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Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Abstract Aims Significant advancements have been made in the management of obstructive hypertrophic cardiomyopathy (oHCM), yet the extent of left ventricular outflow tract (LVOT) gradient reduction achieved with commonly used pharmacological therapies [beta-blockers (BBs), calcium channel blockers (CCBs), disopyramide, and cardiac myosin inhibitors (CMIs)] relative to each other is still unclear. Methods and results PubMed and Scopus were searched up to September 2024. Clinical trials or observational studies that assessed the changes associated with BBs, CCBs, disopyramide, or CMIs in LVOT gradient at rest or with provocation in patients with oHCM were included. Mean changes in LVOT gradients were pooled as mean differences (MD) with 95% confidence intervals (CIs) in a random-effects model. Thirty-seven studies, with 44 arms and 1898 patients, were included in the analysis. At the therapeutic class level, pooled analysis showed that disopyramide was associated with the highest reduction in LVOT gradient at rest [MD: −43.5 (95% CI, −51.6 to −35.3)], followed by CMIs [MD: −34.8 (95% CI, −40.6 to −29.0)], BBs [MD: −20.7 (95% CI, −29.4 to −12.0)], and then CCBs [MD: −14.7 (95% CI, −23.3 to −6.1)], inter-action P < 0.01. Within CMIs, mavacamten had a higher effect than aficamten on gradient reduction; among the included BBs, metoprolol showed the highest gradient reduction, while among CCBs, verapamil was the most effective (inter-action P < 0.01). Similar results were observed for provocable LVOT gradients. Conclusion Pharmacological therapies effectively reduced LVOT gradients in oHCM patients to varying degrees, with disopyramide and CMIs showing the highest effect, followed by BBs and CCBs.

Abstract Rationale: Current guidelines recommend a short course of antibiotic therapy for ventilator-associated pneumonia (VAP) caused by non-fermenting gram-negative bacilli (NF-GNB). However, this approach has been associated with an increased risk of pneumonia recurrence. This meta-analysis aims to address inconsistencies in the literature and evaluate the efficacy of short-course versus long-course antibiotic therapy for VAP, particularly in cases due to NF- GNB. Methods: We systematically searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing short versus long courses of antibiotic therapy in patients with VAP. The primary outcomes were the risk of all-cause mortality and pneumonia recurrence. Data were analyzed using RevMan 5.4, with risk ratio (RR) and mean difference (MD) as effect measures. Results: Our pooled analysis included seven RCTs. There was no significant difference in all- cause mortality between short- and long-course antibiotic regimens (RR 1.02; 95% CI: 0.88-1.18; Figure 1). However, a short course of antibiotics increased the incidence ofpneumonia recurrence, particularly in patients with VAP due to NF-GNB (RR 1.64; 95% CI: 1.18-2.29; Figure 1). There were no significant differences between the two regimens regarding the duration of mechanical ventilation (MD 0.01 days; 95% CI: -0.51 to 0.53 days), ICU (MD 0.10 days; 95% CI: -1.00 to 1.20 days) and hospital stay (MD -0.63 days; 95% CI: -3.18 to 1.91 days), or subsequent infection with or acquisition of resistant organisms (RR 0.89; 95% CI: 0.63-1.24). Conclusions: Our meta-analysis suggests that while a short course of antibiotics increases the risk of pneumonia recurrence in NF-GNB VAP, it does not impact mortality compared to a longer course. The clinical significance of the increased recurrence of pneumonia remains uncertain, as it did not result in worse clinical outcomes. A practical approach incorporating validated clinical criteria and biomarker thresholds to guide the duration of antibiotic therapy may be more effective for patients with NF-GNB VAP. Larger RCTs are needed to drawdefinitive conclusions in this population.

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.

ABSTRACTBackground and AimsNerve conduction studies (NCS) are integral to diagnosing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but their role in predicting treatment outcomes remains underexplored. This study evaluates NCS changes at first follow‐up (first NCS changes) as predictors of treatment success in CIDP, focusing on their correlation with clinical outcomes over time.MethodsNewly diagnosed CIDP patients meeting the 2021 EAN/PNS criteria were retrospectively evaluated. Baseline and first follow‐up NCS parameters were compared with clinical outcomes, assessed by the Neuropathy Impairment Score (NIS) and Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. All patients received first‐line immunotherapy (intravenous immunoglobulin, corticosteroids, or plasma exchange).ResultsOf 39 treated patients, 26 (66.7%) were responders based on improving NIS trends, while 13 (33.3%) were nonresponders. Responders showed significant improvements at the first follow‐up in fibular compound muscle action potential (CMAP) amplitude, ulnar CMAP amplitude, summated CMAP amplitudes, and fibular motor conduction velocity. Changes in fibular CMAP amplitude consistently correlated with NIS (R = −0.8 to −0.6, p ≤ 0.004) and INCAT disability score improvements (R = −0.6 to −0.3, p ≤ 0.032) across all follow‐up intervals up to 60 months. Ulnar and summated CMAP amplitude changes also correlated with clinical outcomes, though their associations were less sustained than those of fibular CMAP amplitude.InterpretationThe first change in fibular CMAP amplitude is a reliable biomarker for predicting CIDP treatment response, with ulnar and summated CMAP amplitudes as alternatives when the fibular response is absent. Our findings highlight the utility of first NCS changes in monitoring and predicting treatment outcomes in CIDP.

686 Background: Blue-light cystoscopy (BLC) is an established procedure for use in the diagnosis and surveillance of patients with non-muscle-invasive bladder cancer (NMIBC). It is associated with improved detection rates compared to white light cystoscopy (WLC); however, limited data is available regarding its role in upstaging and/or upgrading when used alongside WLC. The aim of this study is to assess the incidence and features of patients undergoing upstaging and/or risk-group migration with the implementation of BLC. Methods: Using data from the prospective multi-institutional Cysview Registry (2014-2024), patients with NMIBC who underwent transurethral resection or biopsy of bladder tumors were identified. The patients in whom malignant lesions were exclusively detected by BLC, as well as those experiencing an upward change in risk category (as defined by the American Urological Association [AUA] classification) based on BLC findings, were documented. The clinical features of these patients were subsequently reviewed. Results: In this study, 2,854 patients were enrolled, who collectively underwent 4,158 resections and provided 6,432 separate pathology samples. A total of 201 (7%) patients had at least one malignant lesion detected exclusively by BLC while having negative WLC. These lesions (total 335) included carcinoma in-situ (CIS) in 145 (43%), low-grade Ta in 53 (16%), high-grade Ta in 95 (28%), high-grade T1 in 37 (11%), and high-grade T2 in 5 (1%). In patients with multifocal disease, BLC resulted in AUA risk-group upward migration in 66 (2.3%) patients.Theclinical features of these two groups are presented in the table. Taken together, the total rate of upgrading or upstaging using BLC was 9.3%, including migration to low-risk in 1.2%, intermediate-risk in 2.1%, and high-risk in 6%. Conclusions: Using BLC during transurethral resection or biopsy of bladder tumors results in risk group migration in over 9% of patients with NMIBC. This impacts patient management, including the administration of intravesical therapy when it was not initially planned, an extension in the duration of therapy, or the decision to proceed with radical cystectomy. Clinical features of patients with malignant lesions detected by BLC only (A) and those with risk group migration (B). Clinical features A B Age, median (IQR), year 71 (63-76) 71 (61-77) Gender, n (%) Male Female 140 (74)49 (26) 54 (82)12 (18) History of smoking, n (%) 117 (62) 40 (61) Primary occurrence, n (%) 65 (34) 14 (21) History on intravesical therapy, n (%) 92 (49) 40 (61) Urine cytology * , n (%) Positive Suspicious Atypical Negative/NA 33 (17)21 (10)41 (20)106 (53) 13 (20)7 (11)10 (15)36 (54) IQR: interquartile range; NA: not available. *Detected by either voided urine or bladder wash.

Abstract Aims Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although lipoprotein(a) [Lp(a)] is known to be a well-established risk factor for atherosclerotic cardiovascular disease, its role in the development of AF, independent of this association, remains unclear. Methods and results Adult patients from the three Mayo Clinic sites with a baseline Lp(a) and without AF history were included. Patients were categorized into two groups based on their Lp(a) levels: high Lp(a) (≥50 mg/dL) and low Lp(a) (<50 mg/dL). Survival probabilities free from incident AF were compared between Lp(a) groups, during a follow-up period up to 15 years, using the Kaplan–Meier curve and the log-rank test. Multivariable Cox regression analysis was also conducted. A total of 75 376 patients were included (median age: 55 years, 59% males), with a median follow-up duration of 8.8 (inter-quartile range: 3.4, 14.8) years. Incident AF was detected in 5738 (7.6%) patients. Survival probability free from incident AF was significantly lower in patients with elevated Lp(a) (86%) compared with those with low Lp(a) (88%, log-rank P < 0.001). Multivariable analysis adjusted for potential risk factors of AF showed a statistically significant association of elevated Lp(a) with an 11% increase in AF risk (adjusted hazard ratio: 1.11, 95% confidence interval: 1.05–1.18). Conclusion Our study suggests that elevated Lp(a) (≥50 mg/dL) is an independent risk factor for incident AF. Future prospective studies are warranted to validate our results and to test if reducing Lp(a) could mitigate the burden of AF.