Deficiency of m 6 A RNA methylation promotes ZBP1-mediated cell death.

m 6 A RNA methylation suppresses the immunostimulatory potential of endogenous RNA. Deficiency of m 6 A provokes inflammatory responses and cell death, but the underlying mechanisms remain elusive. Here we showed that the noncoding RNA 7SK gains immunostimulatory potential upon m 6 A depletion and subsequently activates the RIG-I/MAVS axis to spark interferon (IFN) signaling cascades. Concomitant excess of IFN and m 6 A deficiency synergistically facilitate the formation of RNA G-quadruplexes (rG4) to promote ZBP1-mediated necroptotic cell death. Collectively, our findings delineate a hitherto uncharacterized mechanism that links m 6 A dysregulation with ZBP1 activity in triggering inflammatory cell death.

Minimally Invasive Approaches in Reoperations after Conventional Craniotomies : Case Series.

Objective: Reoperations are part of neurosurgical practice. In these cases, an already formed craniotomy seems the most logical and appropriate. However, reoperations via large approaches can be quite traumatic for the patient. Then minimally invasive approaches, being less traumatic, can be a good alternative. Methods: We describe 7 consecutive patients who underwent reoperations using minimally invasive approaches in the areas of conventional craniotomies. Surgical Theater® visualization platform was used for preoperative planning. The study evaluated the size of surgical approach, surgical efficacy, and the presence of complications. Results: The size of a minimally invasive craniotomy was significantly smaller than that of a conventional approach. The preoperative goals were achieved in all described cases. There were no complications in the early postoperative period. Although the anatomy of the operated brain region in reoperations is altered, keyhole approaches can be successfully used with the support of preoperative planning and intraoperative neuronavigation. Given that the goals of reoperations may differ from those of the primary surgery, and a large approach is more traumatic for the patient, minimally invasive craniotomy can be considered as a good alternative. The successful use of minimally invasive approaches in areas of conventional craniotomies reinforces the philosophy of keyhole neurosurgery. In cases where goals can be achieved using small approaches, it makes no sense to use large conventional ones. Conclusion: Minimally invasive approaches can be successfully used during reoperations in patients after conventional craniotomies.

RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.

TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Minimally Invasive Approaches in the Surgical Treatment of Intracranial Meningiomas: An Analysis of 54 Cases.

BACKGROUND: Intracranial meningiomas, being a fairly common disease in the population, often require surgical treatment, which, in turn, can completely heal the patient. The localization of meningiomas often influences treatment even if they are asymptomatic. By modernizing approaches to surgical treatment, it is possible to minimize intra- and postoperative risks, while achieving complete removal of the tumor. One of these methods is minimally invasive neurosurgery, the development of which in recent years allows it to compete with standard surgical methods. The purpose of this study was the objectification of minimally invasive approaches, such as the calculation of the craniotomy area and the ratio of craniotomy area to the resected tumor volume. METHODS: The retrospective study consisted of a group of 54 consecutive patients who were operated on in our neurosurgery clinic specialized on minimally invasive neurosurgery. Preoperative planning was carried out using the Surgical Theater visualization platform. Using this system, the tumor volume and craniotomy surface area were calculated. During the analysis, the symptoms before and after the surgery, classification of tumors, postoperative complications, further treatment and follow-up results were assessed. RESULTS: Twelve (22.2%) patients were men and 42 (77.8%) were women. The mean age of the group was 64.2 years (median 67.5). The craniotomy area ranged from 202 to 2,108 mm² (mean 631 mm²). Tumor volume ranged from 0.85 to 110.1 cm3 (mean 21.6 cm3). The craniotomy size of minimally invasive approaches to the skull base was 3-5 times smaller than standard approaches. Skull base meningiomas accounted for 19 cases (35.2%), convexity meningiomas for 26 cases (48.1%), and falx and tentorium meningiomas for 9 cases (16.7%). Three complications were reported: postoperative hemorrhage, CSF leakage, and ophthalmoplegia. Relapse was detected in 2 patients with a mean follow-up of 26.3 months (median 20). CONCLUSION: Minimally invasive approaches in the surgical treatment of intracranial meningiomas reduce the possibility of operating trauma by several times; they are safe and sufficient for complete removal of the tumor.

Multiple Intracranial Schwannomas of the Vestibular and Trigeminal Nerves: A Technical Note.

BACKGROUND: A schwannoma is a nerve sheath tumor that is formed by Schwann cells. Vestibular schwannomas are thought to account for the majority of intracranial schwannomas. Nonvestibular schwannomas account for about 10%, about half of which are trigeminal schwannomas. Multiple intracranial schwannomas originating from different cranial nerves are extremely rare. METHODS: We describe the clinical case of a 42-year-old female patient with vestibular schwannoma and multiple trigeminal schwannomas. RESULTS: That case shows how multiple trigeminal schwannomas were identified intraoperatively during elective surgery for vestibular schwannoma removal, most of which were resected. No new neurological deficits were observed in the patient. CONCLUSIONS: The presence of multiple intracranial schwannomas is extremely rare in neurosurgical practice and can change the intraoperative strategy and the course of the surgery.

Angiomatoid fibrous histiocytoma: primary intracranial lesion with thoracic spine metastasis and a malignant course. Illustrative case.

BACKGROUND: Angiomatoid fibrous histiocytoma (AFH) is an exceptionally rare soft tissue neoplasm. This tumor primarily presents as a benign soft tissue lesion in children with an average age of 14 years. The standard treatment regimen is wide local excision with interval follow-up. However, newer reports have demonstrated malignant potential with the possibility of intracranial metastasis. OBSERVATIONS: A 45-year-old male with no soft tissue primary tumor presented with a primary intracranial lesion and thoracic spine metastasis refractory to chemotherapy and radiation treatment. LESSONS: This report illustrates the potential for a highly malignant nature of metastatic AFH. In addition, the authors demonstrate an incidence of AFH in a middle-aged male without a primary soft tissue or skin lesion. This report highlights the importance of prompt treatment and excision for AFH, as there is still little understanding of successful options for systemic therapy.

Poor haemorrhagic stroke outcomes during the COVID-19 pandemic are driven by socioeconomic disparities: analysis of nationally representative data.

Background: Nationally representative studies evaluating the impact of the COVID-19 pandemic on haemorrhagic stroke outcomes are lacking. Methods: In this pooled cross-sectional analysis, we identified adults (≥18 years) with primary intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH) from the National Inpatient Sample (2016-2020). We evaluated differences in rates of in-hospital outcomes between the prepandemic (January 2016-February 2020) and pandemic (March-December 2020) periods using segmented logistic regression models. We used multivariable logistic regression to evaluate differences in mortality between patients admitted from April to December 2020, with and without COVID-19, and those admitted from April to December 2019. Stratified analyses were conducted among patients residing in low-income and high-income zip codes, as well as among patients with extreme loss of function (E-LoF) and those with minor to major loss of function (MM-LoF). Results: Overall, 309 965 patients with ICH (47% female, 56% low income) and 112 210 patients with SAH (62% female, 55% low income) were analysed. Prepandemic, ICH mortality decreased by ~1% per month (adjusted OR, 95% CI: 0.99 (0.99 to 1.00); p<0.001). However, during the pandemic, the overall ICH mortality rate increased, relative to prepandemic, by ~2% per month (1.02 (1.00 to 1.04), p<0.05) and ~4% per month (1.04 (1.01 to 1.07), p<0.001) among low-income patients. There was no significant change in trend among high-income patients with ICH (1.00 (0.97 to 1.03)). Patients with comorbid COVID-19 in 2020 had higher odds of mortality (versus 2019 cohort) only among patients with MM-LoF (ICH, 2.15 (1.12 to 4.16), and SAH, 5.77 (1.57 to 21.17)), but not among patients with E-LoF. Conclusion: Sustained efforts are needed to address socioeconomic disparities in healthcare access, quality and outcomes during public health emergencies.

Automated catheter segmentation and tip detection in cerebral angiography with topology-aware geometric deep learning.

BACKGROUND: Visual perception of catheters and guidewires on x-ray fluoroscopy is essential for neurointervention. Endovascular robots with teleoperation capabilities are being developed, but they cannot 'see' intravascular devices, which precludes artificial intelligence (AI) augmentation that could improve precision and autonomy. Deep learning has not been explored for neurointervention and prior works in cardiovascular scenarios are inadequate as they only segment device tips, while neurointervention requires segmentation of the entire structure due to coaxial devices. Therefore, this study develops an automatic and accurate image-based catheter segmentation method in cerebral angiography using deep learning. METHODS: Catheters and guidewires were manually annotated on 3831 fluoroscopy frames collected prospectively from 40 patients undergoing cerebral angiography. We proposed a topology-aware geometric deep learning method (TAG-DL) and compared it with the state-of-the-art deep learning segmentation models, UNet, nnUNet and TransUNet. All models were trained on frontal view sequences and tested on both frontal and lateral view sequences from unseen patients. Results were assessed with centerline Dice score and tip-distance error. RESULTS: The TAG-DL and nnUNet models outperformed TransUNet and UNet. The best performing model was nnUNet, achieving a mean centerline-Dice score of 0.98 ±0.01 and a median tip-distance error of 0.43 (IQR 0.88) mm. Incorporating digital subtraction masks, with or without contrast, significantly improved performance on unseen patients, further enabling exceptional performance on lateral view fluoroscopy despite not being trained on this view. CONCLUSIONS: These results are the first step towards AI augmentation for robotic neurointervention that could amplify the reach, productivity, and safety of a limited neurointerventional workforce.

Surgical corridor formation by minimally invasive lateral occipital infracortical supra-/transtentorial (OICST) approach in pineal region tumor surgery: A review of 11 cases.

INTRODUCTION: The pineal region is a hard-to-reach part of the brain. There is no unequivocal opinion on the choice of a surgical approach to the pineal region. The surgical approaches described differ in both trajectory (infra- and supratentorial, interhemispheric) and size of craniotomy. They have advantages and disadvantages. The minimally invasive lateral occipital infracortical supra-/transtentorial (OICST) approach we have described has all the advantages of the standard supratentorial approach and minimizes its disadvantages, namely, compression and contusion of the occipital lobe. The minimally invasive craniotomy and small surgical corridor facilitate that. METHODS: We describe 11 consecutive patients with various pineal region tumors (7 cases of pineal cysts, 2 cases of pinealocytoma, 1 case of medulloblastoma, and 1 case of meningioma) who were operated on in our hospital using the lateral OICST approach. Preoperative planning was performed using Surgical Theater®. The surgical corridor was formed using a retractor made from half of a syringe shortened according to the length of the surgical corridor. Preoperative lumbar drain was used. RESULTS: The pineal region tumors were completely resected in all cases. The mean craniotomy size was 2.22 × 1.79 cm. No long-term neurological deficits were reported. CONCLUSIONS: The use of semicircular retractors and intraoperative CSF drainage via a lumbar drain allows to form a small surgical corridor to the pineal region via minimally invasive craniotomy. This reduces traction and traumatization of the occipital lobe, as well as minimizes intra- and postoperative risks.

United States regulatory approval of medical devices used for endovascular neurosurgery: A two-decade review of FDA regulatory files.

BACKGROUND: The evolution of neuroendovascular technologies has progressed substantially. Over the last two decades, the introduction of new endovascular devices has facilitated treatment for more patients, and as a result, the regulatory environment concerning neuroendovascular devices has evolved rapidly in response. OBJECTIVE: To examine trends in the approval of neuroendovascular devices by the United States Food and Drug Administration (FDA) over the last 20 years. METHODS: Open-access US FDA databases were queried between January 2000 and December 2022 for all devices approved by the Neurological Devices Advisory Committee. Neuroendovascular devices were manually classified and grouped by category. Device approval data, including approval times, approval pathway, and presence of predicate devices, were examined. RESULTS: A total of 3186 neurological devices were approved via various US FDA pathways during the study period. 320 (10.0%) corresponded to neuroendovascular devices, of which 301 (94.1%) were approved via the 510(k) pathway. The percentage of 510(k) pathway neuroendovascular devices increased from 6.9% to 14.3% of all neuro devices before and after 2015, respectively. There was an increase in approval times for neuroendovascular devices cleared after 2015. CONCLUSION: Over the last two decades, the neuroendovascular device armamentarium has rapidly expanded, especially after positive stroke trials in 2015. Regulatory approval times are significantly affected by device category, generation, company size, and company location, and a vast majority are approved by the 510(k) pathway. These results can guide further innovation in the endovascular device space and may act as a roadmap for future regulatory planning.

lncRNA Sequencing Reveals Neurodegeneration-Associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists in Motor Neurons.

Fused-in sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) and subsequently predicted lncRNA-mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered the expression profiles of mRNAs and lncRNAs in iPSCs. Using this large dataset, we identified and verified six key differentially regulated TAR pairs in iPSCs that were also altered in iMNs. These target transcripts included: GPR149, NR4A, LMO3, SLC15A4, ZNF404, and CRACD. These findings indicated that selected mutant FUS-induced transcriptional alterations persist from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis as likely altered by these FUS mutations. Furthermore, ingenuity pathway analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations between RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into potential molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS.

Fully endoscopic posterior fossa decompression for Chiari malformation type I: illustrative case.

BACKGROUND: Surgery for symptomatic Arnold-Chiari malformation type I involves posterior fossa decompression. There are various approaches, including endoscope-assisted ones. New possibilities and fields of application of fully endoscopic techniques are currently being developed since new and advanced endoscopic equipment and instrumentation are available. OBSERVATIONS: The authors describe the case of a fully endoscopic microsurgical procedure in a 30-year-old female patient with progressive vertigo who was diagnosed with Chiari malformation type I. Neuronavigation and neuromonitoring were used during the surgery. LESSONS: Fully endoscopic surgery can be successfully performed in patients with Chiari malformation I. Intraoperative neuromonitoring and neuronavigation increase safety during this procedure.

Primary thoracic intramedullary spinal cord tumor with likely metastases of glial origin to the lumbosacral vertebrae: Illustrative case.

Background: Metastasis of systemic neoplasms to the spine is common; however, the metastasis of primary spinal cord tumors to other regions in the body is an infrequent occurrence. A few case reports have described the metastasis of primary spinal cord tumors, and in most cases, patients were younger than 30 years of age. Case Description: We present an illustrative case of a 47-year-old female with metastatic lesions to the lumbosacral vertebrae years after the initial diagnosis of an intradural, intramedullary spinal cord tumor (IMSCT). Although the surgical biopsy of the IMSCT was nondiagnostic, the patient was not found to have a separate primary neoplastic source, and the specimens of the metastatic lesions from the lumbar vertebral body were of glial origin. Conclusion: Metastasis from primary IMSCTs is extremely rare. Distant vertebral body and intracranial metastasis are even rarer yet possible. The clinical course is highly aggressive and responds poorly to current standard treatment.

Minimally Invasive Surgery With Thrombolysis for Intracerebral Hemorrhage Evacuation: Bayesian Reanalysis of a Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Bayesian analysis of randomized controlled trials (RCTs) can extend the value of trial data beyond interpretations based on conventional p value-based binary cutoffs. We conducted an exploratory post hoc Bayesian reanalysis of the minimally invasive surgery with thrombolysis for intracerebral hemorrhage (ICH) evacuation (MISTIE-3) trial and derived probabilities of potential intervention effect on functional and survival outcomes. METHODS: MISTIE-3 was a multicenter phase 3 RCT designed to evaluate the efficacy and safety of the MISTIE intervention. Five hundred and six adults (18 years or older) with spontaneous, nontraumatic, supratentorial ICH of ≥30 mL were randomized to receive either the MISTIE intervention (n = 255) or standard medical care (n = 251). We provide Bayesian-derived estimates of the effect of the MISTIE intervention on achieving a good 365-day modified Rankin Scale score (mRS score 0-3) as relative risk (RR) and absolute risk difference (ARD), and the probabilities that these treatment effects are greater than prespecified thresholds. We used 2 sets of prior distributions: (1) reference priors, including minimally informative, enthusiastic, and skeptical priors, and (2) data-derived prior distribution, using a hierarchical random effects model. We additionally evaluated the potential effects of the MISTIE intervention on 180-day and 30-day mRS and 365-, 180-, and 30-day mortality using data-derived priors. RESULTS: The Bayesian-derived probability that MISTIE intervention has any beneficial effect (RR >1) on achieving a good 365-day mRS score was 70% using minimally informative prior, 87% with enthusiastic prior, 68% with skeptical prior, and 73% with data-derived prior. However, these probabilities were ≤55% for RR >1.10 and 0% for RR >1.52 across a range of priors. The probabilities of achieving RR >1 for 180- and 30-day mRS scores are 65% and 80%, respectively. Furthermore, the probabilities of achieving RR <1 for 365-, 180-, and 30-day mortality are 93%, 98%, and 99%, respectively. DISCUSSION: Our exploratory analyses indicate that across a range of priors, the Bayesian-derived probability of MISTIE intervention having any beneficial effect on 365-day mRS for patients with ICH is between 68% and 87%. These analyses do not change the frequentist-based interpretation of the trial. However, unlike the frequentist p values, which indirectly evaluate treatment effects and only provide an arbitrary binary cutoff (such as 0.05), the Bayesian framework directly estimates the probabilities of potential treatment effects. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov/ct2/show/NCT01827046. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that minimally invasive surgery (MIS) + recombinant tissue plasminogen activator (rt-PA) does not significantly improve functional outcome in patients with ICH. However, this study lacks the precision to exclude a potential benefit of MIS + rt-PA.

A Neuro-Informatics Pipeline for Cerebrovascular Disease: Research Registry Development.

BACKGROUND: Although stroke is well recognized as a critical disease, treatment options are often limited. Inpatient stroke encounters carry critical information regarding the mechanisms of stroke and patient outcomes; however, these data are typically formatted to support administrative functions instead of research. To support improvements in the care of patients with stroke, a substantive research data platform is needed. OBJECTIVE: To advance a stroke-oriented learning health care system, we sought to establish a comprehensive research repository of stroke data using the Houston Methodist electronic health record (EHR) system. METHODS: Dedicated processes were developed to import EHR data of patients with primary acute ischemic stroke, intracerebral hemorrhage (ICH), transient ischemic attack, and subarachnoid hemorrhage under a review board-approved protocol. Relevant patients were identified from discharge diagnosis codes and assigned registry patient identification numbers. For identified patients, extract, transform, and load processes imported EHR data of primary cerebrovascular disease admissions and available data from any previous or subsequent admissions. Data were loaded into patient-focused SQL objects to enable cross-sectional and longitudinal analyses. Primary data domains (admission details, comorbidities, laboratory data, medications, imaging data, and discharge characteristics) were loaded into separate relational tables unified by patient and encounter identification numbers. Computed tomography, magnetic resonance, and angiography images were retrieved. Imaging data from patients with ICH were assessed for hemorrhage characteristics and cerebral small vessel disease markers. Patient information needed to interface with other local and national databases was retained. Prospective patient outreach was established, with patients contacted via telephone to assess functional outcomes 30, 90, 180, and 365 days after discharge. Dashboards were constructed to provide investigators with data summaries to support access. RESULTS: The Registry of Neurological Endpoint Assessments among Patients with Ischemic and Hemorrhagic Stroke (REINAH) database was constructed as a series of relational category-specific SQL objects. Encounter summaries and dashboards were constructed to draw from these objects, providing visual data summaries for investigators seeking to build studies based on REINAH data. As of June 2022, the database contains 18,061 total patients, including 1809 (10.02%) with ICH, 13,444 (74.43%) with acute ischemic stroke, 1221 (6.76%) with subarachnoid hemorrhage, and 3165 (17.52%) with transient ischemic attack. Depending on the cohort, imaging data from computed tomography are available for 85.83% (1048/1221) to 98.4% (1780/1809) of patients, with magnetic resonance imaging available for 27.85% (340/1221) to 85.54% (11,500/13,444) of patients. Outcome assessment has successfully contacted 56.1% (240/428) of patients after ICH, with 71.3% (171/240) of responders providing consent for assessment. Responders reported a median modified Rankin Scale score of 3 at 90 days after discharge. CONCLUSIONS: A highly curated and clinically focused research platform for stroke data will establish a foundation for future research that may fundamentally improve poststroke patient care and outcomes.

Seasonal variation in the incidence of primary intracerebral hemorrhage: a 16-year nationwide analysis.

Introduction: Data on nationwide trends and seasonal variations in the incidence of Intracerebral Hemorrhage (ICH) in the United States (US) are lacking. Methods: We used the Nationwide Inpatient Sample (2004-2019) and Census Bureau data to calculate the quarterly (Q1:January-March; Q2:April-June; Q3:July-September; Q4:October-December) incidence rates (IR) of adult (≥18 years) ICH hospitalizations, aggregated across Q1-Q4 and Q2-Q3. We report adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) for differences in the quarterly incidence of ICH, as compared to acute ischemic stroke (AIS), between Q1Q4 and Q2Q3 using a multivariable Poisson regression model. We additionally performed stratified analyses across the four US regions. Results: Among 822,143 (49.0% female) ICH and 6,266,234 (51.9% female) AIS hospitalizations, the average quarterly crude IR of ICH was consistently higher in Q1Q4 compared to Q2Q3 (5.6 vs. 5.2 per 100,000) (aIRR, CI: 1.09, 1.08-1.11)-this pattern was similar across all four US regions. However, a similar variation pattern was not observed for AIS incidence. The incidence (aIRR, CI) of both ICH (1.01, 1.00-1.02) and AIS (1.03, 1.02-1.03) is rising. Conclusion: Unlike AIS, ICH incidence is consistently higher in colder quarters, underscoring the need for evaluation and prevention of factors driving seasonal variations in ICH incidence.

lncRNA Sequencing Reveals Neurodegeneration-associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists In Motor Neurons.

Fused-in Sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and subsequently predicted lncRNA-mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered expression profiles of mRNAs and lncRNAs in iPSCs. We identified key differentially regulated TAR pairs, including LMO3, TMEM132D, ERMN, GPR149, CRACD, and ZNF404 in mutant FUS iPSCs. We performed reverse transcription PCR (RT-PCR) validation in iPSCs and iMNs. Validation confirmed RNA-Seq findings and suggested that mutant FUS-induced transcriptional alterations persisted from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis that were likely altered by FUS mutations. Ingenuity Pathway Analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations related to RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into the molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS.

Stroke severity mediates the effect of socioeconomic disadvantage on poor outcomes among patients with intracerebral hemorrhage.

Background: Socioeconomic deprivation drives poor functional outcomes after intracerebral hemorrhage (ICH). Stroke severity and background cerebral small vessel disease (CSVD) burden have each been linked to socioeconomic status and independently contribute to worse outcomes after ICH, providing distinct, plausible pathways for the effects of deprivation. We investigate whether admission stroke severity or cerebral small vessel disease (CSVD) mediates the effect of socioeconomic deprivation on 90-day functional outcomes. Methods: Electronic medical record data, including demographics, treatments, comorbidities, and physiological data, were analyzed. CSVD burden was graded from 0 to 4, with severe CSVD categorized as ≥3. High deprivation was assessed for patients in the top 30% of state-level area deprivation index scores. Severe disability or death was defined as a 90-day modified Rankin Scale score of 4-6. Stroke severity (NIH stroke scale (NIHSS)) was classified as: none (0), minor (1-4), moderate (5-15), moderate-severe (16-20), and severe (21+). Univariate and multivariate associations with severe disability or death were determined, with mediation evaluated through structural equation modelling. Results: A total of 677 patients were included (46.8% female; 43.9% White, 27.0% Black, 20.7% Hispanic, 6.1% Asian, 2.4% Other). In univariable modelling, high deprivation (odds ratio: 1.54; 95% confidence interval: [1.06-2.23]; p = 0.024), severe CSVD (2.14 [1.42-3.21]; p < 0.001), moderate (8.03 [2.76-17.15]; p < 0.001), moderate-severe (32.79 [11.52-93.29]; p < 0.001), and severe stroke (104.19 [37.66-288.12]; p < 0.001) were associated with severe disability or death. In multivariable modelling, severe CSVD (3.42 [1.75-6.69]; p < 0.001) and moderate (5.84 [2.27-15.01], p < 0.001), moderate-severe (27.59 [7.34-103.69], p < 0.001), and severe stroke (36.41 [9.90-133.85]; p < 0.001) independently increased odds of severe disability or death; high deprivation did not. Stroke severity mediated 94.1% of deprivation's effect on severe disability or death (p = 0.005), while CSVD accounted for 4.9% (p = 0.524). Conclusion: CSVD contributed to poor functional outcome independent of socioeconomic deprivation, while stroke severity mediated the effects of deprivation. Improving awareness and trust among disadvantaged communities may reduce admission stroke severity and improve outcomes.

Geographic Disparities in Case Fatality and Discharge Disposition Among Patients With Primary Intracerebral Hemorrhage.

Background We evaluate nationwide trends and urban-rural disparities in case fatality (in-hospital mortality) and discharge dispositions among patients with primary intracerebral hemorrhage (ICH). Methods and Results In this repeated cross-sectional study, we identified adult patients (≥18 years of age) with primary ICH from the National Inpatient Sample (2004-2018). Using a series of survey design Poisson regression models, with hospital location-time interaction, we report the adjusted risk ratio (aRR), 95% CI, and average marginal effect (AME) for factors associated with ICH case fatality and discharge dispositions. We performed a stratified analysis of each model among patients with extreme loss of function and minor to major loss of function. We identified 908 557 primary ICH hospitalizations (overall mean age [SD], 69.0 [15.0] years; 445 301 [49.0%] women; 49 884 [5.5%] rural ICH hospitalizations). The crude ICH case fatality rate was 25.3% (urban hospitals: 24.9%, rural hospitals:32.5%). Urban (versus rural) hospital patients had a lower likelihood of ICH case fatality (aRR, 0.86 [95% CI, 0.83-0.89]). ICH case fatality is declining over time; however, it is declining faster in urban hospitals (AME, -0.049 [95% CI, -0.051 to -0.047]) compared with rural hospitals (AME, -0.034 [95% CI, -0.040 to -0.027]). Conversely, home discharge is increasing significantly among urban hospitals (AME, 0.011 [95% CI, 0.008-0.014]) but not significantly changing in rural hospitals (AME, -0.001 [95% CI, -0.010 to 0.007]). Among patients with extreme loss of function, hospital location was not significantly associated with ICH case fatality or home discharge. Conclusions Improving access to neurocritical care resources, particularly in resource-limited communities, may reduce the ICH outcomes disparity gap.