Citations

Cancer-induced muscle wasting affects many people with cancer, reducing treatment tolerance and survival. We identified a natural dietary compound, ursolic acid, that attenuates muscle atrophy across five preclinical cancer models spanning pancreatic, colon, and lung cancer. Ursolic acid inhibits cancer-induced changes in muscle mRNA expression, preserves muscle strength, and remains protective during chemotherapy, without affecting food intake or tumor burden. These results identify ursolic acid as a promising, translatable dietary supplement for supportive cancer care.

Background The prevalence and clinical correlates of extra-aortic vascular disease in Marfan syndrome remain incompletely defined, and current surveillance strategies primarily target the thoracic aorta. Methods We conducted a multicentre retrospective cohort study of 783 patients with Marfan syndrome across three tertiary centres, with systematic chart and imaging adjudication to define aneurysm and dissection distribution. Results Extra-aortic aneurysms were identified in 32% of patients, most commonly involving the iliac, carotid and subclavian arteries. Extra-aortic dissections occurred in 5.2%. Extra-aortic aneurysms clustered strongly with markers of advanced aortic disease, including abdominal aortic aneurysm (adjusted OR 3.48), prior aortic dissection (OR 3.39) and extra-aortic dissection (OR 4.44), as well as age >40 years and male sex. Genetic confirmation status was not associated with extra-aortic aneurysm presence. Conclusions Extra-aortic vascular involvement is common in Marfan syndrome and closely linked to advanced aortic pathology. These findings support risk-stratified vascular imaging beyond the thoracic aorta in higher-risk patients.

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

BACKGROUND: Hemorrhagic risk in dural arteriovenous fistulas (dAVFs) is largely determined by venous anatomy, but the contribution of systemic cardiovascular factors and their medical therapy remains poorly defined. This study examined associations between cardiovascular risk factors and antithrombotic use and hemorrhagic presentation, angiographic obliteration, and early functional outcomes after treatment. METHODS: We analyzed 1350 adults with intracranial dAVFs from the international Consortium for Dural Arteriovenous Fistula Outcomes Research registry, which retrospectively accrued cases across 14 centers in 4 countries between 1990 and 2017. Demographics, cardiovascular comorbidities, antithrombotic use, angioarchitectural features, treatment strategies, and follow-up outcomes were collected from prospectively maintained databases. Primary end points were hemorrhagic presentation, angiographic obliteration, and 90-day functional status after treatment. Univariable and multivariable logistic regressions were performed with model-specific adjustments. RESULTS: Hemorrhage occurred in 375 patients (27.8%) and was most strongly associated with high-grade dAVF classification and male sex; antithrombotic therapy was associated with lower odds of hemorrhagic presentation. Other cardiovascular risk factors showed no independent relationship with bleeding. Angiographic obliteration was achieved in 621 of 845 patients (73.5%). Hemorrhagic onset, high dAVF grade, and surgical treatment were independently associated with angiographic obliteration, whereas smoking and embolization demonstrated only nonsignificant trends after adjustment. At 90 days, 934 patients (88.9%) were functionally independent. Baseline modified Rankin Scale score was the strongest factor associated with 90-day functional outcome, while neither cardiovascular comorbidities nor treatment modality independently influenced functional status. CONCLUSIONS: In this large multicenter dAVF cohort, hemorrhagic presentation was most strongly associated with venous angioarchitecture. Male sex and antithrombotic therapy were also independently associated with hemorrhagic presentation. Angiographic obliteration was common, particularly among surgically treated lesions, and 90-day functional outcome was most strongly associated with baseline functional status.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Abstract Background Glioblastoma (GBM) is driven, in part, by glioma stem cells (GSCs), which sustain therapeutic resistance and recurrence. OLIG2 is a key regulator of GSC programs but the signaling pathways that cooperate with Oligodendrocyte transcription factor 2 (OLIG2) to maintain GSC states remain incompletely defined. Although Signal transducer and activator of transcription (STAT) signaling has been implicated in GSC biology, work to date has focused primarily on STAT3, and the contribution of STAT5 remains poorly defined. Here, we investigated whether STAT5B functionally cooperates with OLIG2 in sustaining GSC phenotypes. Methods Transcriptomic analyses, proximity ligation assays and biochemical studies were utilized to define OLIG2-STAT5B interactions in patient-derived GSCs. Functional consequences of OLIG2, STAT5B, BIRC5, and NUSAP1 suppression were assessed using small interfering RNA/short hairpin RNA-knockdown, stemness, and migration assays in EGFRvIII-expressing GSCs. In vivo tumor growth studies were performed using orthotopic xenograft models. Results OLIG2 and STAT5B expression were positively correlated in GBM datasets and patient-derived models. OLIG2 physically associated with STAT5B in EGFRvIII-expressing GSCs, and loss of OLIG2 reduced STAT5 activation, supporting a functional link between these factors. OLIG2 or STAT5B suppression induced convergent transcriptional changes, including downregulation of genes associated with GSC maintenance and proliferation, notably stemness regulators BIRC5 and NUSAP1. Silencing BIRC5 or NUSAP1 impaired GSC self-renewal and migration. In orthotopic models, STAT5B knockdown prolonged survival and phenocopied OLIG2 suppression and stemness loss. Conclusions These findings identify STAT5B as a functional partner of OLIG2 in GBM and define anOLIG2-STAT5B transcriptional axis that sustains GSC maintenance and malignant behavior. Targeting this axis may represent a therapeutic strategy to disrupt treatment-refractory glioma cell states.

Abstract Introduction Central sleep apnea (CSA) may occur as an adverse effect of sodium oxybates, a medication commonly used to treat narcolepsy with cataplexy. Management is challenging, as sodium oxybates remain essential for symptom control in many patients, yet untreated CSA poses substantial respiratory risk. We present a rare case of sodium-oxybate–associated CSA successfully treated with adaptive servo ventilation (ASV), representing, to our knowledge, the first documented use of ASV for this indication. Methods A 49-year-old woman with longstanding narcolepsy with cataplexy presented with worsening daytime sleepiness despite stable use of sodium oxybate. She had been receiving a very high dose prescribed by an outside provider (6.75 g twice nightly), exceeding the recommended maximum of 4.5 g twice nightly, and her dose was subsequently adjusted to 4.5 g twice nightly. An in-lab polysomnogram revealed moderate central sleep apnea (AHI 21; RDI 23) with predominantly central events. Because the patient did not wish to wean or discontinue sodium oxybate—reporting that it remained the only therapy that consistently improved her sleep and cataplexy—adaptive servo ventilation (ASV) titration was pursued as the next step in management. She had previously failed multiple stimulants, wake-promoting agents, and SSRIs due to either limited efficacy or intolerable side effects. Her BMI was 18 kg/m2, she was not taking any CNS depressant medications, and her echocardiogram demonstrated a normal ejection fraction. Results The patient tolerated ASV well. Final settings included an EPAP of 5 cm H₂O with a pressure support range of 3–15 cm H₂O and minimal leak. Her adherence was excellent, with more than 93% of nights exceeding four hours of use. Residual AHI improved to 4.6 events per hour, accompanied by noticeable improvement in daytime alertness. She continued sodium oxybate without any respiratory complications. Conclusion ASV may be an effective and well-tolerated therapy for sodium-oxybate–induced CSA in patients who must continue the medication. Sodium oxybate can induce CSA by acting on GABA-B receptors in the Kölliker–Fuse and pre-Bötzinger complex, suppressing respiratory drive and depressing hypoglossal motor output. This case highlights the successful use of ASV in treating CSA secondary to oxybates when the medication cannot be weaned or discontinued. Support (if any)

Abstract Introduction Hypoglossal nerve stimulators (HGNS) are used in patients with moderate-to-severe obstructive sleep apnea (OSA) who are unable to tolerate or do not respond to continuous positive airway pressure (CPAP) therapy. However, a subgroup of patients fail to achieve resolution of OSA with HGNS alone. Previous studies have shown that lower BMI, lower nadir oxygenation, decreased sleep latency, and higher VOTE score on drug-induced sleep endoscopy (DISE) predict better treatment outcome. We hypothesize that baseline diagnostic polysomnography (PSG) may further predict which patients will achieve successful therapeutic outcome with HGNS therapy. Methods We conducted a retrospective analysis of all adult patients who underwent HGNS implantation at Mayo Clinic Arizona between 2019-2025 and had a pre-implantation diagnostic PSG available for review. Treatment success was defined by Sher Criteria: >50% reduction in post-treatment apnea hypopnea index (AHI) to a final AHI of < 20/hr. Responders met Sher criteria and non-responders did not meet Sher criteria. Demographics, sleep questionnaire results, PSG variables, and VOTE score on DISE were collected and analyzed using Spearman’s rank correlation of reduction in AHI. Results Twenty-three patients (11M/12F, median age: 69[IQR:64,75] years) met inclusion criteria. Median baseline AHI was 24[IQR:19,37]/hr. Median post-implant AHI was 8 [IQR:3, 14]/hr. Responders (n=15, 65%) and non-responders (n=8, 35%) demonstrated median post-implant AHI of 4.5[IQR:2.3,7.3]/hr and 15.7[IQR:12.3,28.5]/hr, respectively. Treatment response was associated with less time with SpO2 < 88% (T88%) (21min [IQR:3,64] vs. 73[IQR:36,105mins]; p=0.023) and higher central apnea index (CAI) (1[IQR:0.1,3] vs. 0[IQR:0,1], p=0.03) on pre-implantation PSG. Conclusion In this small cohort of OSA patients, less nocturnal hypoxemia as defined by T88% and higher baseline central apnea index were predictors of better treatment response to HGNS therapy as measured by Sher criteria. We hypothesize that greater nocturnal hypoxemia likely reflects more severe airway obstruction during sleep. Our analysis also showed that responders had higher baseline CAI than non-responders, however we believe this association is not clinically significant and likely driven by one outlier (CAI 13/hr). Further analysis in a larger HGNS cohort is needed to confirm these findings. Data enrichment efforts and more sophisticated analyses are underway. Support (if any)

Abstract Introduction Positive airway pressure (PAP) therapy is the standard treatment for obstructive sleep apnea (OSA); however, its use may be contraindicated in patients with recurrent pneumothorax, particularly in the presence of emphysematous lung disease and bleb formation. Hypoglossal nerve stimulation (HGNS) offers a non–positive-pressure alternative for appropriately selected patients. We describe what is, to our knowledge, the first reported case of successful HGNS therapy in an older adult with severe OSA and multiple recurrent pneumothoraces. Methods An 87-year-old man with severe OSA (baseline AHI 38, predominantly obstructive events) experienced multiple right-sided pneumothoraces beginning in December 2022, several of which were temporally associated with BiPAP use at 17/9 cm H₂O. His episodes required repeated interventions, including chest tubes, thoracoscopy with apical bleb resection and pleurodesis, and several pigtail catheter placements. Chest CT imaging demonstrated emphysema with multiple blebs, raising concern for the safety of continued PAP therapy. A mandibular advancement device was deemed inappropriate due to disease severity. The patient’s BMI was 27 kg/m2. HGNS was considered a suitable alternative. Results HGNS implantation was completed without complications. At activation, both the sensation and functional thresholds measured 0.8 V, with excellent tongue protrusion and waveform quality. The device was programmed to 0.8–1.8 V with a 30-minute start delay, 12-hour nightly duration, and 15-minute pause. On follow-up, the patient demonstrated excellent adherence (average 70 hours/week), progressed to level 8 (1.6 V), and reported significant clinical improvement with resolution of snoring and apneas. Functional threshold and waveform analysis at 1.6 V remained optimal. Importantly, the patient tolerated HGNS well without any further episodes of pneumothorax following implantation. Conclusion HGNS may represent a safe and effective alternative to PAP therapy in patients at risk for pneumothorax. While positive pressure ventilation can theoretically worsen pneumothorax by increasing pleural pressure, HGNS operates through an entirely different mechanism: it maintains upper airway patency without altering intrathoracic pressure dynamics, making it a potentially safer option for select high-risk OSA patients. Support (if any)