Citations

BACKGROUND: The right ventricular (RV) response to pressure overload is a crucial determinant of outcomes in pulmonary arterial (PA) hypertension. Sotatercept improves clinical outcomes, but its effects on the right ventricle have been inconsistent. We evaluated the effects of sotatercept on load-independent measures of RV contractility, RV–PA coupling, and right heart deformation at rest and exertion in patients with PA hypertension. METHODS: In this prospective trial among participants with PA hypertension recruited between July 2024 and May 2025, we performed simultaneous echocardiography and invasive pressure measurements during rest and exercise to evaluate changes in RV contractility (end-systolic elastance [Ees]), afterload (PA elastance [Ea]), RV–PA coupling (ratio of arterial Ea to Ees), and right heart deformation, including RV and right atrial strain, before and after 24 weeks of sotatercept using mixed models. RESULTS: Among 30 participants (n=21; 70% female; mean age, 49.3 years [SD 13.5]), sotatercept decreased PA Ea. These changes were associated with reduced RV contractility, PA pulsatility index, and the maximal rate of RV pressure increase over time (dP/dt max ; P <0.001 for all). The decrease in Ees was associated with a decrease in PA Ea (r=+0.70 [95% CI, +0.44 to +0.85]; P <0.0001) with preserved RV–PA coupling (mean difference, +0.08 [95% CI, −0.11 to +0.26]; P =0.42). Although systolic indices measured at the base of the right ventricle (tricuspid annular plane systolic excursion and systolic velocity of the lateral tricuspid annulus) decreased after sotatercept use, there was an increase in RV free wall–dependent systolic indices, including resting and exercise RV free wall strain (mean difference, +6.2% [95% CI, +4.5 to +7.8]; P <0.0001) and fractional area change ( P =0.0001). Beyond the right ventricle, there was also improved right atrial filling and contractile performance across rest and exercise ( P <0.0001 for all). CONCLUSIONS: Sotatercept decreases RV contractility in proportion to reduced afterload, while preserving the RV–PA coupling relationship. Despite decreased RV contractility, global measures of right heart performance, such as RV free wall strain and RA strain, improve, alongside redistribution of RV deformation from annular motion to free wall shortening. These data suggest that sotatercept causes an energetically favorable reduction in resting RV contractility to match the lower afterload, which does not appear physiologically detrimental when considering the concurrent improvement in RV free wall contractile mechanics and exertional right heart reserve. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06409026.

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.

ABSTRACT Human intestinal diseases, including inflammatory bowel disease (IBD), are difficult to model because existing animal and in vitro systems do not capture the intestine’s integrated vascular, immune, and metabolic complexity. Here, we establish a custom normothermic machine perfusion platform that maintains surgically resected human intestinal tissue for up to 72 hours under near-physiological conditions. Discarded specimens from patients with nonmalignant intestinal diseases, including IBD and diverticulitis, were continuously perfused at 37°C with real-time hemodynamic and metabolic monitoring. Perfusion preserved tissue viability, mucosal architecture, epithelial integrity, oxygen consumption, metabolic activity, and vascular patency. Daily perfusate sampling enabled longitudinal profiling and experimental modulation of inflammatory mediators, revealing patient-specific immune states. This long-duration platform bridges reductionist in vitro models and clinical disease, enabling mechanistic studies of intestinal inflammation and future testing of personalized therapies in intact patient-derived tissue.

ABSTRACT Patients with newly‐diagnosed acute myeloid leukemia (ND‐AML) derive variable survival benefit from venetoclax (Ven) plus hypomethylating agent (HMA) therapy, and the optimal Ven duration across genetic risk groups remains undefined. Among 540 ND‐AML patients receiving Ven‐HMA at Mayo Clinic, outcomes were compared across Ven 7‐ ( n = 33), 14‐ ( n = 117), 21‐ ( n = 96), and 28‐day ( n = 294) schedules during Cycle 1 and stratified by ELN 2024 and Mayo genetic risk groups. At a median follow‐up of 37.7 months, allogeneic stem cell transplant (ASCT) rates were similar across Ven duration groups (15%, 18%, 18%, and 20% for 7‐, 14‐, 21‐, and 28‐day; p = 0.86). Median transplant‐censored survival was comparable across Ven durations (13.3, 11.9, 16.8, and 13.2 months for 7, 14, 21, 28 days, respectively; p = 0.65), with outcomes driven by ELN risk (6.3, 11.5, 18.3 months for high, intermediate, low; p < 0.01) and Mayo genetic risk (6.9, 17.8 months, not reached; p < 0.01). Survival was comparable across Ven durations within ELN intermediate/low‐risk and all Mayo risk groups. Among ELN high‐risk patients, 14‐day Ven was associated with inferior transplant‐censored survival compared to 21‐ and 28‐day schedules ( p < 0.01). Notably, 30‐ and 60‐day mortality were higher with shorter Ven schedules (7‐day: 9%/18%; 14‐day: 7%/15%) versus 28‐day (2%/6%), which likely reflects treatment selection bias. In ND‐AML, no significant difference in transplant‐censored survival was observed across the 7‐, 14‐, 21‐, and 28‐day Ven schedules; prognosis was determined primarily by Mayo and ELN 2024 genetic risk rather than by Ven duration. Prospective trials are needed to establish risk‐adapted Ven dosing strategies.

Abstract To characterize invasive neuromodulation for insular drug‐resistant epilepsy, we retrospectively evaluated 22 patients treated with responsive neurostimulation (RNS; n = 14) or chronic subthreshold stimulation (CSS; n = 8). Stereoelectroencephalography was performed in 20 cases (91%). Median baseline seizure frequency was 10.5/month. Forty‐one percent had prior epilepsy surgery. At year 3, median seizure reduction (MSR) was 83% ( p = .01, Wilcoxon signed‐rank test), with a responder rate (RR) of 77%; MSR was 92% for CSS and 75% for RNS. There were no significant differences in MSR ( p ≥ .4) or RR ( p > .9) when comparing RNS versus CSS. Three patients achieved seizure freedom by year 3. Patients undergoing combined insular–thalamic stimulation ( n = 5) demonstrated an MSR of 84%, 86%, and 88% at 1, 2, and 3 years; seizure reduction in thalamocortical versus cortical‐only stimulation was not different ( p ≥ .1). Parasagittal lead trajectories achieved closer insular proximity than transopercular trajectories ( p < .0001, Mann–Whitney U ‐test). Median charge density at last follow‐up was 1.3 μC/cm 2 . There were no acute surgical complications and all stimulation‐related side effects resolved with programming adjustments. This study expands the limited literature on insular neuromodulation by demonstrating effectiveness of RNS and CSS, suggesting potential benefit from combined thalamocortical targeting, and defining parasagittal trajectories as a surgical approach for optimal lead proximity.

Background: Tobacco use is a known risk factor for poor healing after rotator cuff repair (RCR), but the effects of nontobacco nicotine products remain unclear. Purpose: To compare postoperative complications among nontobacco nicotine users, tobacco users, and nonusers undergoing RCR. Study Design: Cohort study; Level of evidence, 3. Methods: Using the PearlDiver database, the authors identified patients who underwent arthroscopic RCR with ≥2 years of follow-up. Three 1:1 propensity-matched comparisons were conducted: nontobacco nicotine users versus nonusers (n = 4844), tobacco users versus nonusers (n = 19,182), and nontobacco nicotine users vs tobacco users (n = 4882). Outcomes included 90-day complications and 2-year revision surgeries. Results: Nontobacco nicotine users had mildly higher rates of lysis of adhesions than controls (0.7% vs 0.4%; OR, 1.95; P = .033) but no other significant differences. Tobacco users showed increased rates of acute kidney injury (AKI), pneumonia, infections, emergency department (ED) visits, readmissions, and revision surgery compared to controls. Compared to tobacco users, nontobacco nicotine users had moderately strong lower risks of pneumonia (0.6% vs 1.2%; OR, 0.46), ED visits (8.8% vs 13.6%; OR, 0.62), and readmissions (0.8% vs 1.5%; OR, 0.54) (all P < .01). Conclusion: While nontobacco nicotine use was associated with a modestly increased risk of lysis of adhesions after RCR, it did not significantly elevate the risk of major medical complications, infections, or revision surgery when compared to nonnicotine users. In contrast, tobacco users demonstrated consistently worse postoperative outcomes across multiple domains, including higher rates of AKI, pneumonia, surgical site infection, ED visits, readmissions, and revision procedures. Notably, when compared directly to tobacco users, nontobacco nicotine users had significantly lower rates of pneumonia, ED utilization, and readmissions. These findings suggest that although nontobacco nicotine products may not be entirely benign, their perioperative risk profile appears to be less severe than that of traditional tobacco use.

Aims Two-stage exchange arthroplasty with an antibiotic-eluting cement spacer remains the predominant strategy in the USA for managing chronic periprosthetic joint infection (PJI) following total hip arthroplasty (THA). The aim of this study was to evaluate a commercially available, partially intraoperatively fabricated articulating high-dose antibiotic cement spacer, focusing on survival, complications, and patient-reported outcomes. Methods A total of 298 patients (302 THAs) underwent two-stage exchange arthroplasty for PJI using a specific articulating antibiotic spacer between August 2005 and May 2022. Patients with a previous failed two-stage exchange were excluded, although 121 THAs (302, 40%) had undergone previous PJI-related procedures. The mean age of the patients was 65 years (SD 11), the mean BMI was 32 kg/m 2 (SD 7), and 116 (38%) were female. Most patients were classified as McPherson host B (158; 52%) and limb grade 2 (165; 55%), and 265 (88%) met the 2011 Musculoskeletal Infection Society criteria. The mean follow-up was six years (2 to 16). Results At five years after reimplantation, survival free of reinfection, aseptic rerevision, any rerevision, or any reoperation were 89% (95% CI 85.2 to 93.1), 93% (95% CI 89.3 to 96.1), 86% (95% CI 81.3 to 90.3), and 80% (95% CI 74.7 to 84.9), respectively. Dislocation accounted for most aseptic rerevisions (15/20). McPherson host C (HR 3.7 (95% CI 1.4 to 9.6); p = 0.007) and limb grade 3 (HR 3.3 (95% CI 1.0 to 11.1); p = 0.049) were significantly associated with an increased risk of reinfection. The mean Harris Hip Score at the latest follow-up was 76 (29 to 100). A total of 17 patients underwent revision or removal of a spacer for concerns about persistent infection and two for dislocation of the spacer. Eight patients underwent a non-rerevision reoperation during the spacer interval for wound drainage (n = 5), dislocation of the spacer (n = 2), and perispacer fracture (n = 1). A total of 26 spacer-related complications were treated nonoperatively (15 perispacer fractures, 11 dislocations). Dislocation of the spacer was strongly associated with dislocation after reimplantation (HR 6.2 (95% CI 2.3 to 16.9); p < 0.001). Conclusion This commercially available, partially intraoperatively fabricated articulating spacer showed excellent reinfection-free five-year survival (89%). Spacer-related fracture and dislocation each occurred in 5% of patients. Dislocation of the spacer significantly increased the risk of dislocation following reimplantation, supporting the use of higher-stability bearings in these high-risk patients. Cite this article: Bone Joint J 2026;108-B(9):1104–1112.

ABSTRACT Background Family history of pancreatic cancer (PC), pathogenic germline variants (PGVs), and increased intrapancreatic fat (IPF) are individually associated with increased PC risk. Whether IPF is elevated in high‐risk individuals (HRIs) with PC family history or PGVs is unknown. Although MRI is the preferred modality for IPF measurement, region‐of‐interest–based approaches are prone to sampling bias because pancreatic fat is heterogeneously distributed. We aimed to compare IPF among HRIs and matched non‐HRI controls using an Artificial intelligence (AI)‐based tool for whole pancreatic IPF measurement applied to magnetic resonance imaging (MRI). Methods We developed and validated a deep‐learning pipeline for IPF measurement that incorporates automated pancreas segmentation on T1‐weighted MRI images registered to the corresponding iterative decomposition of water and fat with echo asymmetry and least squares estimation images to compute IPF using proton density fat fraction (PDFF). This pipeline was used to quantify IPF and assess IPF distribution patterns in 85 HRIs and 170 non‐HRIs matched 1:2 for age, sex, BMI, and diabetes status. A surface erosion approach was developed to minimize the impact of peripancreatic fat on IPF measurement. Linear models adjusting for matching variables were used to assess associations. Results Model‐expert agreement for whole‐pancreas PDFF was excellent (intraclass correlation coefficient 0.99; 95% CI, 0.98–0.99 mean absolute error 1.4%). Mean PDFF did not differ between HRIs and controls (25.8% [11.5] vs. 26.9% [11.4]; p = 0.32). PDFF increased with age ( p = 0.015), male sex ( p < 0.001), presence of diabetes ( p = 0.009), BMI ( p < 0.001). IPF distribution patterns did not differ by risk group. Conclusion An AI‐based approach provides accurate, scalable, and objective assessment of IPF quantity and distribution. IPF quantity and spatial distribution do not appear to differ based on germline or familial predisposition to PC.