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Matrix-Assisted Laser Desorption/Ionization Mass Spectrometric Imaging (MALDI-MSI) has developed as a useful tool in generating comprehensive metabolite profiles along with spatial information in model organisms. The ability of MALDI-MSI to generate in situ profiles in whole organisms or specific tissue sections serves as an efficient alternative to solvent extraction protocols, especially for the identification of biomolecules that are unstable under extraction conditions. Herein, we have utilized MALDI-MSI to spatially profile various classes of lipids in two model organisms, Drosophila melanogaster (fruit fly), and Tribolium castaneum (red flour beetle). Five different classes of phospholipids were imaged in positive ionization mode in both insect species. Confirmation of the m/z assignment for selected lipids was performed using on-tissue MS/MS fragmentation.

B cells contribute to the pathogenesis of both cellular- and humoral-mediated central nervous system (CNS) inflammatory diseases through a variety of mechanisms. In such conditions, B cells may enter the CNS parenchyma and contribute to local tissue destruction. It remains unexplored, however, how infection and autoimmunity drive transcriptional phenotypes, repertoire features, and antibody functionality. Here, we profiled B cells from the CNS of murine models of intracranial (i.c.) viral infections and autoimmunity. We identified a population of clonally expanded, antibody-secreting cells (ASCs) that had undergone class-switch recombination and extensive somatic hypermutation following i.c. infection with attenuated lymphocytic choriomeningitis virus (rLCMV). Recombinant expression and characterisation of these antibodies revealed specificity to viral antigens (LCMV glycoprotein GP), correlating with ASC persistence in the brain weeks after resolved infection. Furthermore, these virus-specific ASCs upregulated proliferation and expansion programs in response to the conditional and transient induction of the LCMV GP as a neo-self antigen by astrocytes. This class-switched, clonally expanded, and mutated population persisted and was even more pronounced when peripheral B cells were depleted prior to autoantigen induction in the CNS. In contrast, the most expanded B cell clones in mice with persistent expression of LCMV GP in the CNS did not exhibit neo-self antigen specificity, potentially a consequence of local tolerance induction. Finally, a comparable population of clonally expanded, class-switched, and proliferating ASCs was detected in the cerebrospinal fluid of relapsing multiple sclerosis (RMS) patients. Taken together, our findings support the existence of B cells that populate the CNS and are capable of responding to locally encountered autoantigens.

Background: Posterior reversible encephalopathy syndrome (PRES) can cause short-term cerebrovascular complications, such as brain infarction and hemorrhage. We hypothesized that PRES is also associated with an increased long-term risk of stroke. Methods: We performed a retrospective cohort study in the United States using statewide all-payer claims data from 2016 to 2018 on all admissions to nonfederal hospitals in 11 states. Adults with PRES were compared with adults with renal colic (negative control) and transient ischemic attack (TIA; positive control). Any stroke and the secondary outcomes of ischemic and hemorrhagic stroke were ascertained using International Classification of Diseases, Tenth Revision, Clinical Modification codes . We excluded prevalent stroke. We used time-to-event statistics to calculate incidence rates and Cox proportional hazards analyses to evaluate the association between PRES and stroke, adjusting for demographics and stroke risk factors. In a sensitivity analysis, outcomes within 2 weeks of index admission were excluded. Results: We identified 1606 patients with PRES, 1192 with renal colic, and 38 216 with TIA. Patients with PRES had a mean age of 56±17 years; 72% were women. Over a median follow-up of 0.9 years, the stroke incidence per 100 person-years was 6.1 (95% CI, 5.0–7.4) after PRES, 1.0 (95% CI, 0.62–1.8) after renal colic, and 9.7 (95% CI, 9.4–10.0) after TIA. After statistical adjustment for patient characteristics and risk factors, patients with PRES had an elevated risk of stroke compared with renal colic (hazard ratio [HR], 2.3 [95% CI, 1.7–3.0]), but lower risk than patients with TIA (HR, 0.67 [95% CI, 0.54–0.82]). In secondary analyses, compared with TIA, PRES was associated with hemorrhagic stroke (HR, 2.0 [95% CI, 1.4–2.9]). PRES was associated with ischemic stroke when compared with renal colic (HR, 1.9 [95% CI, 1.4–2.7]) but not when compared with TIA (HR, 0.49 [95% CI, 0.38–0.63]). Results were similar with 2-week washout. Conclusions: Patients with PRES had an elevated risk of incident stroke.

Adaptive immune repertoires are composed by the ensemble of B and T-cell receptors within an individual, reflecting both past and current immune responses. Recent advances in single-cell sequencing enable recovery of the complete adaptive immune receptor sequences in addition to transcriptional information. Here, we recovered transcriptome and immune repertoire information for polyclonal T follicular helper cells following lymphocytic choriomeningitis virus (LCMV) infection, CD8+ T cells with binding specificity restricted to two distinct LCMV peptides, and B and T cells isolated from the nervous system in the context of experimental autoimmune encephalomyelitis. We could relate clonal expansion, germline gene usage, and clonal convergence to cell phenotypes spanning activation, memory, naive, antibody secretion, T-cell inflation, and regulation. Together, this dataset provides a resource for immunologists that can be integrated with future single-cell immune repertoire and transcriptome sequencing datasets., Genes and Immunity, 23, ISSN:1466-4879, ISSN:1476-5470

Background: In patients with intracerebral hemorrhage (ICH), it is unclear whether early neurological deterioration, hematoma expansion (HE), and outcome vary by supratentorial ICH location (deep versus lobar). Herein, we assessed these relationships in a clinical trial cohort that underwent brain imaging early after symptom onset. We hypothesized that HE would occur more frequently, and outcome would be worse in patients with deep ICH. Methods: We performed a post hoc analysis of the FAST (Factor-VII-for-Acute-Hemorrhagic-Stroke-Treatment) trial including all patients with supratentorial hemorrhage. Enrolled patients underwent brain imaging within 3 hours of symptom onset and 24 hours after randomization. Multivariable regression was used to test the association between ICH location and 3 outcomes: HE (increase of ≥33% or 6mL), early neurological deterioration (decrease in Glasgow Coma Scale score ≥2 points or increase in National Institutes of Health Stroke Scale ≥4 points within 24 hours of admission), and 90-day outcome (modified Rankin Scale). Results: Of 841 FAST trial patients, we included 728 (mean age 64 years, 38% women) with supratentorial hemorrhages (deep n=623, lobar n=105). HE (44 versus 27%, P =0.001) and early neurological deterioration (31 versus 17%, P =0.001) were more common in lobar hemorrhages. Deep hemorrhages were smaller than lobar hemorrhages at baseline (12 versus 35mL, P P P =0.03). However, when adjusting for variables included in the ICH score including ICH volume, deep location was associated with worse and lobar location with better outcome (odds ratio lobar location, 0.58 [95% CI, 0.38–0.89]; P =0.01). Conclusions: In this secondary analysis of randomized trial patients, lobar ICH location was associated with larger ICH volume, more HE and early neurological deterioration, and worse outcome than deep ICH. After adjustment for prognostic variables, however, deep ICH was associated with worse outcome, likely due to their proximity to eloquent brain structures.

Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system (CNS) are early hallmarks of multiple sclerosis (MS). High numbers of CD8+ T cells are found in MS lesions, and antigen (Ag) presentation at the BBB has been proposed to promote CD8+ T cell entry into the CNS. Here, we show that brain endothelial cells process and cross-present Ag, leading to effector CD8+ T cell differentiation. Under physiological flow in vitro, endothelial Ag presentation prevented CD8+ T cell crawling and diapedesis resulting in brain endothelial cell apoptosis and BBB breakdown. Brain endothelial Ag presentation in vivo was limited due to Ag uptake by CNS-resident macrophages but still reduced motility of Ag-specific CD8+ T cells within CNS microvessels. MHC class I-restricted Ag presentation at the BBB during neuroinflammation thus prohibits CD8+ T cell entry into the CNS and triggers CD8+ T cell-mediated focal BBB breakdown.

Purpose Transsphenoidal surgery for non-functioning pituitary adenomas (NFPAs) can alter pituitary function. We assessed the rates of improvement and deterioration of pituitary function by axis and searched for predictive factors of these outcomes. Methods We reviewed consecutive medical files from patients having had transsphenoidal surgery for NFPA between 2004 and 2018. Pituitary functions and MRI imaging were analyzed prior and after surgery. The occurrence of recovery and new deficit were documented per axis. Prognostic factors of hormonal recovery and new deficits were searched. Results Among 137 patients analyzed, median tumor size of the NFPA was 24.8 mm and 58.4% of patients presented visual impairment. Before surgery, 91 patients (67%) had at least one abnormal pituitary axis (hypogonadism: 62.4%; hypothyroidism: 41%, adrenal insufficiency: 30.8%, growth hormone deficiency: 29.9%; increased prolactin: 50.8%). Following surgery, the recovery rate of pituitary deficiency of one axis or more was 46% and the rate of new pituitary deficiency was 10%. Rates of LH-FSH, TSH, ACTH and GH deficiency recovery were 35.7%, 30.4%, 15.4%, and 45.5% respectively. Rates of new LH-FSH, TSH, ACTH and GH deficiencies were 8.3%, 1.6%, 9.2% and 5.1% respectively. Altogether, 24.6% of patients had a global pituitary function improvement and only 7% had pituitary function worsening after surgery. Male patients and patients with hyperprolactinemia upon diagnosis were more likely to experience pituitary function recovery. No prognostic factors for the risk of new deficiencies were identified. Conclusion In a real-life cohort of patients with NFPAs, recovery of hypopituitarism after surgery is more frequent than the occurrence of new deficiencies. Hence, hypopituitarism could be considered a relative indication for surgery in patients with NFPAs.

Members of the Regulator of G-protein signaling (Rgs) family regulate the extent and timing of G protein signaling by increasing the GTPase activity of Gα protein subunits. The Rgs family member Rgs1 is one of the most up-regulated genes in tissue-resident memory (TRM) T cells when compared to their circulating T cell counterparts. Functionally, Rgs1 preferentially deactivates Gαq, and Gαi protein subunits and can therefore also attenuate chemokine receptor-mediated immune cell trafficking. The impact of Rgs1 expression on tissue-resident T cell generation, their maintenance, and the immunosurveillance of barrier tissues, however, is only incompletely understood. Here we report that Rgs1 expression is readily induced in naïve OT-I T cells in vivo following intestinal infection with Listeria monocytogenes-OVA. In bone marrow chimeras, Rgs1-/- and Rgs1+/+ T cells were generally present in comparable frequencies in distinct T cell subsets of the intestinal mucosa, mesenteric lymph nodes, and spleen. After intestinal infection with Listeria monocytogenes-OVA, however, OT-I Rgs1+/+ T cells outnumbered the co-transferred OT-I Rgs1-/- T cells in the small intestinal mucosa already early after infection. The underrepresentation of the OT-I Rgs1-/- T cells persisted to become even more pronounced during the memory phase (d30 post-infection). Remarkably, upon intestinal reinfection, mice with intestinal OT-I Rgs1+/+ TRM cells were able to prevent the systemic dissemination of the pathogen more efficiently than those with OT-I Rgs1-/- TRM cells. While the underlying mechanisms are not fully elucidated yet, these data thus identify Rgs1 as a critical regulator for the generation and maintenance of tissue-resident CD8+ T cells as a prerequisite for efficient local immunosurveillance in barrier tissues in case of reinfections with potential pathogens.

Background: Continued smoking after stroke is associated with a high risk of stroke recurrence and other cardiovascular disease. We sought to comprehensively understand the epidemiology of smoking cessation in stroke survivors in the United States. Furthermore, we compared smoking cessation in stroke and cancer survivors because cancer is another smoking-related condition in which smoking cessation is prioritized. Methods: We performed a cross-sectional analysis of data from the Centers for Disease Control and Prevention Behavioral Risk Factor Surveillance System, an annual, nationally representative health survey. Using pooled data from 2013 to 2019, we identified stroke and cancer survivors with a history of smoking. We used survey procedures to estimate frequencies and summarize quit ratios with attention to demographic and geographic (state-wise and rural-urban) factors for stroke survivors. The quit ratio is conventionally defined as the proportion of ever smokers who have quit. Then, we used multivariable logistic regression to compare quit ratios in stroke and cancer survivors while adjusting for demographics and smoking-related comorbidities. Results: Among 4 434 604 Americans with a history of stroke and smoking, the median age was 68 years (interquartile range, 59–76), and 45.4% were women. The overall quit ratio was 60.8% (95% CI, 60.1%–61.6%). Quit ratios varied by age group, sex, race and ethnicity, and several geographic factors. There was marked geographic variation in quit ratios, ranging from 48.3% in Kentucky to 71.5% in California. Furthermore, compared with cancer survivors, stroke survivors were less likely to have quit smoking (odds ratio, 0.72 [95% CI, 0.67–0.79]) after accounting for differences in demographics and smoking-related comorbidities. Conclusions: There were considerable demographic and geographic disparities in smoking quit ratios in stroke survivors, who were less likely to have quit smoking than cancer survivors. A targeted initiative is needed to improve smoking cessation for stroke survivors.

Background The duration and magnitude of increased stroke risk after a hospitalization for acute systolic heart failure (HF) remains uncertain. Methods and Results The authors performed a retrospective cohort study using claims (2008–2018) from a nationally representative 5% sample of Medicare beneficiaries aged ≥66 years. Cox regression models were fitted separately for the groups with and without acute systolic HF to examine its association with the incidence of ischemic stroke after adjustment for demographics, stroke risk factors, and Charlson comorbidities. Corresponding survival probabilities were used to compute the hazard ratio (HR) in each 30‐day interval after discharge. The authors stratified patients by the presence of atrial fibrillation (AF) before or during the hospitalization for acute systolic HF. Among 2 077 501 eligible beneficiaries, 94 641 were hospitalized with acute systolic HF. After adjusting for demographics, stroke risk factors, and Charlson comorbidities, the risk of ischemic stroke was highest in the first 30 days after discharge from an acute systolic HF hospitalization for patients with AF (HR, 2.4 [95% CI, 2.1–2.7]) and without AF (HR, 4.6 [95% CI, 4.0–5.3]). The risk of stroke remained elevated for 60 days in patients with AF (HR, 1.4 [95% CI, 1.2–1.6]) and was not significantly elevated afterward. The risk of stroke remained significantly elevated through 330 days in patients without AF (HR, 2.1 [95% CI, 1.7–2.7]) and was no longer significantly elevated afterward. Conclusions A hospitalization for acute systolic HF is associated with an increased risk of ischemic stroke up to 330 days in patients without concomitant AF.

Background: Administrative data can be useful for stroke research but have historically lacked data on stroke severity. Hospitals increasingly report the National Institutes of Health Stroke Scale (NIHSS) score using an International Classification of Diseases , Tenth Revision ( ICD-10 ) diagnosis code, but this code’s validity remains unclear. Methods: We examined the concordance of ICD-10 NIHSS scores versus NIHSS scores recorded in CAESAR (Cornell Acute Stroke Academic Registry). We included all patients with acute ischemic stroke from October 1, 2015, when US hospitals transitioned to ICD-10 , through 2018, the latest year in our registry. The NIHSS score (range, 0–42) recorded in our registry served as the reference gold standard. ICD-10 NIHSS scores were derived from hospital discharge diagnosis code R29.7xx, with the latter 2 digits representing the NIHSS score. Multiple logistic regression was used to explore factors associated with availability of ICD-10 NIHSS scores. We used ANOVA to examine the proportion of variation ( R 2 ) in the true (registry) NIHSS score that was explained by the ICD-10 NIHSS score. Results: Among 1357 patients, 395 (29.1%) had an ICD-10 NIHSS score recorded. This proportion increased from 0% in 2015 to 46.5% in 2018. In a logistic regression model, only higher registry NIHSS score (odds ratio per point, 1.05 [95% CI, 1.03–1.07]) and cardioembolic stroke (odds ratio, 1.4 [95% CI, 1.0–2.0]) were associated with availability of the ICD-10 NIHSS score. In an ANOVA model, the ICD-10 NIHSS score explained almost all the variation in the registry NIHSS score ( R 2 =0.88). Fewer than 10% of patients had a large discordance (≥4 points) between their ICD-10 and registry NIHSS scores. Conclusions: When present, ICD-10 codes representing NIHSS scores had excellent agreement with NIHSS scores recorded in our stroke registry. However, ICD-10 NIHSS scores were often missing, especially in less severe strokes, limiting the reliability of these codes for risk adjustment.

Intracerebral hemorrhage (ICH) caused by structural vascular lesions is associated with better outcomes than primary ICH, but this relationship is poorly understood. We tested the hypothesis that ICH from a vascular lesion has more benign hematoma characteristics compared to primary ICH. We performed a retrospective study using data from our medical center. The SMASH-U criteria were used to adjudicate the etiology of ICH. The co-primary outcomes were admission parenchymal hematoma volume and hematoma expansion at 24 h. Linear and logistic regression analyses were performed to test associations. A total of 231 patients were included of whom 42 (18%) had a vascular lesion. Compared to primary ICH patients, those with structural vascular lesions were younger (49 vs. 68 years, p 0.001), less likely to have hypertension (29% vs. 74%, p 0.001), had lower mean admission systolic blood pressure (140 ± 23 vs. 164 ± 35, p 0.001), less frequently had IVH (26% vs. 44%, p = 0.03), and had mostly lobar or infratentorial hemorrhages. The median admission hematoma volume was smaller with vascular lesions (5.9 vs. 9.7 mL, p = 0.01). In regression models, ICH from a vascular lesion was associated with smaller admission hematoma volume (beta, -0.67, 95% CI, -1.29 to -0.05, p = 0.03), but no association with hematoma expansion was detected when assessed as a continuous (OR, 0.93; 95% CI, -4.46 to 6.30, p = 0.73) or dichotomous exposure (OR, 1.86; 95% CI, 0.40 to 8.51, p = 0.42). In a single-center cohort, patients with ICH from vascular lesions had smaller hematoma volumes than patients with primary ICH.

The risk of stroke and cerebrovascular disease complicating infection with SARS-CoV-2 has been extensively reported since the onset of the pandemic. The striking efforts of many scientists in cooperation with regulators and governments worldwide have rapidly brought the development of a large landscape of vaccines against SARS-CoV-2. The novel DNA and mRNA vaccines have offered great flexibility in terms of antigen production and led to an unprecedented rapidity in effective and safe vaccine production. However, as mass vaccination has progressed, rare but catastrophic cases of thrombosis have occurred in association with thrombocytopenia and antibodies against PF4 (platelet factor 4). This catastrophic syndrome has been named vaccine-induced immune thrombotic thrombocytopenia. Rarely, ischemic stroke can be the symptom onset of vaccine-induced immune thrombotic thrombocytopenia or can complicate the course of the disease. In this review, we provide an overview of stroke and cerebrovascular disease as a complication of the SARS-CoV-2 infection and outline the main clinical and radiological characteristics of cerebrovascular complications of vaccinations, with a focus on vaccine-induced immune thrombotic thrombocytopenia. Based on the available data from the literature and from our experience, we propose a therapeutic protocol to manage this challenging condition. Finally, we highlight the overlapping pathophysiologic mechanisms of SARS-CoV-2 infection and vaccination leading to thrombosis.

To describe a comprehensive review of the epidemiology, pathophysiology, and treatment of stroke in the era of COVID-19.COVID-19 is associated with myriad neurological disorders, including cerebrovascular disease. While ischemic stroke is the most common, COVID-19 is associated with an increased risk of intracranial hemorrhage, arterial dissection, posterior reversible encephalopathy syndrome, and cerebral venous sinus thrombosis. In this review, we discuss the epidemiology, pathophysiology, and treatment of stroke due to COVID-19. In addition, we describe how COVID-19 has changed the landscape of stroke systems of care and the effect this has had on patients with cerebrovascular disease.While COVID-19 is associated with a heightened risk of stroke, the pandemic has led to advances in stroke systems of care that may reduce the long-term burden of stroke.

International audience; During development, hematopoietic stem cells (HSCs) are produced from the hemogenic endothelium and will expand in a transient hematopoietic niche. Prostaglandin E2 (PGE2) is essential during vertebrate development and HSC specification, but its precise source in the embryo remains elusive. Here, we show that in the zebrafish embryo, PGE2 synthesis genes are expressed by distinct stromal cell populations, myeloid (neutrophils, macrophages), and endothelial cells of the caudal hematopoietic tissue. Ablation of myeloid cells, which produce the PGE2 precursor prostaglandin H2 (PGH2), results in loss of HSCs in the caudal hematopoietic tissue, which could be rescued by exogeneous PGE2 or PGH2 supplementation. Endothelial cells contribute by expressing the PGH2 import transporter slco2b1 and ptges3, the enzyme converting PGH2 into PGE2. Of note, differential niche cell expression of PGE2 biosynthesis enzymes is also observed in the mouse fetal liver. Taken altogether, our data suggest that the triad composed of neutrophils, macrophages, and endothelial cells sequentially and synergistically contributes to blood stem cell expansion during vertebrate development.

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Long-chain fatty acid elongases (ELOs) play important roles in the metabolism of fatty acids in insects. In this study, the genes for two elongases from Aedes aegypti were identified, AeELO2 and AeELO9. Quantitative real time PCR showed that AeELO2 and AeELO9 are expressed at all developmental stages and some body parts, but with different expression patterns. RNAi-mediated knockdown of AeELO2 and AeELO9 was performed to investigate their roles in the development, growth, osmotic balance, and cold tolerance of Ae. aegypti. Knockdown of AeELO2 slowed larval growth and development by causing molting abnormalities. Additionally, 33% ± 3.3% of adults died during oviposition, accompanied by an abnormal extension of cuticles in AeELO2-dsRNA knockdown mosquitos. Knockdown of AeEL09 resulted in abnormal balance of cuticular osmotic pressure and a reduction in egg production. The maximal mRNAs of AeELO2 and AeELO9 were detected in eggs at 72 h after oviposition. Moreover, AeELO2 knockdown reduced the egg hatching rates and AeELO9 knockdown larvae did not develop well. In summary, AeELO2 is involved in larval molting and growth, and its knockdown affects the flexibility and elasticity of adult mosquito cuticles. AeELO9 regulates cold tolerance, osmotic balance, and egg development in Ae. aegypti.

Introduction: While well-established risk factors for cervical artery dissection include trauma and connective tissue disorders, many cases are considered “spontaneous.” Although the incidence of cervical artery dissection is greatest in the young, the prevalence increases with age, suggesting a potential role of vascular disease. In this study, we hypothesized that atherosclerosis may be a risk factor for cervical artery dissection. Methods: We performed a retrospective cohort study using administrative claims data from a 5% sample of Medicare beneficiaries between 2008 and 2018. The exposures of interest were vascular risk factors potentially associated with atherosclerosis including coronary artery disease, hyperlipidemia, hypertension, diabetes mellitus, heart failure, chronic kidney disease, chronic obstructive pulmonary disease, valvular heart disease, atrial fibrillation, tobacco use, and alcohol abuse. The primary outcome was a new diagnosis of cervical artery dissection. Marginal structural Cox models were used to characterize the association between the exposures and outcomes, adjusted for time-dependent confounding, age, sex, race/ethnicity, and prior stroke. Results: Among 2,256,826 eligible Medicare beneficiaries, 1,527 (0.07%) developed cervical artery dissection, with a mean age of 70.8, compared to 71.5 in those without cervical artery dissection. The following exposures were found to be significantly associated with the development of cervical artery dissection: coronary artery disease (1.81 [1.63-2.01]), hyperlipidemia (1.84 [1.61-2.11]), hypertension (2.04 [1.76-2.37]), diabetes mellitus (1.34 [1.21-1.49]), heart failure (1.44 [1.25-1.67]), chronic kidney disease (1.38 [1.20-1.59]), chronic obstructive pulmonary disease (1.3 [1.16-1.46]), valvular heart disease (1.81 [1.60-2.04]), atrial fibrillation (HR 1.75 [95% CI 1.54-1.98]), tobacco use (1.84 [1.57-2.15]), and alcohol abuse (1.84 [1.56-2.16]). Conclusion: In a large population-based cohort of older people, atherosclerotic risk factors were associated with subsequent cervical artery dissection. Further studies exploring the role of atherosclerosis in the development of cervical artery dissection are required.

Introduction: Anticoagulation in patients with acute intracranial hemorrhage (ICH) and mechanical heart valves (MHV) is often held to mitigate the risk of ICH expansion or recurrence; however there exists a competing risk of acute ischemic stroke (AIS). Optimal timing to resume anticoagulation after ICH remains uncertain. Methods: We retrospectively studied ICH patients with MHV at two academic hospitals from April, 2000-August, 2018. The primary outcome was a composite endpoint of symptomatic hematoma expansion or new ICH, AIS, and intracardiac thrombus up to 30 days post-ICH. The exposure was timing of re-initiation of anticoagulation classified as early if therapeutic anticoagulation was resumed up to 7 days after ICH; late if ≥7 and up to 30 days after ICH; and never if not resumed or resumed after 30-days post-ICH. Cox proportional hazard models were built adjusted for age, sex, and covariates significantly different in univariate analysis at a pre-specified p-value threshold of 0.05. Results: We identified 184 patients with ICH and MHV (65 anticoagulated early, 100 resumed late, 19 not resumed by day 30 post-ICH). We observed 12 AIS, 16 new ICH, and 6 intracardiac thromboses. The mean time from ICH to anticoagulation in the cohort was 12.7 days. Patients resumed early versus late were more likely to have atrial fibrillation (62% versus 42%), and less likely to be reversed (75% versus 94%), to undergo hematoma evacuation (23% versus 43%), have midline shift (27% versus 52.9%), and to have intracerebral involvement (26% versus 49%). There was no significant difference in the hazard of AIS, new or symptomatic ICH expansion, or the composite outcome among those resumed early versus late. Patients not resumed within 30 days post-ICH had a significantly higher risk of AIS compared to those resumed within 30 days (HR 15.9; 95% C.I.1.9-129.7, p=0.0098). Discussion: In this study of ICH patients with MHV, there was no difference in the 30-day thrombotic and hemorrhagic brain-related outcomes in patients anticoagulated within 7 days versus 7-30 days. Withholding anticoagulation within the first 30 days was associated with a significantly higher risk of AIS. Our findings provide a discrete time window to guide resumption of anticoagulation in MHV patients with ICH.

Background: Intracerebral hemorrhage (ICH) is associated with an increased risk of ischemic stroke. Whether there are racial and ethnic disparities in the risk of ischemic stroke after ICH is poorly understood. Hypothesis: Non-Hispanic Black and Hispanic ICH patients have a higher risk of ischemic stroke compared to White ICH patients. Methods: We retrospectively analyzed data from the Healthcare Cost and Utilization Project on all hospitalizations at all nonfederal hospitals in Florida from 2005 to 2018 and New York from 2006 to 2016. We included patients with an ICH, and without a prior or concomitant diagnosis of ischemic stroke. ICH and ischemic stroke were ascertained using validated ICD-9-CM and ICD-10-CM codes. Using Cox proportional hazard models, we studied the relationship between race and risk of ischemic stroke, after adjustment of demographics and comorbidities. Results: We included 55,582 patients with ICH- 66% Non-Hispanic White, 19% Non-Hispanic Black, and 13% Hispanic. Black and Hispanic patients were younger and had a higher prevalence of cardiovascular comorbidities; however, atrial fibrillation was more prevalent among White patients. During a median follow up period of 3.6 years (IQR 0.7-7.2), an incident ischemic stroke occurred in 3,361 (9%) Non-Hispanic White, 1,308 (12%) Non-Hispanic Black, and 858 (12%) Hispanic patients (p Conclusions: Among patients with ICH, Non-Hispanic Black and Hispanic patients had a significantly higher risk of ischemic stroke compared to Non-Hispanic White patients.

Introduction: Serum neutrophil-lymphocyte ratio (NLR) is a surrogate marker for the inflammatory response after intracerebral hemorrhage (ICH), and is associated with perihematomal edema and long-term functional outcomes. Whether NLR is associated with short-term ICH complications is poorly understood. Hypothesis: NLR is associated with 30-day infection and thrombotic events after ICH. Methods: We performed a post hoc exploratory analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III trial. The study exposure was the serum NLR obtained at baseline, and on days 3 and 5. The co-primary outcomes, ascertained at 30 days, were any infection and a thrombotic event, defined as composite of cerebral infarction, myocardial infarction, or venous thromboembolism; both infection and thrombotic event were determined via adjudicated adverse event reporting. Binary logistic regression was used to study the relationship between NLR and outcomes, after adjustment for demographics, ICH severity and location, and treatment randomization. Results: Among the 500 patients enrolled in CLEAR III, we included 228 (45.6%) with no missing data on daily NLR in the first week. There were no differences in demographics, comorbidities, or ICH severity between patients with and without data on NLR. In adjusted logistic regression models, NLR at day 3 was associated with infection (OR, 1.2; 95% CI, 1.01-1.26), but not with thrombotic events (OR, 0.96; 95% CI, 0.85-1.10). Conversely, NLR at day 5 was associated with thrombotic events (OR, 1.2, 95% CI, 1.01-1.26), but not with infections (OR, 1.03; 95% CI, 0.94-1.14). NLR at baseline was not associated with either outcome. Conclusions: Serum NLR ascertained between days 3 and 5 was associated with 30-day infection and thrombotic events after ICH, suggesting that NLR could be a potential early biomarker for ICH-related complications.

Introduction: Chronic hypertension is an established long-term risk factor for stroke. However, little is known about short-term stroke risk after an episode of acute severe hypertension without evidence of target organ damage (i.e., hypertensive urgency [HU]). We evaluated the short-term risk of stroke after an ED visit with HU resulting in discharge home (treat-and-release). Methods: We performed a case-crossover study using deidentified administrative claims from all nonfederal EDs and hospitals across 11 states. The study cohort comprised patients diagnosed with any stroke (ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage), defined using validated ICD-10 codes, between 2016-2018. We tabulated and compared incident ED visits for HU during case periods (2-week intervals from 0-24 weeks before the index stroke) to control periods (equivalent time periods exactly 1 year earlier). ED visits with HU were ascertained using the ICD-10 code I16.0, which we validated through detailed chart review of 50 patients at our center resulting in a code sensitivity and specificity of 100% and 96%, respectively. We used McNemar’s test for matched data to calculate risk ratios (RRs) for an ED HU visit occurring before stroke. Results: Among 45,063 patients with stroke, 22,417 (50%) were female and 37,577 (83%) had a prior diagnosis of hypertension. There were 201 patients with stroke who had at least one ED visit for HU during the preceding 24 weeks. An ED visit for HU was significantly more common in the 2 weeks before stroke compared to the 2-week control period 1 year earlier (RR, 5.1; 95% CI, 2.4-12.7; p Conclusion: Treat-and-release ED visits for HU are associated with a significantly increased short-term risk of stroke.

Introduction: Syndromes of cerebrovascular dysregulation such as posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) can be challenging to diagnose given their rarity and the need for advanced neuroimaging to diagnose them. We sought to measure the rate of potential PRES/RCVS misdiagnosis in the ED and identify features associated with misdiagnosis. Methods: We conducted a retrospective cohort study of patients with PRES/RCVS using deidentified administrative claims data from all nonfederal EDs and hospitals across 11 states from 2016-2018. To identify patients with PRES/RCVS, we used the previously validated ICD-10-CM codes I67.841 and I67.83. We defined patients with a probable misdiagnosis of PRES/RCVS as those with an ED visit resulting in discharge to home that occurred within the 14 days prior to their PRES/RCVS hospitalization. Only preceding ED visits where a non-specific neurological condition (e.g., headache, dizziness, numbness) was diagnosed were considered instances of probable ED misdiagnosis. Standard tests of comparison between patients with versus without probable misdiagnosis were used to identify patient-level and ED facility-level features associated with misdiagnosis. Results: We identified 4,633 patients hospitalized for PRES/RCVS; the majority (4,169; 90.0%) had PRES. A total of 210 patients (4.5%, 95% CI: 3.95-5.17) had at least one preceding ED visit with a probable misdiagnosis; these patients were younger (mean age 47.7 vs. 53.8 years; P Conclusion: Probable ED misdiagnosis occurred in nearly 1 of 20 cases of PRES/RCVS in a large, multistate cohort.

The vasculature is a key regulator of leukocyte trafficking into the central nervous system (CNS) during inflammatory diseases including multiple sclerosis (MS). However, the impact of endothelial-derived factors on CNS immune responses remains unknown. Bioactive lipids, in particular oxysterols downstream of Cholesterol-25-hydroxylase (Ch25h), promote neuroinflammation but their functions in the CNS are not well-understood. Using floxed-reporter Ch25h knock-in mice, we trace Ch25h expression to CNS endothelial cells (ECs) and myeloid cells and demonstrate that Ch25h ablation specifically from ECs attenuates experimental autoimmune encephalomyelitis (EAE). Mechanistically, inflamed Ch25h-deficient CNS ECs display altered lipid metabolism favoring polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) expansion, which suppresses encephalitogenic T lymphocyte proliferation. Additionally, endothelial Ch25h-deficiency combined with immature neutrophil mobilization into the blood circulation nearly completely protects mice from EAE. Our findings reveal a central role for CNS endothelial Ch25h in promoting neuroinflammation by inhibiting the expansion of immunosuppressive myeloid cell populations.

Sertoli cell-only syndrome (SCOS) is a condition of male infertility characterized by a total absence of spermatogenic cells in nearly all seminiferous tubules. Apart from well-established genetic changes such as Klinefelter syndrome, CFTR variants, and Y-chromosome microdeletions, several hundred candidate genes were reported as associated with male infertility. We selected 92 evidence-based genes associated with infertility and investigated data from whole-exome sequencing in 6 individuals with clinically diagnosed SCOS. Eight heterozygous variants passed our filtering criteria, including population frequency ≤ 0.1% and high functional impact indicated by Sift, Polyphen, and CADD scores. Out of them, we considered only variants with putative autosomal dominant effects on infertility that were subsequently validated by Sanger sequencing. This filtering pipeline has led to the final likely causative variants detected in CHD7 and SCYP3 genes that potentially explain SCOS in two of our patients. Our discoveries suggest that gene panel testing of patients with SCOS could improve the diagnostic outcome; however, assembling a gene panel consisting of only genuine causative genes is crucial.

UNC-Chapel Hill PSYC 525 Final Project: BDD & Extraversion Associations with Depression

Considering the substantial variability in treatment response across patients with spinal muscular atrophy (SMA), reliable markers for monitoring response to therapy and predicting treatment responders need to be identified. The study aimed to determine if measured concentrations of disease biomarkers (total tau protein, neurofilament light chain, and S100B protein) correlate with the duration of nusinersen treatment and with scores obtained using functional scales for the assessment of motor abilities.A total of 30 subjects with SMA treated with nusinersen between 2017 and 2021 at the Department of Pediatrics, University Hospital Centre Zagreb, Croatia, were included in this study. Cerebrospinal fluid (CSF) samples were collected by lumbar puncture prior to intrathecal application of nusinersen. Protein concentrations in CSF samples were determined by enzyme-linked immunosorbent assay in 26 subjects. The motor functions were assessed using functional motor scales.The main finding was significantly decreased total tau correlating with the number of nusinersen doses and motor improvement in the first 18-24 months of treatment (in all SMA patients and SMA type 1 patients). Neurofilament light chain and S100B were not significantly changed after administration of nusinersen.The measurement of total tau concentration in CSF is a reliable index for monitoring the biomarker and clinical response to nusinersen therapy in patients with SMA.

CD4+FOXP3+ regulatory T cells (Tregs) have demonstrated efficacy in the prevention and treatment of graft-versus-host disease (GVHD). Preclinical and clinical studies indicate that Tregs are able to protect from GVHD without interfering with the graft-versus-tumor (GVT) effect of hematopoietic cell transplantation (HCT), although the underlying molecular mechanisms are largely unknown. To elucidate Treg suppressive function during in vivo suppression of acute GVHD, we performed paired T-cell receptor (TCRα and ΤCRβ genes) repertoire sequencing and RNA sequencing analysis on conventional T cells (Tcons) and Tregs before and after transplantation in a major histocompatibility complex –mismatched mouse model of HCT. We show that both Tregs and Tcons underwent clonal restriction, and Tregs did not interfere with the activation of alloreactive Tcon clones and the breadth of their TCR repertoire but markedly suppressed their expansion. Transcriptomic analysis revealed that Tregs predominantly affected the transcriptome of CD4 Tcons and, to a lesser extent, that of CD8 Tcons, thus modulating the transcription of genes encoding pro- and anti-inflammatory molecules as well as enzymes involved in metabolic processes, inducing a switch from glycolysis to oxidative phosphorylation. Finally, Tregs did not interfere with the induction of gene sets involved in the GVT effect. Our results shed light onto the mechanisms of acute GVHD suppression by Tregs and will support the clinical translation of this immunoregulatory approach.

Zusammenfassung Ziel der Studie Bei der Untersuchung von sozialer Ängstlichkeit haben sich die Fragebögen Liebowitz Social Anxiety Scale (LSAS) und das Social Phobia-Inventory (SPIN) etabliert. Außerdem wird zum Screening sozialer Ängstlichkeit häufig die Subskala Unsicherheit im Sozialkontakt des Brief Symptom Inventory (BSI-53) eingesetzt. Alle drei Skalen geben vor dasselbe Konstrukt zu erfassen. Somit stellt sich die Frage der Konvergenz dieser Skalen. Um Forschungsergebnisse zu sozialer Ängstlichkeit, welche diese Instrumente nutzen, über einen fragebogenübergreifenden Faktor (Common-Faktor) vergleichbar zu machen, wird in der vorliegenden Studie ein Item Response Theorie (IRT) Linking Ansatz verwendet. Methodik 64 deutschsprachige psychiatrische Patienten und 295 Probanden aus der deutschen Normalbevölkerung füllten die drei Fragebögen aus. Verschiedene IRT-Modelle – darunter Graded Response Modelle (GRM) – wurden an die Daten angepasst und verglichen. Basierend auf dem Modell mit dem besten Fit wurden Regressionsanalysen durchgeführt. Der Common-Faktor wurde dabei jeweils von den Fragebogensummenwerten vorhergesagt. Ergebnisse Der Zusammenhang zwischen den verschiedenen Skalen wird am besten durch ein Bi-Faktor GRM erklärt (RMSEA=0,036; CFI=0,977; WRMR=1,061). Anhand der Ergebnisse der Regressionsanalysen lassen sich drei Gleichungen zur Transformation von Fragebogensummenwerten ableiten. Schlussfolgerung Durch den IRT Linking Ansatz konnte ein fragebogenübergreifender genereller Faktor Sozialer Ängstlichkeit abgeleitet werden. Gemeinsamkeiten und Unterschiede wurden dabei berücksichtigt. Dies hat sowohl für die Forschung als auch für die Praxis Vorteile. Eine Replikation dieser Studie sowie die Implementierung weiterer Instrumente wird empfohlen, um die Gültigkeit dieses Ansatzes zu überprüfen und die Ergebnisse zu generalisieren.

Pentameric ligand-gated ion channels represent a large family of receptors comprising an extracellular domain, four transmembrane helices and a cytosolic intracellular domain (ICD). ICDs play important roles in receptor localization and trafficking, thus regulating synaptic activity and plasticity. Glycine and GABA type A receptor ICDs bind to the scaffolding protein gephyrin, a master regulator of inhibitory synapses. Here we report the use of yeast lumazine synthase as soluble pentameric protein scaffold for the study of receptor ICDs derived from GlyR α1− and β-subunits. We were able to create ICDs assemblies in a homo- (LS-βICD) and hetero-pentameric state (LS-αβICD) and provide first-in-class structural insights on their high structural flexibility using small angle X-ray scattering. We report a high-affinity interaction between the LS-αβICD and gephyrin leading to thein vitroformation of high-molecular mega-Dalton complexes composed of three gephyrin trimers and three pentamers as basic building block. Depending on the stoichiometric ratios between gephyrin and LS-ICDs the formed complexes grow or shrink in size. In cells, LS-ICDs efficiently recruited gephyrin and were able to accumulate gephyrin at GABAergic synapses in neurons. Our findings collectively propose a new, potentially general, mechanistic concept for a gephyrin-dependent bridging of GlyRs at the inhibitory synapse.

OBJECTIVE: To evaluate whether patients discharged to home after an emergency department (ED) visit for headache face a heightened short-term risk of stroke. BACKGROUND: Stroke hospitalizations that occur soon after ED visits for headache complaints may reflect diagnostic error. METHODS: We conducted a retrospective cohort study using statewide administrative claims data for all ED visits and admissions at nonfederal hospitals in Florida 2005–2018 and New York 2005–2016. Using standard International Classification of Diseases (ICD) codes, we identified adult patients discharged to home from the ED (treat-and-release visit) with a benign headache diagnosis (cohort of interest) as well as those with a diagnosis of renal colic or back pain (negative controls). The primary study outcome was hospitalization within 30 days for stroke (ischemic or hemorrhagic) defined using validated ICD codes. We assess the relationship between index ED visit discharge diagnosis and stroke hospitalization adjusting for patient demographics and vascular comorbidities. RESULTS: We identified 1,502,831 patients with an ED treat-and-release headache visit; mean age was 41 (standard deviation: 17) years and 1,044,520 (70%) were female. A total of 2150 (0.14%) patients with headache were hospitalized for stroke within 30 days. In adjusted analysis, stroke risk was higher after headache compared to renal colic (hazard ratio [HR]: 2.69; 95% confidence interval [CI]: 2.29–3.16) or back pain (HR: 4.0; 95% CI: 3.74–4.3). In the subgroup of 26,714 (1.78%) patients with headache who received brain magnetic resonance imaging at index ED visit, stroke risk was only slightly elevated compared to renal colic (HR: 1.47; 95% CI: 1.22–1.78) or back pain (HR: 1.49; 95% CI: 1.24–1.80). CONCLUSION: Approximately 1 in 700 patients discharged to home from the ED with a headache diagnosis had a stroke in the following month. Stroke risk was three to four times higher after an ED visit for headache compared to renal colic or back pain.

Severe hypertension can accompany neurological symptoms without obvious signs of target organ damage. However, acute cerebrovascular events can also be a cause and consequence of severe hypertension. We therefore use US population-level data to determine prevalence and clinical characteristics of patients with severe hypertension and neurological complaints.We used nationally representative data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) collected in 2016-2019 to identify adult ED patients with severely elevated blood pressure (BP) defined as systolic BP ≥ 180 mmHg and/or diastolic BP ≥120 mmHg. We used ED reason for visit data fields to define neurological complaints and used diagnosis data fields to define acute target organ damage. We applied survey visit weights to obtain national estimates.Based on 5083 observations, an estimated 40.4 million patients (95% CI: 37.5-43.0 million) in EDs nationwide from 2016 to 2019 had severe hypertension, equating to 6.1% (95% CI: 5.7-6.5%) of all ED visits. Only 2.8% (95% CI: 2.0-3.9%) of ED patients with severe hypertension were diagnosed with acute cerebrovascular disease; hypertensive urgency was diagnosed in 92.0% (95% CI: 90.3-93.4%). Neurological complaints were frequent in both patients with (75.6%) and without (19.9%) cerebrovascular diagnoses. Hypertensive urgency patients with neurological complaints were more often older, female, had prior stroke/TIA, and had neuroimaging than patients without these complaints. Non-migraine headache and vertigo were the most common neurological complaints recorded.In a nationally representative survey, one-in-sixteen ED patients had severely elevated BP and one-fifth of those patients had neurological complaints.

B cells contribute to the pathogenesis of both cellular- and humoral-mediated central nervous system (CNS) inflammatory diseases through a variety of mechanisms. In such conditions, B cells may enter the CNS parenchyma and contribute to local tissue destruction. It remains unexplored, however, how infection and autoimmunity drive transcriptional phenotypes, repertoire features, and antibody functionality. Here, we profiled B cells from the CNS of murine models of intracranial (i.c.) viral infections and autoimmunity. We identified a population of clonally expanded, antibody secreting cells (ASCs) that had undergone class-switch recombination and extensive somatic hypermutation following i.c. infection with attenuated lymphocytic choriomeningitis virus (rLCMV). Recombinant expression and characterisation of these antibodies revealed specificity to viral antigens (LCMV glycoprotein GP), correlating with ASC persistence in the brain weeks after resolved infection. Furthermore, these virus-specific ASCs upregulated proliferation and expansion programs in response to the conditional and transient induction of the LCMV GP as a neo-self antigen by astrocytes. This class-switched, clonally expanded, and mutated population persisted and was even more pronounced when peripheral B cells were depleted prior to autoantigen induction in the CNS. In contrast, the most expanded B cell clones in mice with persistent expression of LCMV GP in the CNS did not exhibit neo-self antigen specificity, potentially a consequence of local tolerance induction. Finally, a comparable population of clonally expanded, class-switched, proliferating ASCs was detected in the cerebrospinal fluid of multiple sclerosis patients. Taken together, our findings support the existence of B cells that populate the CNS and are capable of responding to locally encountered autoantigens.Graphical abstract

Arylalkylamine N-acetyltransferase (aaNAT), considered a potential new insecticide target, catalyzes the acetylation of arylalkylamine substrates such as serotonin and dopamine and, hence, mediates diverse functions in insects. However, the origin of insect aaNATs (iaaNATs) and the evolutionary process that generates multiple aaNATs in mosquitoes remain largely unknown. Here, we have analyzed the genomes of 33 species to explore and expand our understanding of the molecular evolution of this gene family in detail. We show that aaNAT orthologs are present in Bacteria, Cephalochordata, Chondrichthyes, Cnidaria, Crustacea, Mammalia, Placozoa, and Teleoste, as well as those from a number of insects, but are absent in some species of Annelida, Echinozoa, and Mollusca as well as Arachnida. Particularly, more than 10 aaNATs were detected in the Culicinae subfamily of mosquitoes. Molecular evolutionary analysis of aaNAT/aaNAT-like genes in mosquitoes reveals that tandem duplication events led to gene expansion in the Culicinae subfamily of mosquitoes more than 190 million years ago. Further selection analysis demonstrates that mosquito aaNATs evolved under strongly positive pressures that generated functional diversity following gene duplication events. Overall, this study may provide novel insights into the molecular evolution of the aaNAT family in mosquitoes.

Tumor-associated lymphatic vessels promote metastasis and regulate antitumor immune responses. Here, we assessed the impact of cytotoxic T cells on the local lymphatic vasculature and concomitant tumor dissemination during an antitumor response. Interferon-γ (IFN-γ) released by effector T cells enhanced the expression of immunosuppressive markers by tumor-associated lymphatic endothelial cells (LECs). However, at higher effector T cell densities within the tumor, T cell-based immunotherapies induced LEC apoptosis and decreased tumor lymphatic vessel density. As a consequence, lymphatic flow was impaired, and lymph node metastasis was reduced. Mechanistically, T cell-mediated tumor cell death induced the release of tumor antigens and cross-presentation by tumor LECs, resulting in antigen-specific LEC killing by T cells. When LECs lacked the IFN-γ receptor expression, LEC killing was abrogated, indicating that IFN-γ is indispensable for reducing tumor-associated lymphatic vessel density and drainage. This study provides insight into how cytotoxic T cells modulate tumor lymphatic vessels and may help to improve immunotherapeutic protocols.

Ponto-geniculo-occipital (PGO) or pontine (P) waves have long been recognized as an electrophysiological signature of rapid eye movement (REM) sleep. However, P-waves can be observed not just during REM sleep, but also during non-REM (NREM) sleep. Recent studies have uncovered that P-waves are functionally coupled with hippocampal sharp wave-ripples (SWRs) during NREM sleep. However, it remains unclear to what extent P-waves during NREM sleep share their characteristics with P-waves during REM sleep and how the functional coupling to P-waves modulates SWRs. Here, we address these issues by performing multiple types of electrophysiological recordings and fiber photometry in both sexes of mice. P-waves during NREM sleep share their waveform shapes and local neural ensemble dynamics at a short (~100 ms) timescale with their REM sleep counterparts. However, the dynamics of mesopontine cholinergic neurons are distinct at a longer (~10 s) timescale: although P-waves are accompanied by cholinergic transients, the cholinergic tone gradually reduces before P-wave genesis during NREM sleep. While P-waves are coupled to hippocampal theta rhythms during REM sleep, P-waves during NREM sleep are accompanied by a rapid reduction in hippocampal ripple power. SWRs coupled with P-waves are short-lived and hippocampal neural firing is also reduced after P-waves. These results suggest that P-waves play distinct roles in memory consolidation by functionally coupling with hippocampal ensembles in a state-dependent manner.

ObjectiveTo estimate the incidence of hospitalization for reversible cerebral vasoconstriction syndrome (RCVS), we identified RCVS-related hospital admissions across 11 US states in 2016.MethodsWe tested the validity of ICD-10 code I67.841 in 79 patients with hospital admissions for RCVS or other cerebrovascular diseases at 1 academic and 1 community hospital. After determining that this code had a sensitivity of 100% (95% confidence interval [CI], 82%–100%) and a specificity of 90% (95% CI, 79%–96%), we applied it to administrative data from the Healthcare Cost and Utilization Project on all hospital admissions across 11 states. Age- and sex-standardized RCVS incidence was calculated using census data. Descriptive statistics were used to analyze associated diagnoses.ResultsAcross 5,067,250 hospital admissions in our administrative data, we identified 222 patients with a discharge diagnosis of RCVS in 2016. The estimated annual age- and sex-standardized incidence of RCVS hospitalization was 2.7 (95% CI, 2.4–3.1) cases per million adults. Many patients had concomitant neurologic diagnoses, including subarachnoid hemorrhage (37%), ischemic stroke (16%), and intracerebral hemorrhage (10%). In the 90 days before the index admission, 97 patients had an emergency department (ED) visit and 34 patients a hospital admission, most commonly for neurologic, psychiatric, and pregnancy-related diagnoses. Following discharge from the RCVS hospital admission, 58 patients had an ED visit and 31 had a hospital admission, most commonly for neurologic diagnoses.ConclusionsUsing population-wide data, we estimated the age- and sex-standardized incidence of hospitalization for RCVS in US adults as approximately 3 per million per year.