principal components of ancestry were conducted. Results were meta-analyzed using fixed effects models. In total, there were 54,488 patients with AKI and 138,051 non-AKI individuals included in the study. Two novel loci reached genome-wide significance in the meta-analysis: rs11642015 near the FTO locus on chromosome 16 (obesity traits) (odds ratio 1.07 (95% confidence interval, 1.05-1.09)) and rs4859682 near the SHROOM3 locus on chromosome 4 (glomerular filtration barrier integrity) (odds ratio 0.95 (95% confidence interval, 0.93-0.96)). These loci colocalized with previous studies of kidney function, and genetic correlation indicated significant shared genetic architecture between AKI and eGFR. Notably, the association at the FTO locus was attenuated after adjustment for BMI and diabetes, suggesting that this association may be partially driven by obesity. Both FTO and the SHROOM3 loci showed nominal evidence of replication from diagnostic-code-based summary statistics from UK Biobank, FinnGen, and Biobank Japan. Thus, our large GWA meta-analysis found two loci significantly associated with AKI suggesting genetics may explain some risk for AKI., (Published by Elsevier Inc.)

Preeclampsia, a pregnancy complication characterized by hypertension after 20 gestational weeks, is a major cause of maternal and neonatal morbidity and mortality. Mechanisms leading to preeclampsia are unclear; however, there is evidence of high heritability. We evaluated the association of polygenic scores (PGS) for blood pressure traits and preeclampsia to assess whether there is shared genetic architecture. Non-Hispanic Black and White reproductive age females with pregnancy indications and genotypes were obtained from Vanderbilt University's BioVU, Electronic Medical Records and Genomics network, and Penn Medicine Biobank. Preeclampsia was defined by ICD codes. Summary statistics for diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) PGS were acquired from Giri et al. Associations between preeclampsia and each PGS were evaluated separately by race and data source before subsequent meta-analysis. Ten-fold cross validation was used for prediction modeling. In 3504 Black and 5009 White included individuals, the rate of preeclampsia was 15.49%. In cross-ancestry meta-analysis, all PGSs were associated with preeclampsia (OR DBP  = 1.10, 95% CI 1.02-1.17, p = 7.68 × 10 -3 ; OR SBP  = 1.16, 95% CI 1.09-1.23, p = 2.23 × 10 -6 ; OR PP  = 1.14, 95% CI 1.07-1.27, p = 9.86 × 10 -5 ). Addition of PGSs to clinical prediction models did not improve predictive performance. Genetic factors contributing to blood pressure regulation in the general population also predispose to preeclampsia., (© 2024. The Author(s).)

Variability in quantitative traits has clinical, ecological, and evolutionary significance. Most genetic variants identified for complex quantitative traits have only a detectable effect on the mean of trait. We have developed the mean-variance test (MVtest) to simultaneously model the mean and log-variance of a quantitative trait as functions of genotypes and covariates by using estimating equations. The advantages of MVtest include the facts that it can detect effect modification, that multiple testing can follow conventional thresholds, that it is robust to non-normal outcomes, and that association statistics can be meta-analyzed. In simulations, we show control of type I error of MVtest over several alternatives. We identified 51 and 37 previously unreported associations for effects on blood-pressure variance and mean, respectively, in the UK Biobank. Transcriptome-wide association studies revealed 633 significant unique gene associations with blood-pressure mean variance. MVtest is broadly applicable to studies of complex quantitative traits and provides an important opportunity to detect novel loci., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

Competing Interests: Financial Disclosure Digna R. Velez Edwards has served as a Member of the Board of Directors for American Society of Human Genetics. Todd L. Edwards did not report any potential conflicts of interest.

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

Many researchers in genetics and social science incorporate information about race in their work. However, migrations (historical and forced) and social mobility have brought formerly separated populations of humans together, creating younger generations of individuals who have more complex and diverse ancestry and race profiles than older age groups. Here, we sought to better understand how temporal changes in genetic admixture influence levels of heterozygosity and impact health outcomes. We evaluated variation in genetic ancestry over 100 birth years in a cohort of 35,842 individuals with electronic health record (EHR) information in the Southeastern United States. Using the software STRUCTURE, we analyzed 2,678 ancestrally informative markers relative to three ancestral clusters (African, East Asian, and European) and observed rising levels of admixture for all clinically-defined race groups since 1990. Most race groups also exhibited increases in heterozygosity and long-range linkage disequilibrium over time, further supporting the finding of increasing admixture in young individuals in our cohort. These data are consistent with United States Census information from broader geographic areas and highlight the changing demography of the population. This increased diversity challenges classic approaches to studies of genotype-phenotype relationships which motivated us to explore the relationship between heterozygosity and disease diagnosis. Using a phenome-wide association study approach, we explored the relationship between admixture and disease risk and found that increased admixture resulted in protective associations with female reproductive disorders and increased risk for diseases with links to autoimmune dysfunction. These data suggest that tendencies in the United States population are increasing ancestral complexity over time. Further, these observations imply that, because both prevalence and severity of many diseases vary by race groups, complexity of ancestral origins influences health and disparities.

There is a desire in research to move away from the concept of race as a clinical factor because it is a societal construct used as an imprecise proxy for geographic ancestry. In this study, we leverage the biobank from Vanderbilt University Medical Center, BioVU, to investigate relationships between genetic ancestry proportion and the clinical phenome. For all samples in BioVU, we calculated six ancestry proportions based on 1000 Genomes references: eastern African (EAFR), western African (WAFR), northern European (NEUR), southern European (SEUR), eastern Asian (EAS), and southern Asian (SAS). From PheWAS, we found phecode categories significantly enriched neoplasms for EAFR, WAFR, and SEUR, and pregnancy complication in SEUR, NEUR, SAS, and EAS (p < 0.003). We then selected phenotypes hypertension (HTN) and atrial fibrillation (AFib) to further investigate the relationships between these phenotypes and EAFR, WAFR, SEUR, and NEUR using logistic regression modeling and non-linear restricted cubic spline modeling (RCS). For EAS and SAS, we chose renal failure (RF) for further modeling. The relationships between HTN and AFib and the ancestries EAFR, WAFR, and SEUR were best fit by the linear model (beta p < 1x10-4 for all) while the relationships with NEUR were best fit with RCS (HTN ANOVA p = 0.001, AFib ANOVA p < 1x10-4). For RF, the relationship with SAS was best fit with a linear model (beta p < 1x10-4) while RCS model was a better fit for EAS (ANOVA p < 1x10-4). In this study, we identify relationships between genetic ancestry and phenotypes that are best fit with non-linear modeling techniques. The assumption of linearity for regression modeling is integral for proper fitting of a model and there is no knowing a priori to modeling if the relationship is truly linear.

Diseases such as uterine leiomyomata (fibroids and benign tumors of the uterus) and keloids (raised scars) may share common etiology. Fibroids and keloids can co-occur in individuals, and both are highly heritable, suggesting they may share common genetic risk factors. Fibroproliferative diseases are common and characterized by scarring and overgrowth of connective tissue, impacting multiple organ systems. These conditions both have racial disparities in prevalence, with the highest prevalence observed among individuals of African ancestry. Several fibroproliferative diseases are more severe and common in populations of sub-Saharan Africa. This mini-review aims to provide a broad overview of the current knowledge of the evolutionary origins and causes of fibroproliferative diseases. We also discuss current hypotheses proposing that the increased prevalence of these diseases in African-derived populations is due to the selection for profibrotic alleles that are protective against helminth infections and provide examples from knowledge of uterine fibroid and keloid research.

The intersection of women's health and data science is a field of research that has historically trailed other fields, but more recently it has gained momentum. This growth is being driven not only by new investigators who are moving into this area but also by the significant opportunities that have emerged in new methodologies, resources, and technologies in data science. Here, we describe some of the resources and methods being used by women's health researchers today to meet challenges in biomedical data science. We also describe the opportunities and limitations of applying these approaches to advance women's health outcomes and the future of the field, with emphasis on repurposing existing methodologies for women's health.

Endometriosis is a chronic, complex disease for which there are vast disparities in diagnosis and treatment between sociodemographic groups. Clinical presentation of endometriosis can vary from asymptomatic disease-often identified during (in)fertility consultations-to dysmenorrhea and debilitating pelvic pain. Because of this complexity, delayed diagnosis (mean time to diagnosis is 1.7-3.6 years) and misdiagnosis is common. Early and accurate diagnosis of endometriosis remains a research priority for patient advocates and healthcare providers. Electronic health records (EHRs) have been widely adopted as a data source in biomedical research. However, they remain a largely untapped source of data for endometriosis research. EHRs capture diverse, real-world patient populations and care trajectories and can be used to learn patterns of underlying risk factors for endometriosis which, in turn, can be used to inform screening guidelines to help clinicians efficiently and effectively recognize and diagnose the disease in all patient populations reducing inequities in care. Here, we provide an overview of the advantages and limitations of using EHR data to study endometriosis. We describe the prevalence of endometriosis observed in diverse populations from multiple healthcare institutions, examples of variables that can be extracted from EHRs to enhance the accuracy of endometriosis prediction, and opportunities to leverage longitudinal EHR data to improve our understanding of long-term health consequences for all patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Penrod, Okeh, Velez Edwards, Barnhart, Senapati and Verma.)

Objective: Blood pressure is a complex, polygenic trait, and the need to identify prehypertensive risks and new gene targets for blood pressure control therapies or prevention continues. We hypothesize a developmental origins model of blood pressure traits through the life course where the placenta is a conduit mediating genomic and nongenomic transmission of disease risk. Genetic control of placental gene expression has recently been described through expression quantitative trait loci (eQTL) studies which have identified associations with childhood phenotypes., Methods: We conducted a transcriptome-wide gene expression analysis estimating the predicted gene expression of placental tissue in adult individuals with genome-wide association study (GWAS) blood pressure summary statistics. We constructed predicted expression models of 15 154 genes from reference placenta eQTL data and investigated whether genetically-predicted gene expression in placental tissue is associated with blood pressure traits using published GWAS summary statistics. Functional annotation of significant genes was generated using FUMA., Results: We identified 18, 9, and 21 genes where predicted expression in placenta was significantly associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP), respectively. There were 14 gene-tissue associations (13 unique genes) significant only in placenta., Conclusions: In this meta-analysis using S-PrediXcan and GWAS summary statistics, the predicted expression in placenta of 48 genes was statistically significantly associated with blood pressure traits. Notable findings included the association of FGFR1 expression with increased SBP and PP. This evidence of gene expression variation in placenta preceding the onset of adult blood pressure phenotypes is an example of extreme preclinical biological changes which may benefit from intervention., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Females with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women, have an increased risk of developing cardiometabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). While only diagnosable in females, males with a family history of PCOS can also exhibit a poor cardiometabolic profile. Therefore, we aimed to elucidate the role of sex in the cardiometabolic comorbidities observed in PCOS by conducting bidirectional genetic risk score analyses in both sexes. We first conducted a phenome-wide association study (PheWAS) using PCOS polygenic risk scores (PCOSPRS) to identify potential pleiotropic effects of PCOSPRS across 1,380 medical conditions recorded in the Vanderbilt University Medical Center electronic health record (EHR) database, in females and males. After adjusting for age and genetic ancestry, we found that European (EUR)-ancestry males with higher PCOSPRS were significantly more likely to develop hypertensive diseases than females at the same level of genetic risk. We performed the same analysis in an African (AFR)-ancestry population, but observed no significant associations, likely due to poor trans-ancestry performance of the PRS. Based on observed significant associations in the EUR-ancestry population, we then tested whether the PRS for comorbid conditions (e.g., T2D, body mass index (BMI), hypertension, etc.) also increased the odds of a PCOS diagnosis. Only BMIPRS and T2DPRS were significantly associated with a PCOS diagnosis in EUR-ancestry females. We then further adjusted the T2DPRS for measured BMI and BMIresidual (regressed on the BMIPRS and enriched for the environmental contribution to BMI). Results demonstrated that genetically regulated BMI primarily accounted for the relationship between T2DPRS and PCOS. Overall, our findings show that the genetic architecture of PCOS has distinct sex differences in associations with genetically correlated cardiometabolic traits. It is possible that the cardiometabolic comorbidities observed in PCOS are primarily explained by their shared genetic risk factors, which can be further influenced by biological variables including sex and BMI., Competing Interests: The authors declare they have no competing interests., (Copyright: © 2023 Actkins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Epidemiologists face a unique challenge in measuring risk relationships involving time-varying exposures in early pregnancy. Each week in early pregnancy is distinct in its contribution to fetal development, and this period is commonly characterized by shifts in maternal behavior and, consequently, exposures. In this simulation study, we used alcohol as an example of an exposure that often changes during early pregnancy and miscarriage as an outcome affected by early exposures. Data on alcohol consumption patterns from more than 5,000 women in the Right From the Start cohort study (United States, 2000-2012) informed measures of the prevalence of alcohol exposure, the distribution of gestational age at cessation of alcohol use, and the likelihood of miscarriage by week of gestation. We then compared the bias and precision of effect estimates and statistical power from 5 different modeling approaches in distinct simulated relationships. We demonstrate how the accuracy and precision of effect estimates depended on alignment between model assumptions and the underlying simulated relationship. Approaches that incorporated data about patterns of exposure were more powerful and less biased than simpler models when risk depended on timing or duration of exposure. To uncover risk relationships in early pregnancy, it is critical to carefully define the role of exposure timing in the underlying causal hypothesis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)