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ABSTRACT Background Microbial overgrowth (MO) in the small intestine can cause gastrointestinal symptoms and may arise from stasis, such as dysmotility. Microtypes of MO include small intestinal bacterial overgrowth (SIBO) and intestinal methanogen overgrowth (IMO). Dyssynergic defecation (DD) is associated with constipation and slow colonic transit (STC). Our aim was to assess the relationship between DD and MO. Methods We retrospectively identified patients who underwent both anorectal manometry (ARM) and balloon expulsion testing (BET) for DD, and MO testing using either small intestinal aspirate culture or breath testing. SIBO was analyzed using two culture thresholds: ≥ 10 5 CFU/mL and ≥ 10 3 CFU/mL. Chi‐square tests compared positive vs. negative results. Key Results 436 patients underwent culture of SB aspirates. At the ≥ 10 5 CFU/mL threshold, 41.7% were diagnosed with SIBO, and 87.4% at ≥ 10 3 CFU/mL. At ≥ 10 5 CFU/mL, percent anal relaxation was significantly lower in SIBO‐positive patients. SIBO patients were more likely to have reduced anal relaxation ( p = 0.032), but no other ARM parameters or BET > 60 s. At ≥ 10 3 CFU/mL, a more negative recto‐anal pressure differential (RAPD) was observed, along with a combination of RAPD < −45 mmHg and resting anal pressure > 90 mmHg. 637 patients underwent breath testing for MO, with 174 positive results, predominantly showing IMO (73%). In this group, BET was significantly longer, and anal relaxation was significantly lower. SIBO at ≥ 10 3 CFU/mL was more prevalent in DD than STC (85.5% vs. 64.7%, p = 0.002). IMO was more common in DD than STC ( p = 0.021). Conclusion/Inferences DD may be a risk factor for MO, often with evidence of methanogenesis.

BACKGROUND: Although chronic obstructive pulmonary disease (COPD) and heart failure with preserved ejection fraction often coexist with overlapping clinical features, they are usually studied separately. The SPIROMICS HF (Subpopulations and Intermediate Outcome Measures in COPD and Heart Failure Study) is testing hypotheses that new computed tomography emphysema subtypes are associated with specific cardiovascular phenotypes (eg, cor pulmonale , cor pulmonale parvus ), common airway branch variants are associated with right heart dysfunction, and symptomatic tobacco-exposed persons with preserved spirometry have signs of increased left ventricular afterload. METHODS: SPIROMICS is a multicenter observational study of COPD with extensive pulmonary phenotyping of participants with ≥20 pack-years smoking and nonsmoking controls. COPD and COPD severity were defined by standard spirometric criteria and symptomatic tobacco-exposed persons with preserved spirometry by ≥20 pack-years, normal spirometry, and COPD Assessment Test score >10. SPIROMICS HF selected all participants in SPIROMICS visit 5 at major sites. Its comprehensive speckle-tracking echocardiography, which included physiological perturbations of leg raise and low-intensity exercise, was harmonized prospectively with the Multi-Ethnic Study of Atherosclerosis Early Heart Failure and HeartSHARE (Combining Omics, Deep Phenotyping, and Electronic Health Records for Heart Failure Subtypes and Treatment Targets) studies. The cardiopulmonary magnetic resonance imaging protocol with gadolinium administration included myocardial fibrosis sequences, pulmonary angiography, time-resolved 3-dimensional cine magnetic resonance imaging (4-dimensional flow) of venous return, and metronome-paced tachypnea to induce dynamic hyperinflation. Coronary artery calcium was assessed on computed tomography scans. The Kansas City Cardiomyopathy Questionnaire was administered. RESULTS: Of the final sample of 753 participants, 57% had COPD (15% mild, 27% moderate, and 15% severe), 18% had symptomatic tobacco-exposed persons with preserved spirometry, 16% were smoking controls, and 8% were nonsmoking controls. Reproducibility of the main measures from speckle-tracking echocardiography (intraclass correlation coefficient, 0.83–0.99), exercise echocardiography (intraclass correlation coefficient, 0.71–0.99) and magnetic resonance imaging (intraclass correlation coefficient, 0.57–0.99) were good-to-excellent, including in severe COPD. CONCLUSIONS: SPIROMICS HF aims to characterize and understand cardiopulmonary interactions in COPD and COPD-related phenotypes to inform targeted treatments for combined cardiopulmonary failure.

Background: Post-treatment prognosis and monitoring are critical for determining the timing of salvage treatment in glioblastoma patients but has been challenging due to difficulties differentiating progression from treatment effects in conventional images. This exploratory study aimed to establish the correlation of radiomics image features from time series of amino acid tracer 18F-DOPA PET images, with outcomes, using machine learning and dimension reduction analysis. Methods: 18F-DOPA PET images were collected for a patient cohort with wild-type IDH and unmethylated MGMT who underwent dose-escalated radiation therapy. Quantitative features were derived from the high uptake region (T/N > 2.0) in pre- and post-radiation therapy follow-up 18F-DOPA PET images. A customized workflow was utilized for pre-selecting predictive features, followed by manifold learning. Machine learning algorithms were employed to establish associations between imaging features and remaining survival (RS), defined as the time between a follow-up scan and date of death. Results: The ML models exhibited 81–83% ROC_AUC in predicting RS evaluated on an independent test dataset. A RS map is proposed for monitoring tumor alterations through serial 18F-DOPA PET scans, demonstrating superior sensitivity and better correlation with survival compared to the RANO criteria. Conclusions: Our study demonstrates that ML models utilizing FU 18F-DOPA PET images have the potential to effectively predict future survival outcomes in patients with glioblastoma treated with dose-escalated radiation therapy. The capability to assess changes in tumor over time through imaging can potentially assist in patient stratification and the selection of salvage treatments, while also aiding in distinguishing treatment effects from genuine tumor progression.

Background/Objective: Hypertension is the most prevalent chronic disease in primary care and a leading cause of cardiovascular morbidity and mortality. Despite existing guidelines, therapeutic inertia and suboptimal control persist. Large language models (LLMs) offer a potential valuable addition to augment clinical decision-making, yet their reliability for guideline-driven tasks remains unverified. This study evaluated the accuracy and safety of hypertension management recommendations generated by three LLMs compared to expert responses. Methods: Fifty-one clinical vignettes representing 17 core hypertension management concepts were constructed by hypertension experts. Each case was submitted to three LLMs (GPT-4, Gemini, MedLM) and a hypertension expert also wrote the “gold standard” answers. Three blinded expert reviewers rated each response on a 4-point accuracy scale, a binary safety (safe/unsafe) scale, and attempted to identify the source (LLM vs. expert) providing the response. Ratings were analyzed using mean scores, percentages of accurate and safe responses, and inter-rater agreement. Results: GPT-4 had the highest accuracy (83%) and safety (86%) scores among LLMs but remained inferior to expert responses (92% accuracy, 93% safety). Gemini and MedLM performed significantly worse (accuracy: 64% and 35%; safety: 73% and 39%, respectively). GPT-4 generated the most guideline-concordant responses (46%) among the three LLMs (Gemini 35%, MedLM 14%), but remains lower than experts’ responses (68%). Evaluators misidentified LLM responses as expert-written in 10 to 25% of cases, particularly with GPT-4. Inter-rater reliability for accuracy ratings was highest for expert-generated responses (ICC 0.81), with progressively lower agreement for GPT-4 (0.76), Gemini (0.70), and MedLM (0.68). A similar pattern was observed for safety and source discrimination ratings. The agreement was strongest for safety assessments and weakest for source discrimination. Conclusion: Among three tested LLMs, GPT-4 demonstrated closer agreement to expert decisions thereby showing greater potential for supporting hypertension management. However, current LLMs’ versions frequently produce inaccurate or unsafe recommendations and remain inferior to expert judgment. Human-in-the-loop supervision remains essential when deploying LLMs for clinical decision-making.

Background: Cardiac disease is the leading cause of premature mortality in Friedreich Ataxia (FA). However, validated prognostic indicators or early imaging biomarkers that can reliably predict cardiac events are lacking. To address this gap, we created a multicenter FA cardiac registry to characterize disease progression and identify early echocardiographic (echo) predictors of major adverse cardiac events (MACE). Methods: FA subjects from 6 North American centers with at least two echos performed ≥5 years apart were included. Demographics, FA-specific disease characteristics, and MACE (a composite of death, heart failure hospitalization, aborted sudden cardiac death, and/or life-threatening arrhythmia) were abstracted. Digital echo images were re-read at a centralized core lab. Paired T tests were utilized for comparison of the normally distributed first and second echo parameters, and logistic regression models were utilized to evaluate for predictors of MACE. Results: Of 115 subjects, 52 (45%) were female. Mean age at diagnosis was 10 ± 3 years, median GAA1 repeat length (a marker of genetic severity) was 700 (range 66–1200), and median age at first analyzed echo was 12 years (range 4-36). MACE occurred in 35 (30%) of the cohort. Serial echocardiograms demonstrated progressive worsening of multiple cardiac parameters over time, including markers of ventricular thickness and hypertrophy, chamber size, systolic function, and novel markers of atrial and ventricular strain (Table 1). On univariate analysis, several markers of hypertrophy and systolic function from the earliest analyzed echo predicted MACE. However, after adjusting for age of diagnosis, GAA1 repeat length, and collinearity among variables, only posterior wall thickness in diastole (PWTd) remained an independent predictor of MACE (odds ratio 1.8 per mm increase, 95% CI 1.1–3.3, p = 0.028). Conclusions: This multicenter FA registry identifies early posterior wall thickness as a significant and independent predictor of major adverse cardiac events in FA. Each millimeter increase in PWTd on early echo is associated with nearly double the odds of MACE. This commonly acquired parameter is often overlooked and may serve as a powerful early marker of cardiac risk. Further investigation of PWTd as a potential surrogate endpoint for therapeutic trials in FA is warranted.

BACKGROUND: Hypertension, the leading cause of cardiovascular mortality, remains suboptimally controlled. Large language models (LLMs) could improve hypertension control by augmenting clinical decision-making, but their reliability for guideline-driven tasks is unverified. This study evaluated the accuracy and safety of hypertension management recommendations generated by 3 LLMs. METHODS: Fifty-one vignettes were constructed and submitted to the LLMs (GPT-4, Gemini, Medical Large Language Model [by Google; MedLM]) and a hypertension expert to generate the responses. Three blinded reviewers rated each response on a 4-point accuracy scale, a binary safety (safe/unsafe) scale, and attempted to identify the source (LLM versus expert) providing the response. RESULTS: GPT-4 had the highest accuracy (83%) and safety (86%) scores among LLMs but remained inferior to expert responses (92% accuracy, 93% safety). Gemini and MedLM performed significantly worse (accuracy: 64% and 35%; safety: 73% and 39%, respectively). GPT-4 generated the most guideline-concordant responses (46%) among the 3 LLMs (Gemini 35%, MedLM 14%) but was lower than expert responses (68%). Interrater reliability for accuracy ratings was higher for LLM-generated responses (GPT-4 [intraclass correlation coefficient, 0.30], Gemini [intraclass correlation coefficient, 0.61], and MedLM [intraclass correlation coefficient, 0.58]), with lower agreement for expert responses (intraclass correlation coefficient, 0.23). A similar pattern was observed for safety and source discrimination ratings. The agreement was strongest for safety assessments and weakest for source discrimination. CONCLUSIONS: Among the 3 tested LLMs, GPT-4 demonstrated closer agreement to expert decisions, thereby showing greater potential for supporting hypertension management. Despite their potential, current LLM versions are inferior to expert recommendations. Human-in-the-loop supervision remains essential when deploying LLMs for clinical decision-making.

Abstract Background and Aims Malignancy is commonly seen in patients with membranous Nephropathy (MN) with a prevalence up to 22%. M-type phospholipase A2 receptor (PLA2R) antigen and its associated antibody account for up to 80% of the cases but its association with malignancy is less clear. To date, no study has specifically evaluated cancer incidence and risk factors in patients with PLA2R associated MN as most studies were conducted in an era before many MN antigens were identified. Here, we report cancer incidence, types of cancer, and effect of immunosuppressive therapy and clinical parameters in a cohort of patients with PLA2R-associated MN. Method A single center retrospective cohort study in adults with diagnosis of PLA2R associated MN from 1/1/1996 to 12/31/2021. Follow-up was defined as the time from MN diagnosis to the last follow-up or if the patient initiated dialysis or underwent transplantation. The primary outcome in this study was the incidence of cancer events reported as cancer incidence/1000 patients/year. The cancer events were compared to the age-adjusted United States (U.S.) general population using Centers for Disease Control (C.D.C) data. The standardized incidence ratio (SIR) was calculated by dividing the cancer rates in our cohort to the cancer rates in general population. Time-to-event analysis was conducted using the Kaplan-Meier method. The log-rank test compared age, sex, smoking habits, hypertension, diabetes, body mass index (BMI), previous immunosuppression (IS), remission of the MN, PLA2R titers at the time of diagnosis. Cox proportional hazards regression was used to evaluate the associations between baseline characteristics and cancer incidence. For the multivariate model of cancer incidence, we evaluated variables clinically relevant for the outcome. Results We identified 239 patients with PLA2R-associated MN, with mean (±SD) age of 52 (±13) years, with 72.8% male (n = 174), median [IQR] BMI of 29.8 [26.3, 33.6] kg/m2, median eGFR of 68 [45, 94] ml/min, median proteinuria of 8.2 [5.1, 11.2] g/24h, and median PLA2R titers of 38 [9, 122] RU/ml. Common comorbidities included hypertension (60.2%), and diabetes (17.1%). Majority of patients drank alcohol (90.7%) and 32.6% were smokers (active or former). Of 239 patients, 15 had a history of cancer before the MN diagnosis. But in all these patients, cancer had been treated and was considered to be in full remission. A diagnosis of cancer was made in 37 patients (15.4%) during a median follow-up of 60 [27.5, 145.5] months. Incidence of cancer in our cohort was 22.6 [95% CI, 15.9 to 31.1] per 1000 persons/year. In comparison, age adjusted U.S. general population has a lower cancer incidence of 15.9 [95% CI, 15.9 to 16.1] cases per 1000 person/year. The resulting SIR of cancer in our cohort was 1.42. This SIR is lower than the one reported by Bjørneklett and al. (2007) in a Norwegian cohort that included all patients with MN and was not limited to PLA2R-positive MN. The cumulative incidence of cancer diagnosis is shown in Fig. 1. Mean age at cancer diagnosis was 66 (±10.2) years old. Prostate cancer was the most common (n = 11) type of cancer, followed by skin cancer (n = 9), followed by cancer of the urinary tract (n = 5). In univariate and multivariate analysis (Table 1), only older age (&gt;65 years) and tobacco use were associated with statistically significant increased risk of cancer. Other clinical parameters such as sex, eGFR, baseline proteinuria, BMI, hypertension, diabetes, alcohol use, anti-PLA2R antibody titer, type of immunosuppression, remission status (partial, complete, no response) were not associated with a significant increased risk of cancer. Conclusion Patients with PLA2R associated MN are at increased risk of developing cancer following diagnosis compared to general population and routine age-appropriate cancer screening in this population is essential. The increased incidence of cancer is independent of IS therapy, response to therapy or other comorbidities. These data suggests that there are likely mechanisms beyond the traditional risk factors at play that may be unique to the presence of PLA2R antibodies.

Introduction: Excess sodium intake is strongly linked with hypertension and cardiovascular disease (CVD); people with narcolepsy (PwN) have increased CV risk. Hypothesis: Switching from high-sodium oxybate (SXB; Xyrem ® ; 6–9 g for ≥6 wks) to low-sodium oxybate (LXB; Xywav ® ; same regimen) reduces mean 24-hr ambulatory systolic blood pressure (ASBP) after ≈6 wks in PwN, regardless of antihypertensive (anti-HTN) use and site type. Methods: XYLO, an open-label, single-arm study (NCT05869773), assessed PwN aged 18−70 y with office SBPs of 130−155 mmHg. The primary and key secondary endpoints were changes from baseline (BL) to end-of treatment (EOT) in mean 24-hr ASBP and seated resting (“office”) SBP (OSBP), respectively; exploratory endpoints were diastolic BP (DBP) changes. Changes are baseline adjusted. Prespecified subgroup analyses explored BL anti-HTN use and participation site (ie, site-based [at study site] vs decentralized [at-home]). Results: In 43 PwN (mean age, 45 y; female, 65%; anti-HTN, 33%), mean±SD BL OSBP and DBP were 138.0±5.7 and 85.2±6.6 mmHg, respectively. Mean±SD total SXB vs LXB dosages were 8.0±1.1 vs 8.1±1.1 g/night, reflecting 1457±206 vs 118±16 mg sodium (difference: ≈1339 mg); median 24-hr urinary sodium was 4232 mg/d at BL and 2703 mg/d at EOT (median change: 1288 mg/d). Mean change in 24-hr ASBP (least squares mean [95% CI]) was −4.1 (−6.9, −1.4; 1-sided P =0.0019) mmHg (Fig 1) ; mean change in OSBP was −9.2 (−11.9, −6.5; 1-sided P <0.0001). Mean changes in 24-hr ambulatory and office DBP were −2.3 (−4.1, −0.5; 2-sided P =0.0118; nominal) and −3.8 (−6.0, −1.6; 2-sided P =0.0014; nominal) mmHg, respectively. In subgroups, mean change in 24-hr ASBP was −4.6 (−9.6, 0.3) mmHg with BL anti-HTN use and −3.9 (−7.3, −0.5) mmHg without BL anti-HTN use; changes in OSBP were −11.8 (−16.5, −7.1) and −7.9 (−11.1, −4.6) mmHg. Mean change in 24-hr ASBP was −3.6 (−8.0, 0.9) mmHg for site-based and −4.5 (−8.1, −1.0) mmHg for decentralized participation. Corresponding changes in OSBP were −9.0 (−13.3, −4.6; site-based) and −9.3 (−12.8, −5.8; decentralized) mmHg with a downward trend over 6 wks ( Fig 2 ). Treatment-emergent adverse events (all mild/moderate) occurred in 40% of PwN (N=67). Conclusions: Switching from SXB to LXB reduced daily medication-related sodium intake in PwN and was associated with clinically meaningful BP reductions overall and across subgroups, consistent with evidence on dietary and medication-related sodium effects.

BACKGROUND: People with narcolepsy are at increased risk for hypertension and cardiovascular disease; excessive sodium intake is linked to both. METHODS: We studied patients with narcolepsy and office systolic blood pressures (BPs) of 130 to 155 mm Hg taking twice-nightly high-sodium oxybate for ≥6 weeks who switched to low-sodium oxybate at the same dosage. The primary end point was the change from baseline in mean 24-hour ambulatory systolic BP at the end of treatment (≈6 weeks after switching). Secondary and exploratory end points included changes in diastolic BP, office BP, and 24-hour sodium excretion. RESULTS: Patients (n=43) had a mean age of 45 years, were 65% female, 33% on antihypertensives, with baseline mean (SD) office BP of 138.0/85.2 (5.7/6.6). Mean (SD) total high- and low-sodium oxybate dosages of 8.0 (1.1) and 8.1 (1.1) g/night, respectively, represented 1456.5 (206.2) and 117.8 (16.3) mg of sodium. The median 24-hour urinary sodium was 4278 mg/d at baseline and 2703 mg/d at the end of treatment (median change, 1288 mg/d). Mean (SE) 24-hour ambulatory systolic BPs at baseline and study end were 132.3 (1.8) and 128.2 (1.8) mm Hg (least-squares mean change, −4.1 [95% CI, −6.9 to −1.4] mm Hg; 1-sided P =0.0019). BP changes by narcolepsy subtype, sex, body mass index, baseline office BP, and baseline antihypertensive use were consistent with the overall effect size. CONCLUSIONS: People with narcolepsy switching from high- to low-sodium oxybate showed substantially reduced daily medication-related sodium intake and significant 24-hour BP reductions. These results demonstrate the importance of reducing pharmaceutical sodium content in this elevated cardiovascular risk patient population. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05869773.