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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 >115 g/m2 in males or >95 g/m2 in females was used to define high LVMI, and >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<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 Right ventricular (RV) systolic function is an independent predictor of outcome, but a robust automated method of quantitation is lacking. Purpose To develop and validate a deep learning model for quantifying RV systolic function from 2D echo clips and assess its prognostic value in various loading states and left-heart disease. Methods A deep learning convolutional neural network (CNN) was developed to quantitate RV systolic function using all available apical 4 chamber (A4C) views from 13,039 patients (61,187 A4C video clips) in a US institution. Videos were converted to frames of 256x256 grayscale pixels, with graphics, including the ECG, removed. The model used the S3D architecture, a 3D-CNN with many of the spatial and temporal convolutions separated. RV free wall longitudinal strain (RVFWLS) was used to define RV function: normal (≤-25%); mild (-20% to –24%); moderate (-15% to –19%) and severe RV dysfunction (0% to –14%). The AI-estimate was the average of multiple 32-frame segments for each clip identified as an A4C, including both standard and RV-focused variations. The model was validated in four distinct clinical cohorts from independent data sources: 1) 1365 patients referred to an external diagnostic echocardiography lab in a different US state; 2) 569 patients recruited prospectively with known or suspected pulmonary hypertension (PH); 3) 416 patients with moderate or greater tricuspid valve regurgitation (TR); 4) 872 patients imaged at an Eastern European University with left-sided cardiac diseases (valvular disease, cardiomyopathies, etc.), athletes, or healthy volunteers. Results Model output was strongly correlated with the presence of RV dysfunction by manual measurement [AUC 0.907 (95% CI: 0.888-0.926)] in the internal validation set. Results were similar in an external validation US cohort [N=1365; AUC 0.919 (95% CI: 0.899-0.939)]. When the model was applied to 569 patients with known or suspected PH, presence and severity of the AI measures of RV dysfunction were strongly associated with functional class, 6 min walk distance, NT-proBNP levels and right heart failure (p<0.001). The presence and severity of RV dysfunction (as categorized by the AI model) was strongly associated with all-cause mortality in patients with PH (Figure 1A) and in patients with significant TR (Figure 1B). The European cohort was a geographically and institutionally distinct cohort with a low prevalence of >mild TR (10.8%) or PH (6.4%). In this cohort the AI model predicted a reduced RVEF (< 45%) with an AUC of 0.864 (95% CI: 0.831-0.898) and associated with both all-cause mortality (Figure 2A) and a composite endpoint of heart failure hospitalization or death (Figure 2B). Conclusions A fully automated, AI-based assessment of RV systolic function, using 2D apical 4 chamber echo views alone, is highly feasible and can accurately categorize disease severity and predict outcome across a wide spectrum of cardiovascular conditions.Figure 1 Figure 2

Abstract Background Cardiac dysfunction is a common complication in septic population. Though traditionally considered an acute and reversible phenomenon, the true prevalence of reversible cardiac dysfunction and its long-term prognostic implications remain unclear. Purpose Using serial echocardiographic assessments, this study aimed to investigate the prevalence and reversibility of cardiac dysfunction in septic patients, and to determine whether the recovery of cardiac function is associated with improved 5-year mortality. Methods We retrospectively screened 16,041 septic patients who underwent transthoracic echocardiography during their ICU stay. After excluding patients with a history of heart failure, pre-existing cardiac dysfunction, or lacking follow-up echocardiographic assessments post-ICU discharge, 3,112 patients were enrolled for analysis. To assess the reversibility of cardiac dysfunction, paired-sample t-tests were used to evaluate changes in echocardiographic parameters between in-ICU and post-ICU measurements. Furthermore, 5-year mortality were compared among controls and patients with or without recovery of echocardiographic abnormalities. Results Totally 1,604 patients (51.5%) were found to have newly recognized cardiac dysfunction during ICU stay. The mean interval between ICU admission and follow-up echocardiography was 425 days. Most in-ICU echocardiographic abnormalities demonstrated partial recovery over time, with the exception of left atrial volume index (LAVi) and right ventricular fractional area change (RV FAC) (Figure 1). Recovery of left ventricular ejection fraction (LVEF), average E/e', and tricuspid regurgitation (TR) velocity was significantly associated with reduced 5-year mortality (Figure 2). Older age [adjusted hazard ratio (aHR) 0.99, p=0.034], male gender (aHR 0.54, p=0.003), and elevated troponins (aHR 0.87, p=0.006) were negative predictors for LVEF recovery; while older age (aHR 0.099, p=0.043), higher APACHE III scores (aHR 0.99, p=0.018), atrial fibrillation (aHR 0.59, p=0.046), and chronic pulmonary disease (aHR 0.68, p=0.042) were negative predictors for TR velocity recovery. Conclusions Both the presence and recovery of newly recognized echocardiographic abnormalities during ICU stay were significantly associated with long-term mortality. Certain abnormalities, such as increased LAVi, persisted despite resolution of sepsis.Figure 1 Figure 2

Introduction: Porokeratosis is a group of keratinization disorders characterized by the histopathological presence of the cornoid lamella, a hallmark feature across all subtypes. The clinical diagnosis of porokeratosis can be challenging due to its similarity to other dermatological conditions. While polarized light dermatoscopy (PLD) enhances diagnostic accuracy, certain features remain difficult to identify. Ultraviolet-induced fluorescence dermatoscopy (UVFD) is a novel imaging technique that may improve the visualization of porokeratosis features, particularly the peripheral keratin rim. Objectives: This study aimed to assess the diagnostic utility of UVFD compared with PLD in identifying the dermatoscopic features of porokeratosis. Methods: In this retrospective study, dermatologists from five institutions in Chile, Brazil, Poland, and the United States contributed with dermatoscopic images of porokeratosis cases. Both PLD and UVFD images were obtained for each lesion. Two independent investigators evaluated each lesion in PLD and UVFD for the presence of peripheral keratin rim, rim continuity, central scaling, follicular plugs, vascular structures, and photodamaged surrounding skin. A third investigator reviewed discrepancies. Frequencies and means were calculated. McNemar’s chi-square was used for comparison. Results: A total of 136 lesions from 35 patients with biopsy-proven porokeratosis were analyzed. UVFD significantly improved the visualization of the peripheral keratin rim (95.6% vs. 66.2% in PLD; P<0.001) and increased identification rates for central scaling, follicular plugs, and interrupted rims. PLD remained superior for detecting vascular structures(P<0.001). Conclusions: UVFD enhances the visualization of key dermatoscopic features of porokeratosis, particularly the peripheral keratin rim and other keratin-related structures.

Abstract Primary liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), arise from the neoplastic transformation of hepatocytes and cholangiocytes, respectively. Loss or downregulation of PTEN, a tumor suppressor negatively regulating the PI3K/AKT pathway, is frequently observed in CCA and HCC. Notably, PTEN mutations are observed at nearly twice the frequency in combined CCA-HCC tumors than either HCC or CCA alone. Using lineage-specific liver-targeted PTEN-deficient mouse models, we demonstrate that PTEN loss drives cellular dedifferentiation and tumorigenesis, a process that is critically dependent on AKT2. Mechanistically, PTEN deficiency induces activation of NOTCH and upregulation of transcriptional factor SOX9, which plays a central role in tumor cell transformation. In parallel, PTEN loss increases SMAD4 expression and sensitizes the tumor cells to TGFβ signaling, with TGFβ treatment repressing SOX9 expression in tumor cells lacking PTEN. Together, our study defined a critical role for PTEN-AKT2 signaling in maintaining liver epithelial lineage fidelity and revealed how its disruption promotes the conversion of mature hepatocytes or cholangiocytes into liver cancer stem-like cells (LCSCs). Furthermore, we identify a PTEN-dependent crosstalk between NOTCH and TGFβ pathways that governs liver tumor development. Together, this work provides mechanistic insight into lineage plasticity in liver cancer with implications for pathway-directed therapy.

OBJECTIVES: The overall goal of this work is to discuss the various topics associated with critical care advanced practice provider (APP) postgraduate training programs and provide resources for new, developing and existing programs. DESIGN: Three rounds of voting until consensus achieved. SETTING: Electronic surveys, followed by virtual meeting. SUBJECTS: Critical care APPs, physicians, a pharmacist, and a nurse were also included to ensure multidisciplinary representation. All subjects resided and practiced in the United States with a history of education scholarship or post-graduate training leadership. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The workgroup included 14 APPs (ten nurse practitioners and four physician associates), three physicians, one pharmacist, and one registered nurse from 14 institutions across the United States. The workgroup identified six areas of concentration: administration, audience, program structure, curriculum, procedural competence, and accreditation. A survey was generated and employed in three rounds. The first two rounds of voting were completed anonymously, the third round was completed as a live meeting until consensus recommendations, defined as 75% agreement or more, were achieved. CONCLUSIONS: Expert consensus was used to generate consensus recommendations for critical care postgraduate training programs based upon 3 rounds of voting.

Background/Objectives: Standard treatment of multiply relapsed Ewing sarcoma remains to be established. Recent studies evaluating tyrosine kinase inhibitors (TKIs) with anti-angiogenic properties have shown encouraging results. Therefore, we conducted a systematic review and meta-analysis to explore the efficacy and safety of TKIs in patients with Ewing sarcoma. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases for clinical trials (CTs) and cohort studies assessing TKIs in the treatment of advanced Ewing sarcoma patients who received at least one prior line of therapy. The main outcome was objective response rate (ORR). All analyses were conducted using R software (v.4.2.2), employing random effects models with 95% confidence intervals (CIs). Results: We included 14 studies (seven phase II CT and seven retrospective cohorts), comprising 257 patients. The following TKIs were evaluated: cabozantinib, regorafenib, apatinib, anlotinib, sorafenib, lenvatinib, sunitinib, fruquintinib, and imatinib. In a pooled analysis of all Ewing sarcoma patients treated with TKIs, the ORR was 23% (95% CI, 11.2–37.1%) and the DCR was 61.1% (95% CI, 47.3–74.2%). Responses were numerically higher but statistically nonsignificant between clinical trials and real-world studies. The analysis including only single-agent TKIs showed better responses for anlotinib and apatinib, yet these drugs are not available in Western countries. Among the FDA-approved TKIs, superior outcomes were noted with single-agent cabozantinib. (ORR: 21.6%) and regorafenib (ORR: 11.3%). Several studies did not report toxicity data exclusively for Ewing sarcoma patients; thus, conclusions about toxicity are mostly based on the general population of studies and may not be fully representative of Ewing sarcoma patients. Conclusions: Anti-angiogenic TKIs have shown important anti-tumoral activity in patients with Ewing sarcoma. Efficacy was consistently seen in both clinical trials and real-world studies. Nonetheless, there are important differences in study design and population that may limit our interpretation of efficacy and toxicity findings.

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.

Hypertension has been traditionally known to be highlighted by mean blood pressure; however, emerging evidence exhibits that blood pressure variability (BPV), including short-term, day-to-day, and visit-to-visit fluctuations can have an implication across multiple body systems. Elevated BPV reflects repetitive hemodynamic stress, affecting the physiologic hemostasis contributing to vascular injury and end organ damage. This narrative review is a compilation of recent evidence on the prognostic value of BPV, explained by pathophysiology, various devices with its measurement approaches, and, essentially, the clinical implication of BPV and the use of such devices utilizing artificial intelligence. A comprehensive literature search across PubMed, Cochrane Library, Scopus, and Web of Science were conducted, focusing on observational studies, cohorts, randomized trials, and meta-analyses. Higher BPV has been associated with an increased risk of cardiovascular mortality, stroke, coronary events, and heart failure, the progression of chronic kidney disease, cognitive decline, and preeclampsia, among other end organ damage, despite mean blood pressure. The various pathophysiologic mechanisms include autonomic dysregulation, arterial stiffness, endothelial dysfunction, circadian rhythm alteration, and systemic inflammation, which result in vascular remodeling and multisystem damage. Antihypertensive medications such as calcium channel blockers and renin–angiotensin–aldosterone system inhibitors seem to reduce BPV; randomized trials have not specifically investigated their BPV-reducing effects. The aim of this review is to highlight that BPV is a dynamic marker of multisystem risk, and question how various AI-based devices can aid continuous BPV monitoring and patient specific risk stratification.