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Importance Semaglutide, a glucagonlike peptide-1 receptor agonist (GLP-1RA), has recently been implicated in cases of nonarteritic anterior ischemic optic neuropathy (NAION), raising safety concerns in the treatment of type 2 diabetes (T2D). Objective To investigate the potential association between semaglutide and NAION in the Observational Health Data Sciences and Informatics (OHDSI) network. Design, Setting, and Participants This was a retrospective study across 14 databases (6 administrative claims and 8 electronic health records). Included were adults with T2D taking semaglutide, other GLP-1RA (dulaglutide, exenatide), or non–GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from December 1, 2017, to December 31, 2023. The incidence proportion and rate of NAION were calculated. Association between semaglutide and NAION was assessed using 2 approaches: an active-comparator cohort design comparing new users of semaglutide with those taking other GLP-1RAs and non–GLP-1RA drugs, and a self-controlled case-series (SCCS) analysis to compare individuals’ risks during exposure and nonexposure periods for each drug. The cohort design used propensity score–adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). Network-wide HR and IRR estimates were generated using a random-effects meta-analysis model. Exposures GLP-1RA and non–GLP-1RAs. Main Outcomes and Measures NAION under 2 alternative definitions based on diagnosis codes: one more inclusive and sensitive, the other more restrictive and specific. Results The study included 37.1 million individuals with T2D, including 810 390 new semaglutide users. Of the 43 620 new users of semaglutide in the Optum’s deidentified Clinformatics Data Mart Database, 24 473 (56%) were aged 50 to 69 years, and 26 699 (61%) were female. The incidence rate of NAION was 14.5 per 100 000 person-years among semaglutide users. The HR for NAION among new users of semaglutide was not different compared with that of the non–GLP-1RAs using the sensitive NAION definition—empagliflozin (HR, 1.44; 95% CI, 0.78-2.68; P = .12), sitagliptin (HR, 1.30; 95% CI, 0.56-3.01; P = .27), and glipizide (HR, 1.23; 95% CI, 0.66-2.28; P = .25). The risk was higher only compared with patients taking empagliflozin (HR, 2.27; 95% CI, 1.16-4.46; P = .02) using the specific definition. SCCS analysis of semaglutide exposure showed an increased risk of NAION (meta-analysis IRR, 1.32; 95% CI, 1.14-1.54; P < .001). Conclusions and Relevance Results of this study suggest a modest increase in the risk of NAION among individuals with T2D associated with semaglutide use, smaller than that previously reported, and warranting further investigation into the clinical implications of this association.

Aim: According to the results of the MASTRO I living systematic review and meta-analysis, use of the EmboTrap Revascularization ® Device in the treatment of acute ischemic stroke (AIS) results in higher rates of good functional outcomes (90-day modified Rankin Scale [mRS] 0–2) compared with use of the Trevo ® Retriever or the Solitaire™ Revascularization Device. The aim of this analysis was to assess the potential economic impact of achieving improved functional outcomes for three commonly used stent retrievers (SRs) in the treatment of AIS. Methods: An economic model with short-term and long-term costs, representing a healthcare system perspective was developed using a decision tree to simulate a cohort of 1000 hypothetical patients treated for AIS with mechanical thrombectomy (MT) using EmboTrap, Trevo or Solitaire SRs. Based on the proportion of patients who achieved a 90-day mRS score of 0–2 or 3–5 for each device reported in MASTRO I (excluding patients not surviving after 90 days), this model estimated per-patient costs and the associated incremental cost savings. Results are reported from the healthcare system perspective in the US, Canada, the UK, Sweden, Germany, France, Italy, Spain, Belgium and The Netherlands. Results: Across all ten countries, the use of EmboTrap during MT was associated with the lowest short-term (ranging from €8412 in Italy to $66,525 in the US), long-term (ranging from €5249 in Italy to $25,757 in the US) and total (ranging from €13,661 in Italy to $92,282 in the US) per-patient costs. The total per-patient cost was higher with Trevo (ranging from €14,601 in Italy to $97,487 in the US) and Solitaire (ranging from €14,840 in Italy to $98,814 in the US). Cost savings were highest when comparing EmboTrap versus Solitaire, followed by EmboTrap versus Trevo, with Trevo versus Solitaire having the smallest cost savings. Results of sensitivity and scenario analyses supported the robustness of the base-case results. Conclusion: Across the ten countries, treating patients with AIS with EmboTrap resulted in lower short-term, long-term and total costs to the payer. With rising healthcare costs and limited hospital budgets, these results suggest EmboTrap proves to be an evidence-based economical choice of SR for hospitals and healthcare systems.

Abstract Background We sought to evaluate key performance indicators related to an internally developed and deployed artificial intelligence (AI)-augmented kidney stone composition test system for potential improvements in test quality, efficiency, cost-effectiveness, and staff satisfaction. Methods We compared quality, efficiency, staff satisfaction, and financial data from the 6 months after the AI-augmented laboratory test system was deployed (test period) with data from the same 6-month period in the previous year (control period) to determine if AI-augmentation improved key performance indicators of this laboratory test. Results In the 6 months following the deployment (test period) of the AI-augmented kidney stone composition test system, 44 830 kidney stones were analyzed. Of these, 92% of kidney stones were eligible for AI-assisted interpretation. Out of these AI-eligible stones, 45% were able to be auto-released by the AI-augmented test system without human secondary review. Furthermore, the new AI-augmented kidney stone test system resulted in an apparent 40% reduction in incorrect laboratory results. Additionally, the new AI-augmented test system improved laboratory efficiency by 20%, improved staff satisfaction, and reduced the average analysis cost per kidney stone by $0.23. Conclusions The AI-augmented test system improved test quality, efficiency, cost-effectiveness and staff satisfaction related to this kidney stone composition test.

Aim: The aim of this analysis was to assess the cost–effectiveness of the EmboTrap ® Revascularization Device compared with the Solitaire™ Revascularization Device and Trevo ® Retriever for the treatment of acute ischemic stroke (AIS) from the perspective of the Chinese healthcare system. Methods: According to MASTRO I, a recent living systematic literature review and meta-analysis, mechanical thrombectomy (MT) with EmboTrap in the treatment of AIS resulted in better functional outcomes compared with the use of Solitaire or Trevo. Based on the proportion of patients that achieved 90-day modified Rankin Scale (mRS) scores of 0–2, 3–5 and 6 reported in MASTRO I, a combined 90-day short-term decision tree and Markov model with a 10-year time horizon was used to compare the cost–effectiveness of the three devices. The primary outcome was the incremental cost–effectiveness ratio (ICER), representing the incremental cost (in 2022 Chinese Yuan [CNY]) per incremental quality-adjusted life-year (QALY). The ICERs were compared against willingness-to-pay (WTP) thresholds of 1, 1.5 and 3-times the 2022 national gross domestic product (GDP) per capita in China. Results: Treatment with EmboTrap resulted in total QALYs of 3.28 and total costs of 110,058 CNY per patient. Treatment with Trevo resulted in total QALYs of 3.05 and total costs of 116,941 CNY per patient. Treatment with Solitaire resulted in total QALYs of 2.81 and total costs of 99,090 CNY per patient. Trevo was dominated by EmboTrap as it was a more costly and less effective intervention. As such, Trevo was not cost-effective at any WTP threshold. Compared with Solitaire, EmboTrap was more effective and more costly, with an ICER of 23,615 CNY per QALY. This result suggests that EmboTrap is cost-effective when compared with Solitaire since the ICER was lower than all WTP thresholds assessed. Conclusion: EmboTrap dominated Trevo and is cost-effective for the treatment of patients with AIS compared with Solitaire when assessed from the perspective of the Chinese healthcare system and based on the device-level meta-analysis MASTRO I. Selecting a stent retriever (SR) that optimizes 90-day mRS score is an important consideration from both a clinical and healthcare payer perspective in China as it is associated with reduced long-term costs and increased quality of life.

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in 15 to 75% of outpatients. Depending on the assumptions modeled in stratified analyses, we estimated that CCP saved between 16,476 and 66,296 lives. The CCP ideal use might have saved as many as 234,869 lives and prevented 1,136,133 hospitalizations. CCP deployment was a successful strategy for ameliorating the impact of the COVID-19 pandemic in the USA. This experience has important implications for convalescent plasma use in future infectious disease emergencies.

AbstractBackgroundLoss of function mutations in PINK1 and PRKN are the most common causes of early‐onset Parkinson disease (PD). The encoded ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN together regulate the autophagic degradation of dysfunctional mitochondria, termed mitophagy. During this cytoprotective process, PINK1 and PRKN identify and jointly decorate damaged mitochondria with phosphorylated Ub (pS65‐Ub) that serves as the mitophagy tag. Accumulating evidence suggest a pathogenic role for impaired mitophagy in PD and related neurodegenerative conditions. This is in line with our previous finding of increased levels of the mitophagy marker pS65‐Ub in the hippocampus of postmortem Lewy body disease (LBD) brain.MethodWe performed a genome‐wide association study (GWAS) of hippocampal pS65‐Ub level to identify novel regulators of the PINK1‐PRKN‐directed mitophagy in LBD. In our two‐stage GWAS, we obtained 1,012 autopsy confirmed LBD samples (754 discovery stage, 258, replication stage) from Caucasian participants of European ancestry. Using an established, mostly automated workflow, hippocampal sections were immunostained for pS65‐Ub, scanned, and quantified with unbiased algorithms.ResultOur findings identified that APOE rs429358 (β: 0.50, 95% CI: 0.41 to 0.69, p = 8.67×10−25) was very strongly associated with pS65‐Ub levels in LBD brain. The APOE4 genotype is known to exacerbate Aβ and tau deposition. We did observe strong correlations of pS65‐Ub levels with both tau tangle and senile plaque density in the entire LBD cohort. Nevertheless, the increased pS65‐Ub levels in APOE4‐carrying LBD brains were also independent of Aβ and tau deposition in a subgroup (N = 175) with medium levels of these pathologies. To further explore APOE4 effects on mitophagy outside disease context, this observation was also confirmed in APOE‐targeted replacement mice and in induced pluripotent stem cell‐derived astrocytes.ConclusionOur findings nominate a novel mitophagy regulator in LBD brain and highlight a strong association of APOE4 with mitophagy alteration. Our results suggested that APOE4 may mediate mitophagy defects through two mechanisms, by aggravating Alzheimer’s‐type pathologies and also independent of them. With APOE4 being the strongest known risk factor for Alzheimer’s disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.

Introduction Secondary central nervous system (CNS) involvement develops in 2-10% of large B-cell lymphoma (LBCL) cases. Current treatment approaches for relapsed or refractory CNS disease generally do not provide durable responses. Limited data suggest efficacy and feasibility of CAR-T therapy in SCNSL. We report here the largest multicenter retrospective analysis of the safety and efficacy of CD19-directed CAR-T therapy in SCNSL patients. Methods This study included SCNSL patients who received commercial CD19-directed CAR-T therapy at 9 academic institutions in the United States between 2016 and 2022. SCNSL was defined as history of parenchymal and/or leptomeningeal/cerebrospinal fluid (CSF) involvement by lymphoma at any time prior to receiving CAR-T therapy. Systemic response was assessed using the Lugano criteria while CNS response was assessed as per International PCNSL Collaborative Group criteria. Kaplan-Meier curves were generated for progression-free survival (PFS) and overall survival (OS) for entire cohort, as well as subsets of patients with and without active CNS disease at the time of CAR-T infusion. Results Ninety patients were included in the analysis, with baseline characteristics shown in Table 1. CAR-T products utilized include axicabtagene ciloleucel (n= 38, 42%), tisagenlecleucel (n=37, 41%) and lisocabtagene maraleucel (n= 15, 14%). Fludarabine/cyclophosphamide was used as lymphodepletion in 84 patients (93%). 28 patients received CNS directed radiation therapy (RT) prior to CAR-T infusion (31%) within a median time of 28.5 days (range 5 - 906) from last day of RT. Amongst all patients at the time of CAR-T infusion 82 (91.1%) had active CNS and/or systemic involvement while 8 (8.9%) had no evidence of disease; 68 (75.5%) had active CNS involvement while 22 (24.5%) had a prior history of CNS involvement but no active at the time of CAR-T infusion. ( Table 1) Median follow up all patients was 0.5 year (range 0.01 - 4.7). 71 patients (79%) developed cytokine release syndrome (CRS; median time to onset 3 days) with 3.3% patients developing Grade 3-4. Immune effector cell-associated neurotoxicity syndrome (ICANS; median time to onset 5 days) was reported in 55 patients (61%), with 28.8% developing Grade 3-4. No patients died due to CRS or ICANS. At 1-month post CAR-T, 80 patients were evaluable for CNS response and 71 patients in the entire cohort were evaluable for systemic response. Similarly, at 3-months these numbers were 66 and 60, respectively. Objective response rates (ORR) were 75% and 80% at 1-month for CNS and systemic disease respectively, while corresponding ORRs at 3-months were 68% and 76.7%. At 1- and 3-months timepoint 36 (45%) and 33 (50%) patients, respectively achieved CNS complete remission (CR), while 44 (62%) and 42 (70%) patients respectively achieved systemic CR. 1- and 2-year PFS for entire cohort were 25% (95%Cl 15% - 34%) and 16% (95%Cl 8.5% - 28%) respectively, while 1- and 2-year OS were 46% (95%Cl 36% - 59%) and 31% (95%Cl 22% - 46%). Non-relapse mortality (NRM) were 4.6% (95%CI, 1.8% -12%) and 7.2% (95%CI 2.9% - 18%) at 1- and 2-year. Cumulative incidence of relapse at 1- and 2-year were 73% (95%Cl 63% - 83%) and 77% (95%Cl 68% - 88%), respectively. ORRs for CNS response in patients with active CNS disease at 1-month and 3-month interval were 71% (n=45) and 60% (n=31). Similarly, ORR for systemic response with active CNS disease at 1-month and 3-month interval were 85% (n=43) and 74.3% (n=32).The 2-year PFS for patients with and without active CNS disease at CAR-T infusion were 12% (95%Cl 5.4% - 27%) and 28% (95%Cl 12% - 65%) respectively, with a corresponding OS of 25% (95%Cl 15% - 41%) and 58% (95%Cl 37% - 91%). ( Figure 1) The 2-year NRM rates for patients with and without active CNS disease at CAR-T infusion were 4.6% (95%Cl 1.5% - 14%) and 14% (95%Cl 3.6% - 53%) respectively, while the cumulative incidence of relapse in similar order were 83% (95%Cl 73% - 95%) and 58% (95%Cl 39% - 88%). Conclusion In this largest known case series to date, CAR-T therapy appeared safe and feasible in patients with SCNSL, but is associated with high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion. This warrants further study of optimal CNS-directed treatment strategies prior to CAR-T, development of novel cellular therapy platforms or consideration of post CAR-T maintenance therapy in these high-risk patients.