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Introduction: Diabetes affected 529 million people globally by 2021, largely due to rising obesity contributing to Type 2 diabetes (DM2). In the U.S., it is the seventh leading cause of death and closely linked to cardiovascular disease, the leading cause of mortality in this population. Effective, low-cost strategies to improve glycemic and cardiometabolic health are essential. Psyllium, a viscous soluble fiber, has been shown to lower LDL cholesterol and improve glycemic indices, whereas non-viscous fibers like wheat dextrin lack similar benefits. Emerging lipid markers such as ceramides are associated with cardiometabolic risk but have not been studied in response to fiber. The interaction between fiber and GLP-1 agonists is also unclear. Hypothesis: Psyllium supplementation will improve cardiometabolic markers more than wheat dextrin in people with DM2. Methods: In this randomized trial at Mayo Clinic, adults with DM2 (HbA1c 6.5–10%) were randomized to psyllium or wheat dextrin for 12 weeks. Participants were recruited via electronic health records. Key exclusions: GI disease, bariatric surgery, steroid use, and pregnancy. Follow-up visits occurred at weeks 4, 8, and 12. Primary endpoints were changes in HbA1c and fasting glucose; secondary endpoints included lipids, ceramides, hsCRP, and BMI. An ex post facto analysis evaluated GLP-1 use. Primary analysis was intention-to-treat. Adherence = ≥85% dose completion. Results: Ninety-eight participants enrolled (Psyllium n=50, Dextrin n=48) with similar baseline characteristics. At 12 weeks, psyllium significantly reduced HbA1c (-0.38 ± 0.69, p=0.002). Among adherent users, HbA1c dropped further (-0.41 ± 0.70, p=0.001) with reduced fasting glucose (-14.5 ± 38.2, p=0.013). Wheat dextrin showed no benefit. In subgroup analysis, GLP-1 users on psyllium saw greater HbA1c reductions than non-users (-0.45 vs. -0.23), while GLP-1 users on dextrin had no change (+0.06). No significant changes were found in ceramides, lipids, or BMI in any analysis. CRP trended lower in adherent psyllium users (p=0.055). Conclusion: Psyllium significantly reduced HbA1c over 12 weeks in DM2, especially in adherent and GLP-1–treated groups. Effects may be attributed to psyllium's ability to form a gel in the gastrointestinal tract, modulating nutrient absorption. No effects were seen on ceramides or lipids, likely due to low baseline levels in the latter. Psyllium appears to be a safe, accessible adjunct for glycemic control in DM2.

Abstract Disclosure: S.R. Chacko: None. C. Powell: None. B. Ndovu: None. E.Y. Ferreira: None. R. Rosenberg: None. J. Saini: None. S. Nevin: None. K. Yu: None. V. Fell: None. J.J. Larson: None. E. Atkinson: None. I. Bancos: Funding for investigator-initiated research from Esteve. Context: Mild autonomous cortisol secretion (MACS), found in about 50% of patients with adrenal incidentalomas, is associated with increased cardiovascular morbidity. While adrenalectomy improves outcomes in unilateral MACS, safe and effective medical therapy is needed for bilateral MACS. Objectives: To evaluate the tolerability and safety of overnight metyrapone in adults with MACS. Methods: Study design: Open-Label, Phase 2, Clinical Trial (NCT06106295) Participants: Patients >18-years-old with MACS and benign adrenal imaging phenotype were prospectively enrolled between December 2023 and January 2025. MACS was diagnosed based on 1 mg post-dexamethasone suppression test serum cortisol >1.8 mcg/dL. Eligibility required at least one MACS-associated comorbidity (obesity, dysglycemia, dyslipidemia, hypertension, osteopenia or osteoporosis). Intervention: Metyrapone was administered at an initial dose of 250 mg each evening with up titration in 250 mg increments every 2-4 weeks based on tolerance, to a maximum of 1000 mg. Outcomes: The primary endpoint was assessment of treatment-related adverse events (AE), categorized by CTCAE grade. Adrenal insufficiency (AI) was considered an AE, assessed on biochemistry and AddiQoL survey. Sample size: 30 patients projected Results: Twenty-six patients with MACS [median age 66 years (IQR 61-68), 69% women] were enrolled. At the time of analysis, median metyrapone dose was 1000 mg (IQR 750-1000). At median follow-up of 3 months (IQR 2-6), 22 patients (85%) developed at least one AE. None were serious, aside from one patient with an acute kidney injury (AKI), unlikely related to metyrapone. All other AEs were CTCAE Grade 1-2, including dizziness 12%, nausea 6% and fatigue 5%. Of all 90 AEs, 12 (13%) occurred at a dose of 250 mg, 10 (11%) at 500 mg, 20 (22%) at 750 mg and 48 (53%) at 1000 mg. One (1%) was definitely related to metyrapone (hypokalemia), 16 (18%) probably related, 20 (22%) possibly related, 35 (39%) unlikely to be related, and 18 (20%) unrelated to metyrapone. Dose was reduced in 5 patients (19%) due to an AE. Two discontinued metyrapone, one because of AKI, while the other withdrew from the study. Morning serum cortisol was not significantly changed between baseline [11.5 (IQR 9.2-14.8)], 3 months [12.0 (IQR 11.0-15.0)], and 6 months [9.7 (IQR 7.9-12.5)] (normal: 4.8-20 mcg/dL). No patient developed AI (morning serum cortisol <10 mcg/dL and ACTH >60 pg/ml), but plasma ACTH significantly increased from baseline to 3 months [8.0 (IQR 5.4-20.8) vs. 18.0 (IQR 14.0-28.0), P=0.021] (normal: 10-60 pg/ml). Between 3 and 6 months, no significant change occurred in ACTH. AddiQol survey scores did not change significantly between baseline, 3 and 6 months. Conclusion: Metyrapone therapy in patients with MACS demonstrated a favorable safety profile with no occurrence of AI. Further investigation into efficacy and MACS-associated outcomes is warranted. Presentation: Sunday, July 13, 2025

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Abstract Objective The objective of this study is to characterize contemporary surgical management practices and factors influencing surgical decision‐making in the management of Lennox–Gastaut Syndrome (LGS) across pediatric epilepsy centers in the United States. Methods A 45‐item cross‐sectional survey was developed and distributed to Pediatric Epilepsy Research Consortium centers. Domains included institutional demographics, surgical evaluation timing and goals, presurgical workup, procedural utilization and outcomes, and barriers to surgery. Descriptive statistics and thematic analysis were performed. Results Thirty‐two pediatric epilepsy centers participated (38% response), the majority comprising pediatric epileptologists at Level 4 National Association of Epilepsy Centers. Most centers (66%) considered surgery after failure of 3–4 antiseizure medications. Presurgical workup typically included brain magnetic resonance imaging (MRI), long‐term electroencephalography (EEG) monitoring, and neuropsychological assessment, while use of functional imaging, magnetoencephalography, and intracranial EEG varied considerably. All centers offered vagus nerve stimulation and corpus callosotomy; 80%–90% offered resection, hemispherectomy, responsive neurostimulation (RNS); 60%–65% offered deep brain stimulation (DBS) and laser ablation. Among centers offering RNS, half targeted thalamic structures exclusively, and the remainder targeted cortical or combined cortical‐thalamic structures; the centromedian nucleus was the preferred thalamic target for RNS and DBS. Surgical decision‐making was influenced by patient characteristics, procedural considerations, and systemic factors. Seizure frequency, family preference, and multidisciplinary input were highly rated across all interventions. Etiology was critical for resection and hemispherectomy, while financial constraints, insurance barriers, and the need for future neuroimaging impacted neuromodulation selection. Scenario‐specific trends included less frequent consideration of DBS and RNS in children under five years, less use of hemispherectomy in older children, preference for corpus callosotomy in children with predominantly drop seizures, and procedural selection based on MRI findings. Significance Substantial variability exists in the surgical management of LGS. These findings highlight critical opportunities to harmonize practices, reduce disparities, and guide comparative effectiveness research to optimize outcomes. Plain Language Summary Lennox–Gastaut Syndrome (LGS) is a severe form of epilepsy that may require surgery when medications are not effective. This study found that surgical care for LGS varies widely across pediatric epilepsy centers in the United States, including when surgery is recommended, how patients are evaluated, and which procedures are available. Newer approaches such as brain stimulation are being used more often, although access remains inconsistent. These findings highlight the need for clearer treatment pathways to ensure that children with LGS have equitable access to the best possible care.

ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

Background & Aims: Liver transplantation (LT) remains the only cure for severe polycystic liver disease (PLD). However, LT indications and strategies vary across Europe, resulting in (unwanted) practice variation and unequal access to care for patients with PLD. This study aimed to (1) identify existing PLD-specific LT criteria across European countries, (2) assess which criteria are considered relevant by specialist, and (3) map the variation in liver-kidney transplant strategies among patients with autosomal dominant polycystic kidney disease (ADPKD). Methods: National PLD-specific LT criteria were collected, and if unavailable ERN RARE-Liver representatives from that country were asked to provide information. An online survey was conducted amongst hepatologists, LT surgeons, and nephrologists managing patients with PLD. The survey assessed relevant LT indications/listing requirements, clinical case evaluations, and explored preferences for liver-kidney transplantation in patients with ADPKD. Results: Defined LT criteria for patients with PLD were available in only 8 of the 17 assessed countries and showed substantial variation. Sixty-nine clinicians (43 hepatologists, 15 surgeons, 11 nephrologists), predominantly from LT centers (75.4%), completed the survey. Key LT indications were recurrent liver cyst infections (78.3%), significant impaired quality of life (75.4%), and severe malnutrition (75.4%). In ADPKD simultaneous liver-kidney transplantation (SLK) was preferred by 40.4% of respondents, primarily due the favorable immunological profile (47.6%) and prevention of renal failure (33.3%). In contrast, those favoring a liver-first approach (30.8%), followed by sequential kidney transplant, highlighted the potential harm to the kidney graft during SLK (62.5%). Conclusions: Uniform PLD-specific LT criteria in Europe are lacking. While recurrent liver cyst infections, decreased quality of life, and malnutrition are widely recognized as crucial LT indications, they are insufficiently reflected in existing criteria, contributing to unequal access to LT. Moreover, considerable variation exists in liver-kidney transplantation for ADPKD patients, with a current lack of evidence to support one approach over another.

Background There is a global mismatch between the number of adults with congenital heart disease and adult congenital heart disease (ACHD) cardiologists, potentially impacting patient outcomes. This survey explores factors influencing trainees and cardiologists' career choices in ACHD. Methods An online, anonymous global survey on demographics, ACHD as a career choice, encouraging and deterring factors assessed via a 5‐point Likert scale and open‐ended questions on recommending ACHD was distributed through targeted emails and social media. Responses meeting a 75% completion criterion were analyzed using descriptive statistics and thematic analysis. Results Among 811 included responses, most were from women (53.5%), aged 31 to 40 years (48.3%), White individuals (43.3%), non‐Hispanic individuals (85%), from outside the ACHD field (79.0%), and from North America (42.7%). Only 30.9% of non‐ACHD physicians considered specializing in ACHD despite 78.9% recommending it. Encouraging factors included awareness of ACHD significance, mentor influence, and clinical exposure. Key deterrents were inadequate financial incentives, limited job opportunities, and lengthy training. Regional variations showed that longer training duration and lack of compensation incentives were the main deterrents in North America. Suggested solutions included structured training programs, salary improvements, and early ACHD exposure during medical education. Conclusions Less than a third of respondents considered ACHD as a career largely due to inadequate financial incentives, limited job opportunities, and long training duration. Addressing these barriers could enhance recruitment and help meet the growing demands of the ACHD population.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

ImportanceEtiologic heterogeneity in breast carcinogenesis needs to be well characterized for targeted prevention. Associations between menopausal hormonal therapy (MHT) and oral contraceptive (OC) use and breast cancer intrinsic-like subtypes are not well understood.ObjectiveTo examine whether exogenous hormone use is differentially associated with breast cancer subtypes and to evaluate heterogeneity by intrinsic-like subtypes.Design, Setting, and ParticipantsThis study pooled data from 31 nested and population-based case-control studies involved in the Breast Cancer Association Consortium. The study population included individuals with breast cancer and control participants from 13 case-control studies nested in prospective cohorts (recruited between 1982 and 2011) and 18 population-based case-control studies (recruited between 1990 and 2013). Data analysis was performed in June 2024.ExposureMHT use (estrogen-progestin therapy [EPT] or estrogen-only therapy [ET]) in postmenopausal women and OC use in premenopausal women (never, past use, or current use).Main Outcomes and MeasuresBreast cancer intrinsic-like subtypes (luminal A–like, luminal B–like, luminal B–ERBB2 [formerly HER2 or HER2/neu]-like, ERBB2 enriched–like, or triple-negative) were determined by immunohistochemistry of tumor sections. Polytomous logistic regression was performed to estimate the association between exogenous hormones and risk of breast cancer by intrinsic-like subtypes. Analyses by subtypes were stratified by body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; healthy weight, 18.5-<25; overweight, 25-<30; or obesity, ≥30).ResultsThis study included 42 269 individuals with breast cancer (11 901 [28.2%] premenopausal and 30 368 [71.8%] postmenopausal; 23 353 [55.2%] had a known intrinsic-like subtype) and 71 072 control participants. The mean (SD) age of all participants was 57.9 (10.9) years. In postmenopausal women, associations between current MHT use (EPT or ET) and breast cancer differed by subtype. Current EPT users with healthy weight were more likely to be diagnosed with luminal A–like (odds ratio [OR], 2.51 [95% CI, 2.26-2.80]) or luminal B–ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes. These associations were attenuated but remained for individuals with overweight (OR, 1.40 [95% CI, 1.02-1.92]) or obesity (OR, 1.68 [95% CI, 1.01-2.78]). EPT use increased the odds of being diagnosed with luminal B–like tumors solely in women with healthy weight (OR, 1.47 [95% CI, 1.17-1.86]). Current ET use was positively associated with luminal A–like disease in women with healthy weight only (OR, 1.16 [95% CI, 1.01-1.32]), showing inverse associations with higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]). In premenopausal women, recent OC use was associated with luminal B–ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched–like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75 [95% CI, 1.33-2.29]; P < .04 for heterogeneity) tumors.Conclusions and RelevanceIn this study, clear differences were observed in associations between current EPT use and luminal-like breast cancer subtypes and other subtypes. EPT users with healthy weight were more likely to be diagnosed with luminal-like breast cancer compared with nonusers. Subtype heterogeneity was less apparent in associations of OC and ET use. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted.

Vitamin D (VitD) is an essential nutrient for preventing rickets in breastfeeding infants. Maternal supplementation is the preferred method for infant nutrition, yet concentrations of VitD and 25-hydroxyvitamin D (25OHD) in breastmilk are low unless the mother consumes substantial doses of vitamin D. Recently, we reported that sulfate-conjugated forms of vitamin D (VitD-S) and 25-hydroxyvitamin D (25OHD-S) are present in breast milk. Freshly expressed breast milk from mothers who were vitamin D-sufficient (serum 25OHD >50 nmol/L) contained approximately 6 nmol/L VitD-S and 0.5 nmol/L 25OHD-S. It is hypothesized that these sulfated metabolites are contributing to the total vitamin D nutritional value of milk; however, their physiological roles in infant nutrition are not yet understood. In order to assess their nutritional value, we evaluated two aspects that can affect the delivery and uptake of the nutrients by infants: breast milk storage and infant digestion. The United States Centers for Disease Control and Prevention recommends that breast milk can be stored safely at room temperature (22°C) for ≤4 hours, in refrigeration (4°C) for <4 days, or frozen (-20°C) for 6 months. After implementing the recommended storage conditions on breast milk samples, the metabolites, VitD-S and 25OHD-S, were measured by LC-MS/MS and UV spectroscopy. We observed that in breast milk stored at room temperature or 4°C, the metabolites undergo molecular degradation by isomerization within 24 hrs. Therefore, breast milk stored overnight (>8 h) in refrigeration will not provide the sulfated vitamin D metabolites to the infants. To evaluate molecular integrity of the sulfated metabolites during infant digestion, we collected saliva and fecal matter samples from infants, 1-6 months of age, who were either exclusively breastfed or breastfed and supplemented with formula ( ClinicalTrials.gov , NCT 06203041). The sulfatase enzymatic activity was assessed in the saliva and fecal matter samples by colorimetric assay. Overall, the sulfatase activity (mean ± SD) in saliva was 0.8 ± 0.7 nM/mg/min, ranging 0.0-2.5 nM/mg/min (n=13). The sulfatase activity in fecal samples was significantly greater than saliva ( P = 0.009), averaging 1.8 ± 1.4 nM/mg/min and ranging 0.1-4.9 nM/mg/min (n = 9) across infant samples. In a comparison between infants based on diet, we observed greater sulfatase activity in the fecal matter of exclusively breastfed infants than in infants that were breastfed with formula ( P = 0.056). This observational study is ongoing and not yet statistically powered. The presence of sulfatase activity in the infant digesta suggests that VitD-S and 25OHD-S are subject to enzymatic sulfate hydrolysis prior to absorption. Furthermore, infants who are exclusively breastfed may utilize the hydrolysis pathway more effectively than infants who are supplemented with formula. In summary, the nutritional value of VitD-S and 25OHD-S is affected by both milk storage and infant digestion. Future clinical studies investigating vitamin D nutrition in breastfed infants should consider evaluating storage of breast milk and diet of the infant as important parameters in the statistical models and analyses. The Mayo Clinic Parker D. Sanders & Isabella G. Sanders Professor of Family Medicine Endowment, Mayo Clinic Women’s Health Center Pilot Award Project. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.