Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Recent publications
Importance Transvaginal surgery is commonly performed to treat pelvic organ prolapse. Little research focuses on how sexual function relates to clitoral anatomy after vaginal surgery despite the clitoris’ role in the sexual response. Objective To determine how postoperative sexual function after vaginal surgery is associated with clitoral features (size, position, shape). Design, Setting, and Participants This was a cross-sectional ancillary study of magnetic resonance imaging (MRI) data from the Defining Mechanisms of Anterior Vaginal Wall Descent (DEMAND) study. The setting comprised 8 clinical sites in the US Pelvic Floor Disorders Network and included the MRI data of 88 women with uterovaginal prolapse previously randomized to either vaginal mesh hysteropexy or vaginal hysterectomy with uterosacral ligament suspension between 2013 and 2015. Data were analyzed between September 2021 and June 2023. Exposures Participants underwent postoperative pelvic MRI at 30 to 42 months (or earlier if reoperation was desired) between June 2014 and May 2018. Sexual activity and function at baseline (preoperatively) and 24- to 48-month follow-up (postoperatively) were assessed using the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, International Urogynecological Association Revised (PISQ-IR). Clitoral features were derived from postoperative MRI-based 3-dimensional models. Main Outcomes and Measures Correlations between (1) PISQ-IR mean, subscale, and item scores and (2) clitoral size, position, and shape (principal component scores). Results A total of 82 women (median [range] age, 65 [47-79] years) were analyzed (41 received hysteropexy and 41 received hysterectomy). Postoperatively, 37 were sexually active (SA), and 45 were not SA (NSA). Among SA women, better overall postoperative sexual function (higher PISQ-IR summary score) correlated with a larger clitoral glans width (Spearman ρ = 0.37; 95% CI, 0.05-0.62; P = .03) and thickness (Spearman ρ = 0.38; 95% CI, 0.06-0.63; P = .02). Among NSA women, sexual inactivity related to postoperative dyspareunia correlated with a more lateral clitoral position (Spearman ρ = 0.45; 95% CI, 0.18-0.66; P = .002), and sexual inactivity related to incontinence/prolapse correlated with a more posterior clitoral position (Spearman ρ = −0.36; 95% CI, −0.60 to −0.07; P = .02) (farther from the pubic symphysis). Shape analysis demonstrated that poorer postoperative sexual function outcomes in SA women and sexual inactivity in NSA women correlated with a more posteriorly positioned glans, anteriorly oriented clitoral body, medially positioned crura, and lateral vestibular bulbs. Conclusions and Relevance Results of this cross-sectional study suggest that postoperative sexual function after vaginal surgery was associated with clitoral glans size, position, and shape. Results warrant prospective studies on surgery-induced changes in clitoral anatomy and sexual function.
Introduction ARMC5 is the most prevalent gene predisposing to Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH), but germline KDM1A variants have been identified in the rare PBMAH associated with food-dependent Cushing’s syndrome (FDCS). The purpose of this work was to assess the frequency of KDM1A variants in a large series of PBMAH patients. Methods 301 consecutive PBMAH index cases from 8 international Endocrinology departments were included. Clinical, biological and imaging data were collected retrospectively. Results 10 (3.3%) patients carried a germline KDM1A pathogenic or likely pathogenic variant, 60 (19.9%) carried a germline ARMC5 alteration, 231 (76.8%) had no identified genetic predisposition. FDCS was present in all patients with KDM1A variants and absent in the 2 other groups. KDM1A patients had a higher 24h urinary free cortisol (3.0-fold ULN vs 1.36 for ARMC5 patients and 0.66 for wild-type patients, respectively, p=0.0001). In accordance with FDCS pathophysiology, patients with KDM1A variants had a lower morning fasting plasma cortisol (192 nmol/L vs 407 and 428, respectively, p=0.0003) and a higher midnight plasma cortisol (487 nmol/L vs 297 and 171.96, respectively, p=0.0004). Morning/midnight plasma cortisol ratio below 0.65 holds 100% sensitivity and specificity for the detection of FDCS. All patients with KDM1A variants were women, vs 65% of ARMC5 patients and 67% of wild-type patients (p=0.0337). Conclusion KDM1A germline pathogenic variants are rare in PBMAH and account for less than 5% of index cases. KDM1A seems constantly associated with FDCS, which can be evoked in front of a morning/midnight plasma cortisol ratio below 0.65.
Background Dysregulation of maternal glucose homeostasis has been related to an increased risk of morbidity and mortality in mothers and fetuses, yet the mechanism remains unclear. This study investigated the association between maternal glycemic levels and placental epigenetic age acceleration (PAA) in a multiethnic cohort. Methods In a sample of 301 pregnant women (102 Hispanic, 77 White, 72 Black, and 50 Asian/Pacific Islander), the association of glycemic markers cumulative exposure with PAA was tested using linear regression adjusting for fetal sex, maternal age, educational status, and health insurance status. Models were applied in the full cohort and stratified by race/ethnicity. Further, sensitivity analyses were performed after excluding women with GDM or preeclampsia. Results Among Black women, high glucose, HbA1c, and insulin cumulative exposure levels were associated with lower PAA compared to low cumulative exposure levels (β = − 0.75 weeks, 95% CI = − 1.41 to − 0.08); β = − 0.86, 95% CI = − 1.51 to − 0.21; and β = − 0.76, 95% CI = − 1.49 to − 0.03, respectively). Among Asian/Pacific Islander women, medium insulin cumulative exposure level was associated with lower PAA (β = − 0.94 weeks, 95% CI = − 1.74 to − 0.14). No significant association was observed among White and Hispanic women as well as in the full cohort. Conclusions Elevated glucose, HbA1c, and insulin cumulative levels throughout pregnancy were associated with lower PAA in Black and Asian/Pacific Islander women. Placental epigenetic aging may be altered by maternal elevated glycemia and may in part underlie early programming of health outcomes in pregnancy and childhood health outcomes.
Introduction Hemoglobin A1c (HbA1c) measurement in epidemiology studies could be increased if reliability of measurements in frozen stored samples was known. In the Reasons for Geographic And Racial Differences in Stroke, a longitudinal study of 30,239 Black and White U.S. adults, we investigated reliability of HbA1c measurements for two types of samples stored at −80°C for up to 14 years. Methods Among 917 participants without diabetes, HbA1c was measured in 2017 in frozen packed cells from the first visit (2003–2007) and in frozen whole blood samples from the second visit (2013–2016). To study reliability, associations between HbA1c and glycemia‐related characteristics were examined. Results Each 10 mg/dL greater fasting glucose was associated with 0.08% (95% CI: 0.05%–0.11%) greater HbA1c in frozen packed cells (Visit 1) and 0.10% (95% CI: 0.08%–0.12%) greater HbA1c in whole blood (Visit 2). HbA1c was also similarly higher with both methods with increasing age, gender, systolic blood pressure, body mass index, high‐density lipoprotein, triglycerides, C‐reactive protein, and hemoglobin. Using both methods, ≤ 3.5% would be classified with diabetes based on HbA1c ≥ 6.5%. Conclusions In REGARDS participants without diabetes, HbA1c measurement appeared reliable in frozen packed cells or whole blood under long‐term storage, suggesting acceptability for study of the epidemiology of HbA1c.
Background Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare cause of Cushing’s syndrome due to bilateral adrenocortical macronodules. Germline inactivating variants of the tumor suppressor gene ARMC5 are responsible for 20–25% of apparently sporadic PBMAH cases and 80% of familial presentations. ARMC5 screening is now routinely performed for PBMAH patients and families. Based on literature review and own observation, this study aims to give an overview of both published and unpublished ARMC5 genetic alterations and to compile the available evidence to discriminate pathogenic from benign variants. Results 146 different germline variants (110 previously published and 36 novel) are identified, including 46% missense substitutions, 45% truncating variants, 3% affecting splice sites, 4% in-frame variants and 2% large deletions. In addition to the germline events, somatic 16p loss-of-heterozygosity and 104 different somatic events are described. The pathogenicity of ARMC5 variants is established on the basis of their frequency in the general population, in silico predictions, familial segregation and tumor DNA sequencing. Conclusions This is the first extensive review of ARMC5 pathogenic variants. It shows that they are spread on the whole coding sequence. This is a valuable resource for genetic investigations of PBMAH and will help the interpretation of new missense substitutions that are continuously identified.
Metastatic cancer poses significant clinical challenges, necessitating effective immunotherapies with minimal systemic toxicity. Building on prior research demonstrating the rWTC-MBTA vaccine’s ability to inhibit tumor metastasis and growth, this study focuses on its clinical translation by optimizing vaccine composition, dosing regimens, and freezing techniques. The vaccine formula components included three TLR ligands (LTA, Poly I:C, and Resiquimod) and an anti-CD40 antibody, which were tested in melanoma and triple-negative breast cancer (TNBC) models. The formulations were categorized as rWTC-MBT (Mannan-BAM with LTA, Poly I:C, Resiquimod), rWTC-MBL (LTA), rWTC-MBP (Mannan-BAM with Poly I:C), and rWTC-MBR (Resiquimod). In the melanoma models, all the formulations exhibited efficacy that was comparable to that of the full vaccine, while in the “colder” TNBC models, the formulations with multiple TLR ligands or Resiquimod alone performed the best. Vaccine-induced activation of dendritic cell (DC) subsets, including conventional DCs (cDCs), myeloid DCs (mDCs), and plasmacytoid DCs (pDCs), was accompanied by significant CD80+CD86+ population induction, suggesting robust innate immune stimulation. An initial three-dose schedule followed by booster doses (3-1-1-1 or 3-3-3-3) reduced the metastatic burden effectively. Gradual freezing (DMSO-based preservation) maintained vaccine efficacy, underscoring the importance of intact cell structure. These findings highlight the potential of simplified formulations, optimized dosing, and freezing techniques in developing practical, scalable immunotherapies for metastatic cancers.
LARP4 interacts with poly(A)-binding protein (PABP) to protect messenger RNAs (mRNAs) from deadenylation and decay, and recent data indicate it can direct the translation of functionally related mRNA subsets. LARP4 was known to bind RACK1, a ribosome-associated protein, although the specific regions involved and relevance had been undetermined. Here, through a combination of in-cell and in vitro methodologies, we identified positions 615–625 in conserved region-2 (CR2) of LARP4 (and 646–656 in LARP4B) as directly binding RACK1. Consistent with these results, AlphaFold2-Multimer predicted high-confidence interaction of CR2 with RACK1 propellers 5 and 6. CR2 mutations strongly decreased LARP4 association with cellular RACK1 and ribosomes by multiple assays, whereas PABP association was less affected, consistent with independent interactions. The CR2 mutations decreased LARP4’s ability to stabilize a β-globin mRNA reporter containing an AU-rich element (ARE) to higher degree than β-globin and GFP (green fluorescent protein) mRNAs lacking the ARE. We show LARP4 robustly increases translation of β-glo-ARE mRNA, whereas the LARP4 CR2 mutant is impaired. Analysis of nanoLuc-ARE mRNA for production of luciferase activity confirmed LARP4 promotes translation efficiency, while CR2 mutations are disabling. Thus, LARP4 CR2-mediated interaction with RACK1 can promote translational efficiency of some mRNAs.
Non-communicable diseases (NCDs) such as cardiovascular diseases, chronic respiratory diseases, cancers, diabetes, and mental health disorders pose a significant global health challenge, accounting for the majority of fatalities and disability-adjusted life years worldwide. These diseases arise from the complex interactions between genetic, behavioral, and environmental factors, necessitating a thorough understanding of these dynamics to identify effective diagnostic strategies and interventions. Although recent advances in multi-omics technologies have greatly enhanced our ability to explore these interactions, several challenges remain. These challenges include the inherent complexity and heterogeneity of multi-omic datasets, limitations in analytical approaches, and severe underrepresentation of non-European genetic ancestries in most omics datasets, which restricts the generalizability of findings and exacerbates health disparities. This scoping review evaluates the global landscape of multi-omics data related to NCDs from 2000 to 2024, focusing on recent advancements in multi-omics data integration, translational applications, and equity considerations. We highlight the need for standardized protocols, harmonized data-sharing policies, and advanced approaches such as artificial intelligence/machine learning to integrate multi-omics data and study gene-environment interactions. We also explore challenges and opportunities in translating insights from gene-environment (GxE) research into precision medicine strategies. We underscore the potential of global multi-omics research in advancing our understanding of NCDs and enhancing patient outcomes across diverse and underserved populations, emphasizing the need for equity and fairness-centered research and strategic investments to build local capacities in underrepresented populations and regions.
Context: Our study explores the impact of human PTH 1-34 injections (PTH therapy) on growth, areal bone mineral density (BMD), and bone quality (measured by trabecular bone score, TBS) in hypoparathyroidism due to autoimmune polyendocrine syndrome type 1 (APS-1) or an activating variant of the calcium sensing receptor (CaR). Objective: To assess associations of 1) age and PTH therapy duration with age-standardized Z-scores for height (HAZ), BMD (BMD-Z), and TBS (TBS-Z) in CaR or APS-1, and 2) APS-1 disease severity with BMD-Z and TBS-Z. Methods: This secondary analysis pooled linear growth and lumbar spine (LS) DXA data from studies of hypoparathyroidism with mean baseline age of 13.7±5.5y. Comparing the two diagnostic etiologies (18 APS-1 and 9 CaR), we examined the impact of age and PTH duration on HAZ, LS-BMD-Z, and LS-TBS-Z using longitudinal mixed-effects modeling. Results: During PTH therapy, mean HAZ remained below zero in the APS-1 group at all ages, whereas HAZ increased in the CaR group (age by group interaction p<0.0001). Mean LS-BMD-Z were normal (BMD-Z:0±1) for both groups. Mean LS-TBS-Z were near or above zero and differed by group; CaR showed an upward trajectory according to time on PTH whereas the APS-1 group maintained a LS-TBS-Z of approximately 0 (time by group interaction p=0.02). The APS-1 group with greater disease severity (≥7 manifestations) had lower LS-BMD-Z and LS-TBS-Z compared to the less severe APS-1 or CaR groups. Conclusion: Our study highlights distinct growth and BMD patterns in APS-1 and CaR and underscores the need for careful monitoring and tailored treatment strategies to optimize growth and bone health.
The mammalian Hippo kinases, MST1 and MST2, regulate organ development and suppress tumor formation by balancing cell proliferation and death. In macrophages, inflammasomes detect molecular patterns from invading pathogens or damaged host cells and trigger programmed cell death. In addition to lytic pyroptosis, the signatures associated with apoptosis are induced by inflammasome activation, but how the inflammasomes coordinate different cell death processes remains unclear. Here, we identify the crucial role of MST1/2 in inflammasome-triggered cell death. Macrophages proteolytically convert full-length MST1/2 into the MST1/2 N-terminal fragments (MST1/2-NT) when the NLRC4 inflammasome detects flagellin from the pathogenic bacterium, Legionella pneumophila . Activation of the NLRP3 inflammasome by the damage-associated molecular pattern, extracellular ATP, also produces MST1/2-NT. Caspase-1, the protease activated by these inflammasomes, directly cleaves MST1/2, and blockage of caspase-1 inhibits MST1/2-NT production in macrophages challenged with L. pneumophila . Importantly, MST1/2-NT production is critical for macrophages to trigger a set of death processes associated with apoptosis upon inflammasome activation and knocking out Mst1/2 causes dysregulated gasdermin protein cleavage for pyroptotic death. Furthermore, macrophages lacking MST1/2 have increased susceptibility to virulent L. pneumophila, revealing that the Hippo kinases are important restriction factors against the pathogen. These findings demonstrate that proteolytic cleavage of MST1/2 induced by inflammatory stimuli is an immune pathway to regulate programmed cell death in macrophages and uncover a unique link between the tumor-suppressive Hippo kinases and the inflammasomes in innate immunity.
Traumatic brain injury (TBI) is a risk factor for neurodegeneration, however little is known about how this kind of injury alters neuron subtypes. In this study, we follow neuronal populations over time after a single mild TBI (mTBI) to assess long ranging consequences of injury at the level of single, transcriptionally defined neuronal classes. We find that the stress-responsive Activating Transcription Factor 3 (ATF3) defines a population of cortical neurons after mTBI. Using an inducible reporter linked to ATF3, we genetically mark these damaged cells to track them over time. We find that a population in layer V undergoes cell death acutely after injury, while another in layer II/III survives long term and remains electrically active. To investigate the mechanism controlling layer V neuron death, we genetically silenced candidate stress response pathways. We found that the axon injury responsive dual leucine zipper kinase (DLK) is required for the layer V neuron death. This work provides a rationale for targeting the DLK signaling pathway as a therapeutic intervention for traumatic brain injury. Beyond this, our approach to track neurons after a mild, subclinical injury can inform our understanding of neuronal susceptibility to repeated impacts.
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102 members
Daniel Castranova
  • Program in Genomics of Differentiation
Jean-Charles Grivel
  • Program on Physical Biology
Paul S Blank
  • Section on Integrative Biophysics
Ajay B Chitnis
  • Program in Genomics of Differentiation
Rajeshwari Sundaram
  • Division of Intramural Population Health Research
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