Citations

ABSTRACT Background Antiplatelet management in patients hospitalised for gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI) requires balancing risks of rebleeding and clinical vascular events. Aims Evaluate the impact of antiplatelet resumption timing post‐endoscopy on rebleeding and clinical vascular events. Methods We performed a retrospective nationwide cohort study of patients hospitalised with post‐PCI GIB on dual antiplatelet therapy (DAPT) using the Vizient Clinical Database. Co‐primary outcomes were 30‐day rebleeding and 90‐day clinical vascular events after endoscopy. Multivariable Cox proportional hazards regression analysis was performed. Results Among 2979 patients with both antiplatelet agents held before endoscopy for GIB (46.0% upper; 34.8% lower), antiplatelet resumption > 7 days post‐endoscopy was associated with decreased 30‐day rebleeding (hazard ratio [HR] 0.66; 95% confidence interval [CI] [0.49–0.87]) and increased 90‐day clinical vascular events (HR 1.18 [1.02–1.36]) compared to restarting ≤ 1 day post‐endoscopy. Among 869 patients with one antiplatelet agent held before endoscopy for GIB (47.3% upper; 36.3% lower), resumption at > 7 days vs. ≤ 1 day had HR 0.69 (0.41–1.14) for rebleeding and HR 1.41 (0.97–2.04) for clinical vascular events. HRs for antiplatelet resumption > 3 days vs. ≤ 1 day post‐endoscopy were similar. Conclusions Antiplatelet resumption > 7 days after endoscopy in patients hospitalised with post‐PCI GIB is associated with decreased 30‐day rebleeding but increased 90‐day clinical vascular events compared with resumption ≤ 1 day post‐endoscopy. Similar tradeoffs were noted with antiplatelet resumption > 3 days post‐endoscopy. To optimise competing risks of rebleeding versus clinical vascular events, antiplatelet therapy should be resumed no later than 7 days post‐endoscopy, and preferably within 3–4 days.

Abstract One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell interactions between tumour and immune cells may provide insight into critical intercellular communications and manipulations occurring within the tumour immune microenvironment (TME). We hypothesised that the key cell-cell interactions in MYC-driven primary and recurrent MB may reveal dominant immune-suppressive mechanisms and uncover targetable therapeutic vulnerabilities. Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for 10X MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of both CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models of primary and recurrent MB, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. Key cellular interactions and therapeutic vulnerabilities within the tumour microenvironment of MYC-driven medulloblastoma (MB) have been identified, highlighting the CD74-MIF axis as a target for next-generation immunotherapies.

ABSTRACT Background A decrease in renal blood flow (RBF) precedes estimated glomerular filtration rate (eGFR) decline among patients with autosomal dominant polycystic kidney disease (ADPKD) and inversely associates with disease severity and progression. However, it is unknown whether RBF independently predicts progression to kidney failure in patients with ADPKD. Methods A total of 379 participants with early-stage ADPKD (mean age 36.6 ± 8.5 years; eGFR: 92.9 ± 17.1 ml/min/1.73 m2) who participated in the Halt Progression of Polycystic Kidney Disease Study A (HALT PKD A; NCT00283686) with baseline RBF (phase contrast magnetic resonance imaging) data were included in the primary analysis. Kaplan–Meier survival analysis and multivariate Cox proportional hazard models were used to determine the association of baseline RBF as a continuous and categorical variable with kidney failure risk (during the HALT study and subsequently linked to the US Renal Data System) over a median follow-up period of 13.1 years (interquartile range 7.5–14.5) (primary outcome). All-cause mortality was also considered as a competing risk (Fine and Gray method). The associations of RBF with eGFR slope and the change in height-adjusted total kidney volume (∆htTKV) were evaluated with linear and logistic regression models. Results The kidney failure incidence rate was the highest among those with the lowest RBF tertile {1.90 [95% confidence interval (CI) 1.31–2.78] versus 0.34 [95% CI 0.14–0.83] events/100 person-years in tertile 3}. In the fully adjusted model, the lowest RBF tertile was associated with a higher risk of progression to kidney failure [hazard ratio (HR) 3.19 (95% CI 1.05–9.67] versus the highest tertile]. The association of RBF with kidney failure risk was slightly attenuated in adjusted models. All associations remained similar when considering death as a competing risk [HR 0.82 (95% CI 0.67–1.00) per 100 ml/min/1.73 m2 higher RBF]. Higher RBF was associated with a slower eGFR decline and lower odds of rapid annual ∆htTKV. Conclusions Lower baseline RBF independently associates with a greater risk of progression to kidney failure in early-stage patients with ADPKD.

Abstract Endoscopic sleeve gastroplasty (ESG) facilitates 13.6%–16.2% total body weight loss (TBWL) at 12 months, but falls short of that seen with surgical vertical sleeve gastrectomy, in part owing to the retention of the gastric fundus. In adults with obesity, gastric fundal mucosal ablation (GFMA) reduces fasting plasma ghrelin (FPG), hunger, cravings, and accommodation. Combined GFMA-ESG could improve TBWL. This study aimed to evaluate the effectiveness and safety of sequential GFMA followed by ESG in adults with obesity, building on previously published 6-month results of GFMA alone. This was a prospective, first-in-human, two-phase clinical trial. Ten participants underwent GFMA, followed by ESG at month 6, and were followed for 12 months post-ESG (18 months total). GFMA was performed using hybrid argon plasma coagulation to lift and ablate the entire gastric fundal mucosa. ESG was performed using standard full-thickness endoscopic suturing of the gastric body. The primary end point was TBWL; secondary end points were safety and changes in FPG, maximum tolerated volume (MTV), and validated appetite questionnaires. Mean TBWL was 22.5% (SD 8.3%) at month 18. Hunger-related behaviors and eating self-efficacy showed sustained improvements. FPG was decreased at month 6 and returned toward baseline by month 18, while MTV remained suppressed. No serious adverse events occurred. Sequential GFMA-ESG is safe and induces substantial weight loss, reduced MTV of ingested nutrients, and improved behavioral measures. This combination approach builds on prior traditional ESG and GFMA-only results and may represent a promising advancement of endoscopic therapeutic options for weight loss.

Abstract Background The ability of large language models (LLMs) to work collaboratively and screen studies in a systematic review (SR) is under-explored. Hence, we aimed to evaluate the effectiveness of LLMs in automating the process of screening in systematic reviews. Methods This is an observational study which included labeled data (title and abstracts) for five SRs. Originally, two reviewers screened the citations independently for eligibility. A third reviewer cross-checked each citation for quality assurance. GPT-4, Claude-3-Sonnet, and Gemini-Pro-1.0 were used using zero-shot chain-of-thought prompting. Collaborative approaches included (i): conflict resolution using benefit of the doubt, (ii) majority voting using an independent third LLM and (iii) conflict resolution using an informed third LLM. Performance was assessed using accuracy, precision for exclusion, and recall for inclusion. Work saved over samples (WSS) was computed to estimate the reduction in manual human effort. Results A total of 11300 articles were included in this study. The individual models, GPT-4, Claude-3-Sonnet, and Gemini-Pro-1.0 exhibited a high precision for exclusion, achieving 99.7%, 99.7%, and 99.2% and high recall for inclusion achieving 95.5%, 96.6% and 85.7%, respectively. However, the collaborative approach utilizing the two best-performing models (GPT-4 and Claude-3S) achieved an average precision of 99.9% and a recall of 98.5% (across all collaborative approaches). Furthermore, the proposed collaborative approach resulted in an average WSS of 63.5%, compared to the average WSS of 45.2% for individual models. Conversational LLM interactions showed a consistent pattern of results. Limitations This study was limited due to reliance on proprietary models, and evaluation on oncology datasets. Conclusion Evidence shows that collaborative LLMs enable efficient, high-performing screening in systematic reviews, supporting continuous evidence updates. Primary funding source NIH (U24CA265879-01-1) and Carolyn-Ann-Kennedy-Bacon Fund.

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.

OBJECTIVE Brain metastases significantly impact neurocognitive function and overall survival. Stereotactic radiosurgery (SRS) is a cornerstone of treatment for patients with limited metastases and expected survival beyond 3 months. Despite current guidelines, up to 20% of patients with brain metastases undergoing SRS have been reported to die within 90 days. This study retrospectively evaluated prognostic factors associated with 90-day survival after SRS, aiming to improve patient selection. METHODS The authors retrospectively analyzed a cohort of 1546 patients who underwent Gamma Knife SRS for brain metastases at their institution between 2015 and 2023. One hundred seventy patients who survived less than 90 days after SRS were identified and case matched to 170 patients who survived over 90 days. Measured variables included patient demographic characteristics, tumor characteristics, treatment history, functional status, and control of the primary cancer. The authors modeled post-SRS 90-day survival using binomial and multivariate logistic regression. RESULTS Multivariate analysis highlighted Karnofsky Performance Score (KPS) < 70 (OR 17.4, p < 0.001), prior whole-brain radiation (OR 6, p = 0.004), and focal neurological deficits (OR 3.02, p = 0.003) as significant predictors of poor survival, whereas CNS progression before SRS (OR 0.22, p < 0.001) and control of systemic cancer (OR 0.556, p = 0.002) were associated with survival < 90 days. The predictive model demonstrated acceptable performance with an area under the curve (AUC) of 0.85, accuracy of 80%, sensitivity of 87%, and specificity of 71%. CONCLUSIONS Key predictors of 90-day survival after SRS for brain metastases include functional status (KPS), control of systemic cancer, CNS progression status, and focal neurological deficits. These findings are complementary factors that can assist in making decisions and SRS patient selection.

Aims Total elbow arthroplasty (TEA) has shown favourable outcomes in the management of severely comminuted distal humeral fractures in low-demand elderly patients, leading to its increased use in recent years. Less is known about the outcomes of TEA when used for the failure of either internal fixation or conservative management, particularly whether not performing TEA acutely influences the options for further management if fixation fails. This systematic review aimed to assess the clinical and functional outcomes following TEA when used for the post-traumatic sequelae of a distal humeral fracture, and to compare these outcomes with those in patients with a distal humeral fracture who undergo TEA acutely. Methods MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus databases were searched from January 2000 to September 2024 for studies reporting complications, reoperations, the range of motion of the elbow, or functional outcomes following the use of TEA in the management of the post-traumatic sequelae of distal humeral fractures, including those due to failed fixation, nonunion, and post-traumatic arthritis. Demographic and clinical data were collected, descriptive statistics were summarized, and meta-analyses were undertaken to compare the outcomes between salvage and acute TEA. Results A total of 16 studies were included, with a total of 380 patients who underwent salvage TEA and 251 who underwent TEA as the initial management. Salvage TEA was associated with a significantly higher overall risk of complications (odds ratio (OR) 2.5 (95% CI 1.0 to 5.9)), though the rate of reoperations did not differ from those who underwent TEA acutely (OR 1.4 (95% CI 0.8 to 2.4)). Pooled analyses revealed a similar postoperative range of flexion (mean difference (MD) -2.4° (95% CI -9.1 to 4.3)) and extension of the elbow (MD 1.1° (95% CI -2.3 to 4.5)) and pronation (MD 0.0° (95% CI -1.1 to 1.1)) and supination (MD -0.0° (95% CI -1.0 to 0.9)) of the forearm. However, salvage TEA showed significantly inferior functional outcomes, as assessed by the Mayo Elbow Performance Score (MD 9.7 (95% CI -18.8 to -0.6)). Conclusion These findings indicate that salvage TEA represents a viable option for the management of post-traumatic sequelae following the teatment of a distal humeral fracture, although patients who underwent salvage TEA had a significantly increased rate of complications and significantly inferior functional outcomes compared with those who underwent TEA acutely. Cite this article: Bone Joint J 2026;108-B(1):21–29.