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Abstract Background Left ventricular ejection fraction (LVEF) and diastolic dysfunction (DD) are key prognostic factors in patients with ST-segment elevation myocardial infarction (STEMI). AI-enabled ECG (AI-ECG) has been shown to have excellent agreement with transthoracic echocardiography (TTE) assessment and incremental prognostic value to LVEF. Methods We retrospectively analyzed 1,005 adult acute STEMI patients referred for echocardiography (10/2007–01/2025) who had ECGs within seven days before and after the reference echocardiogram. The ECG closest to the TTE date was designated as the pre-STEMI and post-STEMI ECG, respectively. AI-ECG was used to classify diastolic function grades and grades 2 and 3 were considered as DD. Patients were stratified by LVEF (≤50% vs. >50%) at the time of TTE and the association between AI-ECG-determined DD and 10-year mortality was assessed using Cox regression and Kaplan-Meier curves. Results Among 1,005 patients (mean age 66.4 ± 13.4 years, 29.9% females), AI-ECG-determined DD prior to STEMI was present in 47.9% of patients with LVEF ≤50% and 30.3% of those with preserved LVEF (>50%). DD status remained unchanged post-STEMI in 79.3% of cases, while 10.2% showed worsening diastolic function. Regardless of LVEF, AI-ECG-determined DD prior to STEMI was associated with higher mortality risk (LVEF ≤50%: HR 3.03, 95% CI 2.16–4.24, p < 0.001; LVEF >50%: HR 2.32, 95% CI 1.58–3.41, p < 0.001). Post STEMI AI-ECG-determined DD remained a significant predictor of mortality (LVEF ≤50%: HR 2.54, 95% CI 1.82–3.53, p < 0.001; LVEF >50%: HR 2.43, 95% CI 1.66–3.58, p < 0.001). Echocardiographically determined DD also correlated with higher mortality (LVEF ≤50%: HR 4.91, 95% CI 2.95–8.15, p < 0.001; LVEF >50%: HR 2.72, 95% CI 1.68–4.41, p < 0.001). In patients with LVEF ≤50%, AI-ECG-determined DD remained associated with higher mortality even after adjusting for echocardiographically determined DD (pre-STEMI: HR 1.85, 95% CI 1.23–2.80, p < 0.001; post-STEMI: HR 1.90, 95% CI 1.23–2.91, p < 0.001). Conclusion AI-ECG-determined DD is a significant predictor of mortality in STEMI, independent of LVEF. The presence of normal filling pressure may indicate a better clinical outcome in patients with reduced LVEF patients. These findings underscore the clinical utility of AI-ECG in refining risk stratification beyond conventional LVEF assessment.

Abstract When using real-world data to construct an external comparator arm for a single-arm trial, there may be differences in how and when patients are assessed for disease between trial and real-world settings. Such differences can generate outcome measurement error when comparing time-to-event endpoints and lead to biased findings. Recent methods have been developed to mitigate measurement error bias in real-world endpoints; however, they rely on the existence of a validation sample, ie, data on a set of patients where both the “true” trial-like and “mis-measured” real-world measures are collected. We demonstrate how novel statistical methods can be leveraged as quantitative bias analyses (QBA) to contextualize real-world evidence findings when outcome measurement error is of concern, but validation samples are infeasible to collect. Quantitative bias analyses allow researchers to set plausible ranges for the amount of error when not directly measurable. We highlight how to conduct QBA with two recent methods, cumulative incidence curve correction and survival regression calibration, and illustrate how to generate plausible parameter values through simulation. We provide an illustrative QBA example in a cohort of real-world patients with newly diagnosed multiple myeloma and provide practical guidance to apply QBA for outcome measurement error and interpret results.

Abstract Background Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets. Methods We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease. Results We observed a shift toward a heightened immunosuppressive TME at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance. Conclusions Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.

Background: Anterior cervical discectomy and fusion (ACDF) is a widely performed procedure for treating degenerative cervical spine conditions. While it effectively addresses neural decompression and restores segmental alignment, the interplay of baseline alignment and implant-specific factors on postoperative segmental alignment remains underexplored. This study evaluates the influence of preoperative cervical alignment and interbody cage design on segmental alignment changes following 1- to 3-level ACDF. Methods: Following institutional review board approval, we identified 258 patients undergoing ACDF for degenerative pathology between 1 January 2010 and 31 December 2023. Preoperative and postoperative radiographs were analyzed for cervical alignment, disc height, and segmental lordosis. Cage dimensions, lordosis, and positioning relative to vertebral landmarks were recorded. Multivariable linear regression models evaluated predictors of postoperative disc height, segmental lordosis, and their respective changes. Results: Postoperative disc height was positively associated with greater cage height (β = 1.13 mm per mm, p < 0.001) and negatively associated with greater cage lordosis (β = −0.10 mm per °, p = 0.001). Segmental lordosis was positively influenced by cage height (β = 0.78° per mm, p = 0.002) and lordosis (β = 0.42° per °, p = 0.002) but was negatively correlated with the distance of the cage from the anterior edge of the cranial vertebra (β = −1.76° per mm, p = 0.004). Greater preoperative segmental kyphosis predicted more significant postoperative lordosis correction (β = −1.07° per °, p < 0.001). Conclusions: This study underscores the importance of preoperative alignment and interbody cage design in achieving optimal segmental correction following ACDF. While cage height primarily drives disc height restoration, surgical technique, particularly anterior placement of the cage, is pivotal for enhancing segmental lordosis. These findings support personalized surgical planning to optimize alignment and patient outcomes.

Abstract Background Left ventricular (LV) remodeling in patients with valvular heart disease may vary according to the type of overload (pressure vs volume) as well as patients’ characteristics and comorbidities. Different LV remodeling patterns can be defined based on either an increase in LV mass index (LVMI), relative wall thickness (RWT), or both, and have been largely studied in patients with aortic valve disease but not in patients with primary mitral regurgitation (PMR). Purpose To describe the prevalence and baseline characteristics of the different LV remodeling patterns in PMR patients undergoing mitral valve (MV) surgery, and their association with outcome. Methods Four LV remodeling patterns were identified before MV surgery according to LVMI and RWT (Fig1-a). A cutoff of &gt;115 g/m2 in males or &gt;95 g/m2 in females was used to define high LVMI, and &gt;0.42 was used to define high RWT. Patients with more than mild concomitant aortic stenosis were excluded. The study outcome was all-cause mortality. Results A total of 1538 patients were included, of which 362 (23.5%) had normal LV geometry (NG), 774 (50.3%) had eccentric hypertrophy (EH), 286 (18.6%) had concentric hypertrophy (CH), and 116 (7.5%) had concentric remodeling (Fig 1-a). Compared to the NG group (Fig 2), the EH group had more females, with larger LV size and left atrial volume index (LAVI). Compared to the NG group, patients in the CH group were significantly older and had more proportion of females. Moreover, they were more symptomatic, had higher prevalence of arterial hypertension, atrial fibrillation, and worse renal function, with smaller LV end-diastolic diameters and thicker LV walls.. Compared to the NG group, the CR group included patients with significantly smaller LV cavities and thicker LV walls, but interestingly similar LAVI and systolic pulmonary pressure, suggesting that this group might represent patients with a rather acute onset MR. Of note, there was no difference among the groups as regards LV systolic dysfunction (ejection fraction ≤ 60%, P=0.314). However, patients with CH and CR had significantly worse e’ and E/e’ ratio. After a median follow-up of 6.2 years, 211 (13.7%) patients died. Kaplan-Meier analysis showed similar survival between the NG and EH groups (91.4 vs 91.6%, P = 0.964), with significantly lower survival in the CH (76.6%, P&lt;0.001) and CR (81.9%, P=0.028) groups, compared to NG (Fig 1-b). On multivariable analysis, after correcting for all the significant variables (Fig 1-c), CH and CR patterns carried higher risk of mortality (HR 1.7, P=0.024 and 2.0, P=0.017) compared to NG, while EH carried no additional risk (P=0.768). Conclusion LV remodeling patterns help in phenotyping patients with PMR undergoing MV surgery, and are independently associated with different risks of post-operative mortality.Figure 1:Prevalence and outcome Figure 2:Baseline characteristics

Abstract Background: Although hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are inherited disorders expected to display a 1:1 sex ratio, most studies report a strong female dominance. This study analyzed sex differences in 122 self-reported symptoms and comorbidities in patients diagnosed with hEDS or HSD using the 2017 criteria. Methods: Self-reported data was obtained from November 1, 2019, to April 25, 2025, ( n =2,451) from an Intake Questionnaire of adult (≤18 years old) patients diagnosed with hEDS or HSD at the EDS Clinic at Mayo Clinic Florida and analyzed by sex. Results: We found that 90.6% ( n =575) of hEDS patients were female and 9.4% ( n =60) were male, with a sex ratio of 9.6:1 female-to-male, while 95.2% ( n =1,728) of HSD patients were female and 4.8% ( n =88) were male, with a sex ratio of 19.6:1 female-to-male. Females were older than males: hEDS 35 vs. 28 years of age ( p <0.001), HSD 34 vs. 31 years of age ( p =0.004). Overall, females self-reported more symptoms/comorbidities than males: hEDS 31/122 (25.4%), HSD 59/122 (48.4%). In contrast, only 5/122 (4.1%) symptoms/comorbidities were self-reported more often in males including attention deficit disorder/attention deficit hyperactivity disorder, delay in developmental milestones, snoring, autism spectrum disorder, and obstructive sleep apnea. Females with HSD had more mast cell-related symptoms (i.e., hives p <0.001) which were reflected in higher mast cell scores than males ( p <0.001). Patients with higher mast cell scores also had higher serum levels of total IgE ( p =0.029). More females with HSD were diagnosed with fibromyalgia ( p <0.001) and reported symptoms associated with autonomic dysfunction than males. Aside from abuse, which was higher in females (hEDS p =0.039, HSD p <0.001), few sex differences were reported for psychological symptoms/comorbidities. In support for the idea that elevated mast cell activity in females may lead to extracellular matrix remodeling that promotes hypermobility, females with hEDS/HSD had greater serum collagen-4α1 ( p <0.0001) and fibronectin ( p =0.015) than males by ELISA. Conclusions: Females with hEDS and HSD report a higher burden of symptoms/comorbidities than males, providing a possible explanation for fewer males being reported in demographic data. Sex differences in symptoms/comorbidities may reflect sex differences in pathogenic drivers of disease.

Resistant hypertension (RH) is a high-risk phenotype characterized by blood pressure readings ≥130/80 mmHg despite maximally tolerated therapy with three antihypertensive agents, including a diuretic, or controlled blood pressure requiring four or more medications. The diagnosis of RH requires a structured evaluation that confirms accurate blood pressure measurement, excludes pseudoresistance—particularly nonadherence and white coat hypertension—and identifies secondary causes such as obstructive sleep apnea, primary aldosteronism, renovascular disease, pheochromocytoma, and Cushing syndrome. RH arises from overlapping mechanisms, including activation of the renin–angiotensin–aldosterone system (RAAS), sympathetic overactivity, arterial stiffness, volume expansion, and immune-mediated pathways. Management begins with lifestyle modification and optimized triple therapy, followed by mineralocorticoid receptor antagonists as the preferred fourth-line treatment. Emerging pharmacological options, such as sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, endothelin receptor antagonists, aldosterone synthase inhibitors, and angiotensin receptor and neprilysin inhibitors (ARNIs), offer additional therapeutic potential; meanwhile, device-based interventions, including renal denervation and baroreflex activation therapy, have shown sustained blood pressure reductions in selected patients. Future directions highlight precision medicine, digital health technologies, and artificial intelligence as methods to improve diagnosis, guide individualized therapy, and enhance long-term blood pressure control.

Background: Sinonasal undifferentiated carcinoma (SNUC) is an extremely rare, high-grade, and aggressive tumor of the sinonasal tract. Due to the rarity of this malignancy, current treatment guidelines are based on small and often/mainly single-center retrospective datasets. In the absence of a universally accepted standard of care for SNUC, treatment approaches vary across countries and institutions, reflecting real-world clinical practice. The primary aim of this study was to describe real-world treatment and outcomes for patients with confirmed SNUC. Methods: This was an international, multi-center, retrospective, observational cohort study that pooled patients into the largest SNUC dataset to date. Fifteen centers were enrolled to contribute data, including seven from Europe, four from the United States, three from the United Kingdom, and one from Canada. In the absence of a universally accepted standard of care for SNUC, treatment approaches varied across countries and institutions, reflecting real-world clinical practice. Patients included were those with histologically confirmed SNUC who were treated between 1997 and 2021. Results: This study yielded 485 patients treated for SNUC. The median age at diagnosis was 55.6 years (IQR: 44.5–67.6), and 63.7% were male. Most cases presented at advanced stages, with 70.8% as T4a or T4b. Overall survival (OS) outcomes were available for 412 patients, with a median follow-up of 26.0 months. The 5- and 10-year OS were 47.2% (95% CI: 40.8–53.3%) and 39.6% (95% CI: 32.5–46.6%), respectively. Advanced age, dichotomized T-stage (T4a/b vs. T1–3), M-stage, and orbital involvement were significant poor prognostic factors on univariable analysis (p’s < 0.01). On multivariable analysis, orbital involvement (HR: 2.73, 95% CI: 1.42–5.27, p = 0.003) and distance metastasis stage (HR: 3.00, 95% CI: 1.25–7.21, p = 0.014) were both independently associated with worse OS. Conclusions: This observational study presents the largest multi-center cohort analysis of SNUC to date, providing new insights into prognostic factors for a rare cancer treated at global centers of excellence. Orbital involvement and the presence of metastases are candidate independent risk factors associated with poorer OS.