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Introduction Approximately 50% of patients with uveal melanoma develop metastatic disease, most commonly involving the liver, and prognosis remains poor. Immunoembolization (IE) is an established liver-directed therapy for patients with liver-dominant metastatic uveal melanoma (mUM), though comparative data with other regional therapies remain limited. We present a single-center retrospective analysis of IE in hepatic mUM and compare outcomes with those reported in the Phase 3 FOCUS trial evaluating melphalan via percutaneous hepatic perfusion. Methods All patients with liver-dominant mUM treated with IE between 2010 and 2023 at our institution were included. Clinical records were reviewed for demographics, tumor characteristics, treatment details, and outcomes. The primary endpoint was disease control rate (DCR), defined as complete response (CR), partial response (PR), or stable disease (SD). Secondary endpoints included progression-free survival (PFS) and overall survival (OS), with subgroup analyses based on prior systemic therapy exposure. Descriptive statistics were used for analysis. Results Forty-three patients (62.8% female; median age 62 years; all Caucasian) underwent 249 IE procedures (mean 5.8 procedures per patient) over a median treatment duration of 9.1 months. Choroidal primaries accounted for 95.3% of cases, and 90.7% had liver-only metastases. The overall DCR was 27.9% (CR 4.7%, PR 20.9%, SD 2.3%), while 62.8% experienced disease progression. Median PFS was 0.85 months, and median OS was 32.7 months. One- and two-year OS rates were 69.8% and 55.8%, respectively. In subgroup analysis, patients who had received prior systemic therapy (n=12) demonstrated improved outcomes compared with treatment-naïve patients, with longer median PFS (29.9 vs. 7.2 months) and higher 2-year OS (60.0% vs. 47.0%). Compared with outcomes reported in the FOCUS trial, IE demonstrated shorter median PFS (0.85 vs. 9.0 months) and lower DCR (27.9% vs. 73.6%), but longer median OS (32.7 vs. 20.5 months). Discussion IE produced overall survival outcomes comparable to hepatic melphalan delivery despite lower radiographic response rates. Notably, patients previously treated with systemic therapy experienced improved outcomes, suggesting a potential sequencing effect. These findings support IE as a viable liver-directed therapy for liver-dominant mUM. Prospective, multicenter trials are warranted to clarify optimal sequencing strategies and enhance therapeutic outcomes.

Abstract Background The rare APOE3 ‐Christchurch ( APOE3Ch ) variant is associated with remarkable protective effects, delaying the age at onset of PSEN1 ‐E280A driven autosomal dominant Alzheimer's disease (AD). While much of the research on APOE3C h has focused on its role in AD, little is known about how this variant impacts APOE biology under non‐disease conditions. Using cortical organoids as a model system, we aim to investigate the fundamental mechanisms by which APOE3Ch alters APOE biology, including its effects on metabolism and cellular interactions, to better understand its unique properties and potential implications for broader applications. Method Cortical organoids were derived from the isogenic neurodegeneration iPSC line series, with either the APOE3 or APOE3Ch genotype. Single‐cell RNA sequencing (scRNA‐seq) was performed on three independent batches of 6‐month‐old cerebral organoids to identify pathways differentially regulated by APOE3Ch. To further investigate APOE lipidation and its effects on lipid metabolism, lipidomics analysis was conducted on 8‐month‐old cerebral organoids, offering additional insights into APOE3Ch ‐specific biological mechanisms. Validation was also carried out using iPSC‐derived astrocytes and neurons to confirm key findings. Result ScRNA‐seq revealed differences in cell populations and astrocyte subtypes between APOE3 and APOE3Ch organoids, with mitochondrial‐related pathways differentially regulated in APOE3Ch cerebral organoids. These findings were validated in iPSC‐derived astrocytes. APOE3Ch iPSC‐derived astrocytes exhibited increased APOE secretion compared to APOE3 . They also demonstrated enhanced mitochondrial function, as evidenced by increased spare respiratory capacity measured by Seahorse stress assays. Furthermore, APOE3Ch astrocytes showed reduced lipid droplet formation following oleic acid treatment. Lipidomics analysis of APOE3Ch cerebral organoids revealed decreased cholesterol ester levels, suggesting alterations in lipid metabolism. Conclusion Our findings provide novel insights into how the APOE3Ch variant alters APOE biology, revealing differences in mitochondrial function and lipid metabolism. The differential regulation of mitochondrial pathways in APOE3Ch cerebral organoids, along with the enhanced mitochondrial capacity and altered lipid metabolism observed in APOE3Ch astrocytes, highlights the unique properties of this variant. These results offer valuable mechanistic understanding that may inform future therapeutic strategies targeting APOE biology, particularly in the context of AD.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

OBJECTIVE Anterior cervical discectomy and fusion (ACDF) is an established treatment for cervical degenerative disc disease; however, the procedure can cause loss of cervical spine range of motion and potentially accelerate adjacent segment degeneration. Cervical disc arthroplasty (CDA) seeks to preserve native motion of the cervical spine, which can theoretically reduce the incidence of adjacent level degeneration. The literature regarding the relative efficacy of ACDF versus CDA remains inconsistent. In this study, the authors investigate the difference in outcomes between ACDF and CDA and identify factors contributing to the heterogeneity in the literature. METHODS The Ovid, Embase, Scopus, Cochrane, and ClinicalTrials.gov databases were systematically searched from inception to September 5, 2023, for randomized controlled trials (RCTs) comparing ACDF and CDA for degenerative disc disease. Studies were extracted by two authors and verified by a third. Random-effects meta-analysis was performed. The primary outcome was the difference in clinical outcomes between the two surgical groups. The secondary outcomes were the differences in radiological outcomes, surgical characteristics, complication rates, and hospital lengths of stay. The study was registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration no. CRD42023469204) and adhered to the PRISMA guidelines. RESULTS From 584 articles uploaded to the Covidence platform for screening, 35 studies derived from 25 RCTs were included in this systematic review and meta-analysis. A total of 4530 patients were treated with ACDF (2081) and CDA (2449). Forty-six percent of the patients (2063) were male, and the mean age of the study cohort was 45 ± 3 years. In terms of the primary outcome, CDA showed higher rates of neurological and overall success. Regarding the secondary outcomes, CDA demonstrated a significantly lower rate of adjacent level disease, higher rate of heterotopic ossification, and greater range of motion at the operated level. Additionally, CDA had lower rates of reoperation but significantly longer operative times than ACDF. The inclusion of myelopathic patients and variations in follow-up between the surgical groups contributed to the observed effect heterogeneity among studies. CONCLUSIONS In this study, CDA showed comparable or potentially greater success in overall and neurological outcomes, along with a lower incidence of adjacent level degeneration and reoperation rates but longer operative times.

The integration of mobile health (mHealth) technologies is transforming neurosurgery. Despite its potential, many uses remain unrealized due to the unique challenges and complexity of developing mHealth technology. While neurosurgeons bring invaluable clinical expertise and an understanding of patient needs, the technical intricacies of application development often require collaboration with developers and computer scientists, a process that can feel unfamiliar and difficult to navigate. The aim of this article was to demystify mHealth development by providing a guide for neurosurgeons seeking to develop disease-specific mHealth applications. We outline this process using the development of SynapTrack, an mHealth tool designed to provide objective assessments of degenerative cervical myelopathy, a chronic condition caused by symptomatic compression of the cervical spinal cord. This article offers neurosurgeons concrete guidance on navigating key considerations such as design decisions, algorithm integration, database architecture, and data security. By grounding these insights with SynapTrack, this guide offers a transparent view into the development process and provides a practical framework that can be adapted to the development of other mHealth tools. The aim of this work was to foster interdisciplinary collaboration and enable neurosurgeons to develop mHealth applications tailored to the specific needs of their specialty.

e21600 Background: Uveal melanoma (UM), the most common intraocular malignancy in the U.S., metastasizes in 50% of patients, frequently to the liver (~90%) with poor prognosis (median overall survival [mOS] 1 year). Metastatic UM (mUM) literature is limited (due to its rarity/complexity) and management remains challenging, as standard therapies—liver-directed approaches (e.g. transarterial chemoembolization [TACE]) and systemic therapy with tebentafusp (limited to HLA-A*02:01-positivity)—offer limited efficacy, with no durable responses or significant survival benefits. Interestingly, Delcath’s recent FOCUS Phase 3 trial demonstrated the efficacy of the melphalan/Hepatic Delivery System for unresectable mUM, with an objective response rate (ORR) of 36.3%, 1-year OS of 80%, and median progression-free survival (PFS) of 9 months. Here, we present a large retrospective study of liver-predominant mUM treated with immunoembolization (IE) at a tertiary academic center. This study provides valuable data to the underreported mUM literature. We also compare our findings with Delcath’s trial to contextualize results and identify clinical factors influencing treatment response and prognosis. Methods: We retrospectively reviewed charts of mUM patients treated with IE (age ≥18 years, 2010–2023). Data collected included demographics, clinical/pathology/molecular details, and management/outcomes. Subgroup analysis on prior systemic therapy use was performed (similar to Delcath). The primary outcome was OS at 12 and 24 months. Results: 43 patients were included (100% White, 62.8% female, median age 62). Most had choroidal type (95.3%), hepatic-only metastases (90.7%), and were treatment-naïve before IE (72.1%). Across 249 IE procedures (5.8 per patient, mean duration 9.1 months), we observed median PFS and OS of 9.2 and 23 months, respectively - comparable to Delcath’s trial (9 and 20.5 months). Despite higher disease progression in our study (62.8% vs. 25.3%) and lower best clinical response (27.9% vs. 73.7%), 1-year (67% vs. 80%) and 2-year OS rates (49% vs. 43%) were similar. Subgroup analysis revealed better outcomes in previously treated patients (n = 12) compared to treatment-naïve patients (n = 31), with improved median PFS (29.9 vs. 7.2 months) and 1- and 2-year OS (75% vs. 65% and 58.3% vs. 41.9%, respectively). This contrasts with Delcath’s findings, where prior therapy did not significantly affect PFS or OS. Median PFS was comparable in treatment-naïve groups (7.2 vs. 9 months) but markedly improved in our previously treated group (29.9 vs. 9.2 months). Conclusions: We highlight IE’s comparable efficacy to Delcath’s melphalan/Hepatic Delivery System regarding mUM PFS and OS, with added benefits for previously treated patients. While our findings advance understanding of mUM management, more prospective studies are needed to improve therapeutic strategies/patient outcomes.

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.

The novel Coronavirus Disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, created a need for evidence-based guidelines for the evaluation, management, and follow-up after infection. Data have become rapidly available, creating a challenge for medical providers to stay abreast of the ever-evolving recommendations. This article, written collaboratively by pediatric cardiovascular experts, pediatricians, and sports medicine specialists, is focused on SARS-CoV- 2-related pediatric cardiac manifestations. It aims to provide a systematic review of high-yield literature related to all cardiovascular entities as a tool for primary pediatric clinicians to utilize as they consider the cardiac consequences of acute SARS-CoV-2 infection, MIS-C, vaccine-related myocarditis, return-to-play, and long COVID-19 syndrome.

Importance Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration ClinicalTrials.gov Identifier: NCT04623242