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ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

ABSTRACT Background Ventricular tachycardia (VT) is a major contributor to sudden cardiac death among patients with ischemic heart disease (IHD). While catheter ablation reduces the arrhythmic burden, the impact on long‐term outcomes remains uncertain. We assess the efficacy of catheter ablation in patients with IHD. Methods We performed a meta‐analysis by systematically searching electronic databases from inception to April 2025. Pairwise, reconstructed time‐to‐event data meta‐analyses and Trial Sequential analyses were conducted. Results A total of seven studies (1192 participants) were included. Among patients with IHD with ICD, VT ablation was associated with a significant reduction in ICD shocks (RR = 0.50, 95% CI = [0.34–0.74]), a trend toward reduced VT storm (RR = 0.64, 95% CI = [0.40–1.04], p = 0.07), and lower rates of cardiovascular hospitalization (RR = 0.73, 95% CI = [0.53–1.01], p = 0.06) compared to ICD alone. However, no significant differences were observed when compared to patients receiving ICD plus antiarrhythmic drugs (AADs). VT ablation showed no significant impact on mortality or VT/VF recurrence compared to either ICD alone or ICD with AADs. Reconstructed Kaplan–Meier analysis for all‐cause mortality showed no significant difference between VT ablation and AAD + ICD. Trial Sequential Analysis provided conclusive evidence for VT/VF recurrence, while further data is required for other outcomes. Conclusion Among patients with IHD with ICD, VT ablation reduces ICD shocks, VT storm, and cardiovascular hospitalizations compared to ICD‐only therapy, but offers no significant advantage over ICD combined with AADs. VT ablation does not impact overall mortality or the recurrence of VT/VF. Trial sequential analysis confirmed conclusive evidence for VT/VF recurrence, while additional data is needed for other outcomes.

Objective: The purpose of this study was to evaluate the potential clinical value of spectral CT for image guidance during percutaneous thermal ablation, particularly investigating high monoenergetic (MonoE) for metal artifact reduction. Materials and Methods: A phantom experiment was performed in which an ablation probe was scanned in “continuous CT” (CCT) mode on a spectral CT scanner. ROI measurements quantified metal artifacts for conventional and MonoE CCT images. Subsequently, a retrospective reader study was conducted with 10 patient cases. Three radiologists reviewed cases to select the optimal MonoE setting and perform a Likert score rating (+2: MonoE preferred, −2: conventional preferred). Results: Phantom measurements indicated a reduction in metal artifact for high MonoE (150 keV: −46 HU) relative to conventional CCT (−122 HU). The MonoE setting preference was 151±21 keV. The mean Likert score was 1.2±0.7. Radiologists indicated a perceived benefit of high MonoE CCT when probe placement was near a critical structure. Conclusions: This study indicates a clinical preference for high MonoE CCT compared with conventional CCT. Insofar as spectral CCT can be offered at a clinically feasible time frame, our results support the assessment of 150 keV image to reduce metal artifact while maintaining satisfactory soft tissue contrast.

Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

When long bones fracture, healing occurs spontaneously in about 90% of cases, while the remaining 10% result in non-union, presenting significant clinical challenges. The standard treatment for non-unions is autologous bone grafting, but this approach has limitations, including high complication rates, donor site morbidity, and limited graft availability. An alternative strategy involves using growth factors to promote bone regeneration, with recombinant bone morphogenetic protein-2 (rBMP-2) being the most common. Although effective, rBMP-2 requires supra-physiological doses that cause inflammation, poor bone quality, and severe side effects. Our previous work suggests that genetic delivery of BMP-2 may offer more controlled healing. We aim to develop a more effective therapy for non-unions using adeno-associated viral vectors. By lyophilizing the vector onto a scaffold, we also aim to increase treatment potency, reduce leakage, and improve transduction using cryoprotectant buffers.AAV6-GFP-Luciferase was used to compare the activity of AAV6 stored at −80°C versus lyophilized in cryoprotectant buffer. A rat critical-sized defect model was employed, as described in [1]. For standard storage, AAV was added to the collagen sponge before implantation into a 5mm defect. For lyophilization, AAV was mixed with cryoprotectant, loaded onto the sponge, and lyophilized. Rats were imaged at 7- and 10-days using IVIS. To assess therapeutic relevance, the experiment was repeated with AAV6-BMP2-IL1Ra, implanted into 5mm femoral defects on collagen sponges, with healing monitored by X-ray every 4 weeks (continuing through 12-weeks post-operation).The reporter and therapeutic vectors showed improved transduction efficiency with lyophilization. The reporter vector exhibited higher transgene expression at days 7 and 10. This boost in expression either remained significant through 4 weeks or continued to show better signal at that time, correlating with improved healing seen in the X-rays (Fig. 2).Preliminary data suggest that lyophilization could reduce the therapeutic dose of AAV needed for treating osseous nonunion with a bicistronic vector. Lyophilization offers various benefits: enhanced transduction efficiency, improved stability of the gene product at logistically feasible conditions, and reduced off-target effects due to less AAV leakage from the implantation site. While in vivo experiments with AAV6-BMP2-IL1Ra are ongoing, these findings warrant further investigation into lyophilized AAV therapies for this application.For any figures or tables, please contact the authors directly.

Abstract OBJECTIVES: · To determine if patients with knee flexion contracture after distal femur fracture have poorer outcomes than patients who regain full knee extension. · To determine if factors such as patient age, gender, open fracture or implant used favors knee flexion contracture. METHODS: Design: Prospective, multicenter trial Setting: Twenty academic level I trauma centers Patient Selection Criteria: Patients with a distal femur fracture. Patients were evaluated for knee flexion contracture at 3, 6 and 12 months post-operatively. Outcome Measures and Comparisons: SMFA, Bother Index and EQ Health Index scores were recorded. Walking and stair climbing ability were assessed. RESULTS: · 126 patients had radiographic follow up for 12 months. There was clinical follow-up for 99 patients at 3 months, 90 patients at 6 months and 74 pts at 12 months. · Patients with full knee extension had better SMFA scores at 12 months than patients with knee flexion contracture (p = 0.308). · Bother Index (p = 0.29) and EQ Health State (p = 0.12) scores did not demonstrate a difference between patients with or without knee flexion contracture at any time point. · Patients with full knee extension had improved walking ability compared to patients with flexion contracture (p = 0.008). Patients with full knee extension had better stair climbing ability than patients with flexion contracture (p = 0.02). · Only older patient age showed a difference in likelihood of flexion contracture (p = 0.01) The rates of flexion contracture in women versus men (p = 0.51), RIMN versus LLP (p = 0.74) and open versus closed fracture (p = 0.24) were not statistically different. CONCLUSIONS: · Patients with knee flexion contractures after distal femur fracture do worse than patients who regain full extension. · Older patients with distal femur fractures are at greater risk for knee flexion contracture. LEVEL OF EVIDENCE: Level I

OBJECTIVE The purpose of this study was to evaluate whether level selection for a three-column osteotomy (3CO) impacts cervical deformity correction outcomes, including neurological, radiographic, and patient-reported outcomes. METHODS A retrospective review was performed of patients who underwent a cervical or upper thoracic 3CO for cervical deformity correction by the senior author from 2008 to 2024. Collected outcome measures included neurological outcomes, mechanical complication rates, spinopelvic alignment, and patient-reported outcomes. The minimum follow-up was 1 year. RESULTS One hundred fifteen patients were identified who underwent a cervical or upper thoracic 3CO for cervical deformity correction, of whom 77 met inclusion criteria for this study with a minimum follow-up of 1 year. The median age was 66 years, the median BMI was 27, and 43% of patients were male. Sixteen patients underwent a 3CO at the C7–T1 levels and 61 patients at T2–6 levels. Patients who underwent C7–T1 3CO were more likely to experience a new postoperative neurological deficit compared with those who underwent T2–6 3CO (56% vs 18%, p = 0.004), had less correction in their T1 slope (6° vs 18°, p = 0.027), had less correction in C2–T4 sagittal vertical axis (2.8 cm vs 4.9 cm, p = 0.043), and had a worse Neck Disability Index (NDI) score at 1 year compared with baseline (an increase of 7 vs a decrease of 12, p = 0.033). CONCLUSIONS Cervical deformity patients who underwent a 3CO at C7–T1 had a higher rate of postoperative neurological deficits, less radiographic correction, and worse NDI scores at 1 year compared with patients who underwent a 3CO from T2 to T6. Although 3CO level selection is multifactorial and patient specific, surgeons should consider a 3CO level caudal to T1 when feasible.

OBJECTIVE Degenerative lumbar spondylolisthesis is a common cause of back and leg pain influenced by factors like instability, disc degeneration, facet arthropathy, and psychosocial phenotype. Patients’ experience of high-severity pain is complex, with significant implications for surgical planning. The goal of this study was to assess the impact of back pain catastrophizing on long-term outcomes following lumbar spondylolisthesis surgery. METHODS This study uses the Quality Outcomes Database (QOD) lumbar spondylolisthesis dataset and includes prospectively collected data from the 12 highest-enrolling clinical sites participating in the QOD lumbar module. The authors reviewed patients undergoing single-segment surgery for grade 1 degenerative lumbar spondylolisthesis. Severe baseline numeric rating scale for back pain (NRS-BP) scores (≥ 8) were classified as "catastrophizing," and mild to moderate pain scores (< 8) were classified as "non-catastrophizing." Patient-reported outcomes (PROs) were compared for catastrophizing versus non-catastrophizing patients at 60 months. Univariate and multivariate analyses were conducted to assess the impact of catastrophizing on PROs, with multivariate analysis controlling for variables initially reaching a p value < 0.10. RESULTS Of the 608 patients in this analysis, 260 (42.8%) experienced catastrophizing while 348 (57.2%) did not. Catastrophizing patients were significantly younger (59.9 ± 12.2 years vs 63.9 ± 11.7 years, p < 0.001), less often had ≥ 4 years of college education (31.2% vs 42.5%, p = 0.004), and more often used private insurance (58.8% vs 47.7%, p = 0.01). The catastrophizing cohort also had higher rates of depression (24.6% vs 17.0%, p = 0.02) and back pain predominance (45.4% vs 32.2%, p < 0.001). Surgical and perioperative characteristics did not significantly differ between cohorts. Although catastrophizing patients typically reported worse PRO scores at both baseline and 60 months, they demonstrated significantly greater improvement and minimal clinically important difference (MCID) achievement across almost all PROs at 60 months (p < 0.05). However, North American Spine Society (NASS) satisfaction scores at 60 months did not differ significantly between cohorts. Multivariate analysis found that catastrophizing significantly predicted 60-month NRS-BP change (β −1.45, 95% CI −1.81 to −1.09; p < 0.001) and MCID achievement (OR 1.98, 95% CI 1.52–2.58; p < 0.001) but not mean NRS-BP score or other metrics, including NASS satisfaction. CONCLUSIONS Despite presenting with worse baseline symptoms, patients with pain catastrophizing experienced substantial and clinically meaningful improvement following surgery for degenerative lumbar spondylolisthesis. Patient satisfaction was comparable between cohorts, reflecting a nuanced balance between greater absolute improvement and persistence of residual symptoms. These findings underscore that catastrophizing should not be viewed as a barrier to surgical success, while pointing to the need for proactive expectation setting and shared decision-making.

OBJECTIVE The present investigation aimed to 1) develop a new CT-based assessment of endplate bone density (endplate Hounsfield unit [EP-HU]) and 2) analyze if EP-HU was a better predictor than vertebral Hounsfield unit (HU) for subsidence after anterior cervical discectomy and fusion (ACDF). METHODS All adult patients who underwent one- to three-level ACDF with a titanium interbody for radiculopathy and/or myelopathy at an academic center between 2018 and 2020 were retrospectively identified. Based on preoperative sagittal CT scans (left, right, and middle cuts), 2-mm superior and inferior endplate regions were circumscribed with the free draw tool to account for endplate surface undulations. The average of the superior and inferior EP-HUs on all CT cuts was used to calculate EP-HU. Cervical vertebral HUs were determined from the average of axial CT cranial, middle, and caudal cuts circumscribing only trabecular bone. The interbody subsidence of the cranial and caudal endplates of each ACDF level was directly measured on the endplate-facing surface of both coronal and sagittal cuts of postoperative CT scans (at 1 year) to determine the maximum subsidence (subsidence defined as ≥ 2 mm). Univariate and stepwise logistic regression analyses were used to compare subsidence based on CT bone metrics. Receiver operating characteristic (ROC) curve analyses were used to determine the probability of subsidence based on EP-HUs and vertebral HUs. RESULTS A total of 35 patients were included. Subsidence occurred at 32 of 67 unique fusion levels. Subsidence was associated with older age (p = 0.008), diabetes diagnosis (p = 0.015), and decreased interbody length (p = 0.019). EP-HUs exhibited moderate correlation with cervical vertebral HUs (Pearson’s ρ = 0.63). Subsidence was significantly associated with decreased total EP-HUs (subsidence: 475 HU, no subsidence: 543 HU; p = 0.019) and decreased lumbar vertebral HUs (subsidence: 296 HU, no subsidence: 341 HU; p = 0.011). ROC curve analysis identified an optimal EP-HU cutoff of 512.30 (area under the curve [AUC] = 0.701) to predict subsidence. The AUC of the vertebral HUs with respect to subsidence was 0.662. EP-HUs < 512.30 predicted subsidence (OR 6.67, p = 0.001) independent of significant demographic and surgical factors. CONCLUSIONS CT cervical EP-HUs rather than vertebral cervical trabecular HUs may be more efficacious in predicting subsidence after ACDF.

Objectives To compare survival and oncological outcomes of cisplatin‐ineligible patients (Cis‐I) and cisplatin‐eligible (Cis‐E) patients with muscle‐invasive bladder cancer (MIBC) undergoing immediate radical cystectomy (IRC), as IRC is currently considered the standard‐of‐care for Cis‐I patients with MIBC. Patients and Methods Data from patients with clinical (c)T2–4cN0–1M0 MIBC undergoing IRC, between 2006 and 2021, were retrospectively analysed from four tertiary care centres in the United States. Overall, recurrence‐free and event‐free survival were described using the Kaplan–Meier method and tested using the log‐rank test. For context, we compared survival outcomes against those in Cis‐E patients with MIBC undergoing IRC from the Southwest Oncology Group (SWOG)‐8710 trial. Results Overall, 379 Cis‐I and 125 Cis‐E patients with cT2–4cN0–1M0 MIBC who underwent IRC were included. Cis‐I patients included 44.8% cT3/4 vs 60% cT3/4 in the Cis‐E group. Overall, 83.3% of Cis‐I and 79.2% of Cis‐E patients died during follow‐up. The median event‐free and overall survival were 12.1 and 14.5 months for the Cis‐I group and 28.8 and 60.1 months for the Cis‐E group ( P < 0.001). [Correction added on 10 October 2025, after first online publication: The preceding sentence has been revised in this version.] Limitations include retrospective comparison of contemporary multi‐institutional data with that of a randomised control trial. Conclusions The Cis‐I patients with MIBC undergoing IRC fared poorly, with a median overall survival of 14.5 (95% confidence interval 11.1–17.9) months, mostly due to non‐cancer‐related deaths. These results provide a benchmark for clinical trials exploring novel agents or alternative chemotherapy regimens in Cis‐I patients with MIBC.