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A Distinct Immunological Signature in Late-Onset Myasthenia Gravis: Insights from an Exploratory Proteomics Study
No full textOBJECTIVE: Approximately 80% of patients with myasthenia gravis (MG) have autoantibodies against acetylcholine receptor, and clinical characteristics may vary between early-onset (symptom onset age \u3c50 years) and late-onset MG (EOMG and LOMG), but the pathophysiological differences between EOMG and LOMG are not well established. METHODS: We performed an exploratory in-depth proteomics analysis examining 768 inflammatory proteins utilizing the baseline serum samples from the BeatMG study (NCT02110706). We performed pathway enrichment analysis to assess the pathways involved in LOMG. A total of 15 selected proteins from the initial analysis were further examined using the UK Biobank and further quantified in a separate validation cohort. RESULTS: A total of 21 patients with EOMG (age 38.3 ± 12.1 years, 16 women [76.2%]) and 28 patients with LOMG (age 67.3 ± 8.6 years, 7 women [25%]) from the BeatMG study were included in the exploratory analysis. Several proteins involved in the regulation of leukocyte differentiation and myeloid leukocyte differentiation and migration pathways were more abundant in the LOMG group. Among them, 7 were significantly different in the UK Biobank cohort. A total of 80 participants (39 MG patients (age 54.33 ± 18.9 years, 17 women [43.6%]) and 41 healthy controls (age 49.56 ± 17.06 years, 21 women [66.1%]) were included in the validation cohort, and IL18R1, CXCL17, and CCL11 were validated to be specific for LOMG. INTERPRETATION: Growing evidence supports that LOMG has a distinct immune pathomechanism. Further prospective studies are warranted to confirm the utility of these proteins as biomarkers of LOMG, and the feasibility of using them for more precise therapeutic targets to improve patient outcomes. ANN NEUROL 2025
Gender Identity and Gender-Related Medical Outcomes of Autistic Young Adults Who Experienced Transgender Identity as Adolescents
No full textPURPOSE: We examined gender identity and gender-affirming care outcomes of autistic transgender adolescents followed into young adulthood, as well as relationships between gender-related medical care receipt and mental health across time. METHODS: This longitudinal two-timepoint study was conducted between 2018 and 2024, with 4 years between timepoints. Twenty-seven autistic transgender youth participated, with one lost to follow-up. Measures included self-reported gender, interest in and receipt of gender-related medical care, LGBT-related stigma (via the LGBT Stigma Scale), and anxiety and depression symptoms (via the Achenbach System of Empirically Based Assessment). Intelligence quotients were estimated using the Wechsler Abbreviated Scale of Intelligence-2. We employed data visualization of gender and gender-related care trajectories and multiple linear regression to understand the relationships between care trajectories and mental health. RESULTS: Most youth remained gender-diverse at Time 2. Two of 26 identified as cisgender as young adults. Half of the sample moved toward nonbinary identities either as an additional component to a binary identity (e.g., transgender nonbinary woman) or shifted from a binary identity to a nonbinary identity. For those who wanted gender-related care, earlier care receipt was associated with a significant reduction in anxiety across time. Care timing was not significantly related to changes in depression across time. CONCLUSION: A majority of autistic gender-diverse youth (24/26; 92.3%) remained gender diverse into young adulthood. Unlike previous studies of autistic youth entering adulthood, which report worsening mental health, participants showed reductions in anxiety across time. Earlier receipt of gender-related care was associated with fewer anxiety symptoms at Time 2
Biology of ovarian cancer: Models, microenvironment, and therapeutics: 15th Biennial Rivkin Center Ovarian Cancer Research Symposium
No full textThe 15th Biennial Ovarian Cancer Research Symposium presented by the Rivkin Center for Ovarian Cancer and the American Association for Cancer Research held on September 20-21, 2024, in Seattle, WA covered cutting-edge research on the etiology and pathobiology of ovarian cancer. Several sessions focused on novel therapies including targeting the immunosuppressive microenvironment and advances in early detection. In this article we provide an overview of the key findings presented in the biology of ovarian cancer session, which covered novel model systems that accurately represent the disease, features of the tumor microenvironment (TME), and advances in understanding the genomic landscape and biomarkers of response
Creation and Evaluation of New Growth Charts With a Gradual Transition From WHO to CDC Values
No full textBACKGROUND AND OBJECTIVES: At age 2 years, the Centers for Disease Control and Prevention (CDC) recommends switching from the World Health Organization (WHO) Growth Standards to the CDC 2000 Growth Reference. This abrupt switch may affect growth assessment, such as causing a clinically important change in growth z score in a child with a stable growth pattern. We sought to create growth charts that gradually transition between WHO and CDC and to evaluate their impact on growth assessment of young children using real-world data. METHODS: We iteratively developed methods to create new charts for body mass index (BMI)-, weight-, and length/height-for-age. We performed a retrospective cohort study comparing the mean change in z scores for these parameters between 1.5 and 2 years for the CDC-recommended vs the new, gradually transitioned (gradual) charts. We also compared the prevalence of a large change in z score: \u3c-1 (drop) or \u3e1 (rise). RESULTS: We transitioned between the charts using a weighted average from ages 2 to 5 years. In 7429 children, there was a large decrease in mean body mass index-for-age z score (BMIz) and weight-for-age z score (WTz) in the CDC-recommended charts (BMIz -0.59, WTz -0.35) that was not seen in the gradual charts (BMIz -0.09, WTz -0.01). Correspondingly, using the CDC-recommended charts, the proportion with a drop in BMIz or WTz was much higher for the CDC-recommended (BMIz 28.3%, WTz 6.0%) than the gradual charts (BMIz 11.6%, WTz 0.85%). CONCLUSIONS: We created growth charts that gradually transition between WHO and CDC and may reduce overidentification of slow weight gain. These charts may be useful in clinical care and research
Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies
No full textNeurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5, encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila, we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor cell stemness, causing deficits in higher-order functions, including learning and locomotion. Pharmacological targeting of integrated stress response kinases reveals a mechanistic link between proteotoxic stress and spontaneous type I interferon activation. These findings expand our understanding of proteasome-dependent quality control in neurodevelopment and suggest potential therapeutic strategies for neurodevelopmental proteasomopathies
Early treatment with IV iron is associated with improved maternal hemorrhage-related outcomes
No full textBACKGROUND: Anemia in pregnancy is associated with maternal hemorrhage-related morbidity and mortality, neonatal neurodevelopmental effects, and postnatal neonatal anemia. This study evaluates how the timing of IV iron therapy prior to delivery impacts maternal and fetal outcomes and to better understand how neighborhood context impacts the timing of IV iron administration. STUDY DESIGN: This retrospective cohort study included pregnant patients who received antenatal IV iron therapy for anemia from January 2017 through November 2023. Timing of IV iron administration in relation to the delivery date was analyzed. The primary outcome was hemorrhage-associated morbidity. The Area Deprivation Index (ADI) was used as a surrogate of socioeconomic disadvantage to understand how neighborhood context impacts IV iron administration in relation to the delivery date. RESULTS: Of 183 included pregnancies with iron deficiency anemia (IDA), 128 (69.9%) received IV iron therapy more than 10 days prior to delivery, while 55 (30.1%) received IV iron therapy fewer than 10 days before delivery. Pregnant patients who received their final transfusion of IV iron \u3e10 days before delivery had significantly higher hemoglobin at delivery admission (11.1 vs. 9.7, p \u3c .001) and were less likely to receive a blood transfusion (p = .03), have a preterm delivery (p = .003), or receive uterotonics during delivery (all p ≤ .05). Additionally, in patients who received IV iron, neighborhood disadvantage did not contribute to late diagnosis or treatment of IDA. DISCUSSION: Patients who received IV iron more than 10 days before delivery had improved maternal and fetal outcomes, including fewer maternal blood transfusions and preterm births
Impact of Pulmonary Tumor Burden in Favorable Histology Wilms Tumor Outcomes: A Report From the Children\u27s Oncology Group Study AREN0533
No full textPURPOSE: Children with favorable histology Wilms tumor (FHWT) with pulmonary metastases have inferior outcomes compared with those with localized disease. We evaluated the impact of pulmonary tumor burden within subgroups of similarly treated children with stage IV FHWT. METHODS: Children with FHWT with pulmonary-only metastasis enrolled in AREN0533 were included. Lung nodule response assessment, by chest computed tomography after two cycles of vincristine/dactinomycin/doxorubicin (Regimen DD-4A) chemotherapy, identified rapid complete responses (RCRs) and slow incomplete pulmonary nodule responses (SIRs). Event-free survival (EFS) and overall survival (OS) were compared by number and size of pulmonary metastases within two cohorts: (1) RCR treated with additional DD-4A without lung radiation therapy (RT) and (2) SIR treated with the original three drugs plus cyclophosphamide/etoposide (Regimen M) with lung RT. The multivariable Cox proportional hazards model for EFS and OS stratified by treatment assessed the impact of the number and size of pulmonary metastases adjusted for tumor 1q gain. RESULTS: AREN0533 enrolled 288 children with stage IV pulmonary-only metastases, of whom 251 met inclusion criteria for outcome analyses. In the RCR cohort (n = 105), EFS and OS were not significantly different based on the number of lung metastases, whereas size of pulmonary metastases was significantly associated with EFS (P = .022), but not OS. In the SIR cohort (n = 146), EFS and OS did not differ by the number or size of lung metastases. In multivariable models, neither number nor size of lung metastases was significantly associated with EFS or OS although 1q gain was significant (EFS P = .0015; OS P = .039) after adjustment for these factors. CONCLUSION: 1q gain is a superior prognostic indicator to pulmonary tumor burden in patients with FHWT with pulmonary-only metastasis
Shape Variations in RV 3D Geometry Are Associated With Adverse Outcomes in Hypoplastic Left Heart Syndrome Patients: A Fontan Outcomes Registry Using CMR Examination (FORCE) Study
No full textBACKGROUND: Assessment of the systemic right ventricle (RV) is critical for patients with hypoplastic left heart syndrome (HLHS). Traditional imaging metrics fail to capture the RV\u27s complex geometry and remodeling in HLHS, limiting risk stratification. We aimed to apply statistical shape modeling to a large multicenter cohort of cardiac magnetic resonance data sets to define RV shape variants and evaluate associations with clinical outcomes. METHODS: Cardiac magnetic resonance from the FORCE (Fontan Outcomes Registry Using CMR Examinations) was analyzed for patients with HLHS post-Fontan. Three-dimensional RV models were segmented at end-diastole and processed using statistical shape modeling (ShapeWorks). Shape modes were extracted via principal component analysis and correlated with RV function, tricuspid regurgitation, remnant left ventricular morphology, and clinical outcomes, including mortality, transplant, and a composite adverse outcome including heart failure. RESULTS: The mean RV shape template of 329 patients with HLHS (mean age, 14.7±6.3 years) depicted a circumferentially dilated RV with loss of septal concavity. RV end-diastolic volume was independently associated with composite adverse outcome (odds ratio, 6.50; P=0.001). Distinct shape modes were identified, including an apical bulge phenotype that was independently associated with composite adverse outcome (odds ratio, 2.45; P=0.047) and mortality/transplant (odds ratio, 4.24; P=0.004). This variant also correlated with RV dilation, hypertrophy, and impaired regional strain. A spheroidal shape was associated with ≥moderate tricuspid regurgitation and tricuspid annular dilation. Remnant left ventricular morphology influenced RV shape and function but not transplant-free survival. CONCLUSIONS: Our statistical shape modeling analyses provide novel insights into RV geometric remodeling in HLHS and identify specific shape phenotypes associated with dysfunction and adverse outcomes. Shape-based metrics offer additive prognostic value beyond conventional volumetric analysis, with potential implications for risk stratification and surgical decision-making in single-ventricle physiology
Integration of Mental Health Care into Food Allergy Practices: A Work Group Report of the AAAAI Integrative Medicine Committee
No full textPatients with food allergy, clinicians, and researchers have identified mental health support for patients diagnosed with IgE-mediated food allergy and their caregivers as a clinical priority. However, resources that provide guidance on how to integrate mental health professionals into food allergy clinics are lacking. A work group within the Integrative Medicine Committee of the American Academy of Allergy, Asthma & Immunology convened to develop a guidance paper that fills this gap. The report was developed as a practical guide for providers working with patients with food allergy. The report provides specific information on evidence-based mental health treatment approaches and models of care for meeting the mental health needs of patients with food allergy. Further, the report discusses ways that mental health professionals can contribute to food allergy clinics beyond clinical care, including training and research. Tables in the report provide concrete recommendations and resources supporting integration of mental health supports in food allergy clinics