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OBJECTIVE Mechanical thrombectomy (MT) is well established for large-vessel occlusion (LVO) strokes, but its safety in distal and medium-vessel occlusions (DMVOs) requires further investigation. This study analyzed the relationship between procedural approaches, petechial hemorrhage (PetH), and clinical outcomes in DMVO thrombectomy, with particular attention to technical considerations and the complex interplay between tissue injury and hemorrhagic complications. METHODS A retrospective cohort study was conducted on DMVO stroke patients treated with MT at 37 stroke centers worldwide from 2016 to 2024. Patients were categorized based on follow-up imaging into those with or without PetH. Four logistic regression models analyzed the association of PetH with favorable functional outcomes (modified Rankin Scale score ≤ 2) at 90 days, early neurological improvement (≥ 4-point National Institutes of Health Stroke Scale score decrease at 24 hours), all-cause mortality, and independent determinants of PetH. Adjusted odds ratios (aORs), 95% confidence intervals, and p values were reported. RESULTS Of 1428 patients, 439 (30.7%) developed PetH. Factors independently associated with PetH were multiple thrombectomy passes (aOR 1.58, 95% CI 1.21–2.06; p = 0.001), IV thrombolysis (aOR 1.31, 95% CI 1.01–1.69; p = 0.04), and the combined use of a stent retriever with aspiration as the first-line method compared with aspiration alone (aOR 1.66, 95% CI 1.15–2.38; p = 0.007). Conversely, general anesthesia (aOR 0.55, 95% CI 0.40–0.77; p < 0.001), higher Alberta Stroke Program Early CT Scores (aOR 0.76, 95% CI 0.69–0.83; p < 0.001), and successful recanalization (aOR 0.56, 95% CI 0.39–0.80; p = 0.002) were significantly associated with a lower odds of PetH. PetH was associated with a decreased odds of favorable functional outcomes (aOR 0.51, 95% CI 0.36–0.73; p < 0.001), reduced early neurological improvement (aOR 0.59, 95% CI 0.44–0.79; p < 0.001), and increased all-cause mortality (aOR 1.84, 95% CI 1.23–2.76; p < 0.001). CONCLUSIONS PetH is a frequent sequela following MT in DMVO strokes and is associated with poorer outcomes, likely reflecting underlying ischemic injury rather than direct causation. Procedural factors influence PetH risk, suggesting medical treatment as first-line therapy for DMVOs, with MT reserved for refractory cases using less aggressive approaches.

Abstract Aim Develop an AI-generated Global Surgery podcast series tailored to healthcare professionals’ needs in specific countries, focussing on Uganda as a pilot. This precision education model addresses disparities in global surgical education, historically driven by high-income countries (HICs). Podcasts were chosen for their scalability, accessibility, and self-directed learning. Method Building on prior data from our international trainee-based needs assessment (145 survey respondents from 18 countries; 94 from Low-and-Middle-Income-Countries, LMICs; 51 from High-Income-Countries, HICs). Generative AI (ChatGPT 4.0, OpenAI) and prompt engineering were used to develop a global surgery curriculum from survey data from Ugandan respondents (selected because Uganda had one of the highest response rates, n=31). The resultant curriculum was then adapted into a podcast format featuring country-specific themes using NotebookLM (Google), using a format of exercises, case studies, and expert interviews. Results The preliminary outputs of the survey and podcasts highlight diverse country-specific priorities; for HICs these include access to resources, research opportunities, and infrastructure development; for LMICs they emphasise the burden of surgical disease, use of local case studies, and foundational concepts in global surgery. Conclusions By tailoring content to regional needs and leveraging storytelling to foster engagement, podcasts can complement traditional curricula to address gaps in access and relevance. Limitations include current AI-generative software offering only US accents, which may not suit learners elsewhere, reflecting concerns about HICs bias in AI-generated content. Future research will validate the podcasts through focus groups with Ugandan surgical trainees, and explore speech-processing for regional accents, or blending human voice with AI-generated transcripts.

5048 Background: Ra-223, an alpha-emitting radionuclide, is the first agent of its kind approved for the treatment of mCRPC. Although a pivotal phase 3 study evaluated its short-term safety, there is a need to investigate its long-term safety. The REASSURE study prospectively examined the long-term safety of Ra-223, including secondary primary malignancies (SPMs), in a large patient (pt) population enrolled across Europe, the United States, Israel, and Latin America. Methods: We report final analyses (data cut-off Oct 24, 2024) of REASSURE (NCT02141438), a global, noninterventional study (enrolment 2014–2017). Primary outcomes were the incidence of SPMs, short- (30 days) and long-term (7 years) safety events, and bone marrow suppression (BMS) management in pts who had ≥1 Ra-223 dose. Secondary outcomes included overall survival (OS). Results: Analyses included 1472 pts; median follow-up was 17 months (range 0.3–95.4). Median age was 73 years and 80% of pts had an ECOG PS of 0/1. In evaluable pts, median alkaline phosphatase, prostate-specific antigen, and lactate dehydrogenase levels were 133 U/L, 59 ng/mL, and 266 U/L, respectively. Overall, 81% of pts had bone-only metastases at baseline; 19% of pts had metastases in the bone plus other sites (mostly lymph nodes). Prior treatments included abiraterone (48% of pts), enzalutamide (39%), docetaxel (39%), and cabazitaxel (9%). Pts received a median of 6 Ra-223 doses; 67% received ≥5 doses. SPMs occurred in 2% of pts (25 SPMs in 24 pts). Of these pts, 16 (67%) and 1 (4%) had received prior or concomitant radiotherapy, respectively. Overall, 3% of pts had drug-related serious adverse events >30 days after completing Ra-223. Fractures were reported in 10% of pts and were less common in pts with (7% of 605) than without (12% of 867) concomitant BHA use. During Ra-223 and up to 30 days after the last dose, there was no notable difference in the incidence of abnormal platelet counts between pts with (3%) or without (2%) prior chemotherapy; similar findings were seen for abnormal neutrophil counts (5% and 5%, respectively). BMS treatments, assessed from the start of Ra-223, were more common in pts who had received prior taxanes (38%) than in those who had not (26%). The most common life-prolonging therapies received after Ra-223 were docetaxel (18%), enzalutamide (15%), abiraterone (11%), and cabazitaxel (11%). Median OS was 15.6 months (95% CI, 14.6, 16.4); pt subgroups that survived the longest will be characterized and presented. Conclusions: This real-world safety analysis of pts with mCRPC is the longest follow-up of a radiopharmaceutical reported to date and supports the well-established favorable safety profile of Ra-223. The incidence of SPMs was low. The rate of fracture was low, especially in the presence of BHAs. Prior taxane chemotherapy use had no impact on hematological toxicity. Clinical trial information: NCT02141438 .

ABSTRACT Background and hypothesis Podocytopathy associated with likely pathogenic/pathogenic variants of Transient receptor potential cation channel subfamily C member 6 (TRPC6) (TRPC6-AP) has been recognized for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype–phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterized clinical, histological and genetic correlates of familial and sporadic patients with TRPC6-AP. Methods In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes [age of onset, clinical presentation, treatment response, kidney biopsy findings and progression to kidney failure (KF)]. Logistic regression, Cox proportional hazards model and Kaplan–Meier analyses investigated the associations between genetic variants and disease progression. Results Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C&gt;T p.(Arg895Cys) and c.523C&gt;T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range 17–40) years, 48.9% (69/141) of patients had progressed to KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P = .001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85–10.15); P = .001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P = .004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40–5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01–2.81), respectively, log-rank P = .005]. Conclusion Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.

Background: Total hip arthroplasty (THA) effectively restores mobility, reduces pain, and enhances the quality of life of patients of all ages. Despite its benefits, concerns regarding the long-term effects of high-impact activities and sports on implant longevity require further study. This study investigated the effect of activity level on long-term radiographic wear of highly cross-linked polyethylene (HXLPE) in young patients undergoing THA. Methods: Between 1999 and 2008, 785 patients (909 hips) aged ≤50 underwent primary THA using first-generation HXLPE liners from 4 different vendors with either metal or ceramic heads. Functional activity and participation questionnaires, including the Hip Injury and Osteoarthritis Outcome Score (HOOS Jr), University of California Los Angeles (UCLA) activity scale, and High-Activity Arthroplasty Score (HAAS), were surveyed in 2018 to 2019. The response rate was 44%. Radiographic linear wear rates were measured using the ROMAN software in patients who had completed questionnaires and had radiographs taken at least 10 years apart, leaving a final cohort of 249 patients (284 hips). Multivariate analyses were performed to determine the relationship between HXLPE wear rates and activity scores. Results: At the time of the survey, approximately 10% of the patients performed high-impact activities not-recommended by consensus guidelines. The HXLPE linear wear rate was 0.036 mm/year (SD: 0.026). Patients with higher activity levels, as measured on the continuous UCLA/HAAS activity scale, did not exhibit increased wear (β = -0.0009; p = 0.31). Stair climbing was correlated with increased wear rates (β = 0.0066; p = 0.004), whereas walking (β = 0.0005; p = 0.66) and running (β = 0.0017; p = 0.30) were not significantly correlated. Patients performing nonrecommended activities did not show increased wear rates compared with those performing recommended activities (β = 0.0063; p = 0.19). Conclusions: Linear wear rates of first-generation HXLPE were not related to functional activity or participation in high-impact activities. Future research should include longitudinal assessments of activity levels and data on other potential complications related to high-impact sports to provide robust evidence regarding recommended activity level postoperatively. Level of Evidence: Level III , Retrospective Comparative Study. See Instructions for Authors for a complete description of levels of evidence.

Acute right ventricular failure (ARVF) is commonly seen in the intensive care unit and constitutes a significant clinical challenge, with associated high in-hospital mortality. Recently, the treatment of ARVF has significantly changed, with the progressive implementation of mechanical circulatory support devices that now represent important tools for clinicians in treating this condition. However, despite recent advancements, the optimal approach for ARVF remains elusive, and precise treatment algorithms and comprehensive management protocols are still lacking. In the present review, we explore the pathophysiology of ARVF, highlighting the different mechanisms that may lead to this clinical entity and emphasizing the left and right heart’s complex interplay. We analyze the different therapeutic options that are now available for short- and long-term management of ARVF, with a particular focus on the advantages and disadvantages of the mechanical circulatory support devices actually used. Furthermore, we propose future directions in the field and a possible flowchart for the treatment of this condition.

Abstract Rationale: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pulmonary condition characterised by neuroendocrine cell proliferation along respiratory bronchioles resulting in tumourlet formation which may progress to pulmonary carcinoid. DIPNECH is a rare and under-recognised condition that predominantly affects females, with an estimated worldwide incidence of 5-6 people per million population. Given it's rarity and the poor understanding around the pathogenesis and treatment of this condition, we undertook the largest international case series to date of DIPNECH patients. We aim to further characterise this patient cohort to better understand the clinical features, identify common pulmonary function test (PFT) patterns and radiographic findings and describe current treatment practices. Methods: We collated data from 17 centres across 8 different countries comprising a total of 258 patients. Data collected included patient demographics, smoking history, symptoms, co-morbidities, pathological diagnosis, imaging findings, PFT pattern and therapies. Results: In total 258 patients were identified. The median age was 65 (SD+/- 10.6). 241 (93%) were female. 39% (n= 94/243) were ex-smokers. 79% (n=186/234) of patients reported pulmonary symptoms with cough being the most common symptom reported in 81% (n=151/186) of patients. Many patients were polysymptomatic, with cough and dyspnoea being the most common combination of symptoms described. (50.54%; n=94/186). Complete spirometry pattern was documented for 180 patients (69.78%) with an obstructive pattern being the most commonly observed (n=76/180; 42%). 27.5% (n=41/139) had clinically significant FEV1 reversibility post bronchodilator administration. Pathology specimens were available in 219 cases. Most common pathological features were neuroendocrine hyperplasia which was observed in 75% (n=165/219) and tumourlets in 74% (n=162/219) of cases. Carcinoid, either typical or atypical, was observed in 64% (n=141/219) of samples. 252 patients had computed tomography (CT) imaging performed. Pulmonary nodules were the most common feature identified in 99.60% of cases (248/250). Mosaic attenuation (69.30%; n=50/173) and airway dilatation (28.90%; n=50/173) were also frequently reported. There was no significant correlation between symptoms (cough, dyspnoea, wheeze) and airway dilatation (p=0.496), mosaic attenuation (p=0.496) and PFT pattern (p=0.837). There was a significant association between presence of symptoms and mosaic attenuation on CT (p=0.003). Conclusions: DIPNECH, while a rare disorder, is understudied. This international case series is the largest performed to date and highlights the complexity in management of these patients.

Abstract RATIONALE: 4G4G/4G5G SERPINE1 genotypes produce high concentrations of plasminogen activator inhibitor-1 and are associated with worse asthma outcomes. A secondary analysis of the American Lung Association (ALA) SOYA trial showed that soy isoflavones significantly reduced asthma exacerbations versus placebo among patients with 4G4G/4G5G SERPINE1 genotypes. We hypothesized that baseline characteristics predict optimal responders to soy isoflavones among this subgroup. METHODS: ALA-SOYA was a randomized controlled trial that tested the efficacy of soy isoflavones vs. placebo for reducing asthma exacerbations among adolescents and adults with symptomatic asthma. In this responder analysis among participants with 4G4G/4G5G SERPINE1 genotypes, baseline demographic and clinical characteristics were tested for effect modification of the treatment assignment (soy/placebo) on the primary outcome of annualized number of asthma exacerbations using interaction terms in negative binomial regression models, with a significance threshold of p-interaction=0.15. RESULTS: Data were available for n=168 participants. Soy reduced the annualized number of asthma exacerbations relative to placebo among patients with 4G4G/4G5G SERPINE1 genotypes (incident rate ratio (IRR)=0.37, 95% confidence interval (CI): 0.15-0.90, p=0.028). Self-reported adherence to baseline controller therapy was the only significant effect modifier of this association (interaction p=0.115), with those using inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) controller therapy at least twice weekly experiencing reductions in asthma exacerbations with soy versus placebo (IRR = 0.25, 95% CI: 0.09-0.69; p= 0.007) but not among those using ICS/LABA controller therapy less frequently (IRR = 1.33, 95% CI: 0.22-8.02; p= 0.757). CONCLUSION: Soy isoflavones reduce asthma exacerbations among patients with the 4G4G/4G5G SERPINE1 genotypes and are most effective in those with greater adherence to asthma controller therapy regimens.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.