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Background: The implementation of preventive therapies among patients with stroke remains inadequately explored, especially when compared with patients with myocardial infarction (MI), despite sharing similar vascular risk profiles. We tested the hypothesis that participants with a history of stroke have a worse cardiovascular prevention profile in comparison to participants with MI., Methods and Results: In cross-sectional analyses within the UK Biobank and All of Us Research Program, involving 14 760 (9193 strokes, 5567 MIs) and 7315 (2948 strokes, 4367 MIs) participants, respectively, we evaluated cardiovascular prevention profiles assessing low-density lipoprotein (<100 mg/dL), blood pressure (systolic, <140 mm Hg; and diastolic, <90 mm Hg), statin and antiplatelet use, and a cardiovascular prevention score that required meeting at least 3 of these criteria. The results revealed that, within the UK Biobank, patients with stroke had significantly lower odds of meeting all the preventive criteria compared with patients with MI: low-density lipoprotein control (odds ratio [OR], 0.73 [95% CI, 0.68-0.78]; P <0.001), blood pressure control (OR, 0.63 [95% CI, 0.59-0.68]; P <0.001), statin use (OR, 0.45 [95% CI, 0.42-0.48]; P <0.001), antiplatelet therapy use (OR, 0.30 [95% CI, 0.27-0.32]; P <0.001), and cardiovascular prevention score (OR, 0.42 [95% CI, 0.39-0.45]; P <0.001). Similar patterns were observed in the All of Us Research Program, with significant differences across all comparisons ( P <0.05), and further analysis suggested that the odds of having a good cardiovascular prevention score were influenced by race and ethnicity as well as neighborhood deprivation levels (interaction P <0.05 in both cases)., Conclusions: In 2 independent national cohorts, patients with stroke showed poorer cardiovascular prevention profiles and lower adherence to guideline-directed therapies compared with patients with MI. These findings underscore the need to explore the reasons behind the underuse of secondary prevention in vulnerable stroke survivors.

This scoping review of randomised controlled trials on artificial intelligence (AI) in clinical practice reveals an expanding interest in AI across clinical specialties and locations. The USA and China are leading in the number of trials, with a focus on deep learning systems for medical imaging, particularly in gastroenterology and radiology. A majority of trials (70 [81%] of 86) report positive primary endpoints, primarily related to diagnostic yield or performance; however, the predominance of single-centre trials, little demographic reporting, and varying reports of operational efficiency raise concerns about the generalisability and practicality of these results. Despite the promising outcomes, considering the likelihood of publication bias and the need for more comprehensive research including multicentre trials, diverse outcome measures, and improved reporting standards is crucial. Future AI trials should prioritise patient-relevant outcomes to fully understand AI's true effects and limitations in health care., Competing Interests: Declaration of interests EJT receives funding from the National Center for Advancing Translational Sciences/National Institutes of Health (grant number UL1TR002550). JNA is an employee of Rad AI, outside of the submitted work. RH receives funding from the National Institute of General Medical Sciences (grant number T32 GM008042), and was formerly employed at Quadrant Health, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Importance: Stroke is a leading cause of death and disability in the US. Accurate and updated measures of stroke burden are needed to guide public health policies., Objective: To present burden estimates of ischemic and hemorrhagic stroke in the US in 2019 and describe trends from 1990 to 2019 by age, sex, and geographic location., Design, Setting, and Participants: An in-depth cross-sectional analysis of the 2019 Global Burden of Disease study was conducted. The setting included the time period of 1990 to 2019 in the US. The study encompassed estimates for various types of strokes, including all strokes, ischemic strokes, intracerebral hemorrhages (ICHs), and subarachnoid hemorrhages (SAHs). The 2019 Global Burden of Disease results were released on October 20, 2020., Exposures: In this study, no particular exposure was specifically targeted., Main Outcomes and Measures: The primary focus of this analysis centered on both overall and age-standardized estimates, stroke incidence, prevalence, mortality, and DALYs per 100 000 individuals., Results: In 2019, the US recorded 7.09 million prevalent strokes (4.07 million women [57.4%]; 3.02 million men [42.6%]), with 5.87 million being ischemic strokes (82.7%). Prevalence also included 0.66 million ICHs and 0.85 million SAHs. Although the absolute numbers of stroke cases, mortality, and DALYs surged from 1990 to 2019, the age-standardized rates either declined or remained steady. Notably, hemorrhagic strokes manifested a substantial increase, especially in mortality, compared with ischemic strokes (incidence of ischemic stroke increased by 13% [95% uncertainty interval (UI), 14.2%-11.9%]; incidence of ICH increased by 39.8% [95% UI, 38.9%-39.7%]; incidence of SAH increased by 50.9% [95% UI, 49.2%-52.6%]). The downturn in stroke mortality plateaued in the recent decade. There was a discernible heterogeneity in stroke burden trends, with older adults (50-74 years) experiencing a decrease in incidence in coastal areas (decreases up to 3.9% in Vermont), in contrast to an uptick observed in younger demographics (15-49 years) in the South and Midwest US (with increases up to 8.4% in Minnesota)., Conclusions and Relevance: In this cross-sectional study, the declining age-standardized stroke rates over the past 3 decades suggest progress in managing stroke-related outcomes. However, the increasing absolute burden of stroke, coupled with a notable rise in hemorrhagic stroke, suggests an evolving and substantial public health challenge in the US. Moreover, the significant disparities in stroke burden trends across different age groups and geographic locations underscore the necessity for region- and demography-specific interventions and policies to effectively mitigate the multifaceted and escalating burden of stroke in the country.

Background and Objectives: We aimed to investigate the white matter (WM) microstructural/cytostructural disintegrity patterns related to higher systolic blood pressure (SBP), and whether they mediate SBP effects on cognitive performance in middle-aged adults., Methods: Using the UK Biobank study of community-dwelling volunteers aged 40-69 years, we included participants without a history of stroke, dementia, demyelinating disease or traumatic brain injury. We investigated the association of SBP with MRI diffusion metrics: fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (a measure of neurite density), isotropic (free) water volume fraction (ISOVF) and orientation dispersion across WM tracts. Then, we determined whether WM diffusion metrics mediated the effects of SBP on cognitive function., Results: We analysed 31 363 participants-mean age of 63.8 years (SD: 7.7), and 16 523 (53%) females. Higher SBP was associated with lower FA and neurite density, but higher MD and ISOVF. Among different WM tracts, diffusion metrics of the internal capsule anterior limb, external capsule, superior and posterior corona radiata were most affected by higher SBP. Among seven cognitive metrics, SBP levels were only associated with 'fluid intelligence' (adjusted p<0.001). In mediation analysis, the averaged FA of external capsule, internal capsule anterior limb and superior cerebellar peduncle mediated 13%, 9% and 13% of SBP effects on fluid intelligence, while the averaged MD of external capsule, internal capsule anterior and posterior limbs, and superior corona radiata mediated 5%, 7%, 7% and 6% of SBP effects on fluid intelligence, respectively., Discussion: Among asymptomatic adults, higher SBP is associated with pervasive WM microstructure disintegrity, partially due to reduced neuronal count, which appears to mediate SBP adverse effects on fluid intelligence. Diffusion metrics of select WM tracts, which are most reflective of SBP-related parenchymal damage and cognitive impairment, may serve as imaging biomarkers to assess treatment response in antihypertensive trials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Frailty is an aging-related clinical phenotype defined as a state in which there is an increase in a person's vulnerability for dependency and/or mortality when exposed to a stressor. While underlying mechanisms leading to the occurrence of frailty are complex, the importance of genetic factors has not been fully investigated. We conducted a large-scale genome-wide association study (GWAS) of frailty, as defined by the five criteria (weight loss, exhaustion, physical activity, walking speed, and grip strength) captured in the Fried Frailty Score (FFS), in 386,565 European descent participants enrolled in the UK Biobank (mean age 57 [SD 8] years, 208,481 [54%] females). We identified 37 independent, novel loci associated with the FFS (p < 5 × 10 -8 ), including seven loci without prior described associations with other traits. The variants associated with FFS were significantly enriched in brain tissues as well as aging-related pathways. Our post-GWAS bioinformatic analyses revealed significant genetic correlations between FFS and cardiovascular-, neurological-, and inflammation-related diseases/traits, and subsequent Mendelian Randomization analyses identified causal associations with chronic pain, obesity, diabetes, education-related traits, joint disorders, and depressive/neurological, metabolic, and respiratory diseases. The GWAS signals were replicated in the Health and Retirement Study (HRS, n = 9,720, mean age 73 [SD 7], 5,582 [57%] females), where the polygenic risk score built from UKB GWAS was significantly associated with the FFS in HRS individuals (OR per SD of the score 1.27, 95% CI 1.22-1.31, p = 1.3 × 10 -11 ). These results provide new insight into the biology of frailty by comprehensively evaluating its genetic architecture., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Background and Objectives: Mounting evidence indicates that hypertension leads to a higher risk of dementia. Hypertension is a highly heritable trait, and a higher polygenic susceptibility to hypertension (PSH) is known to associate with a higher risk of dementia. We tested the hypothesis that a higher PSH leads to worse cognitive performance in middle-aged persons without dementia. Confirming this hypothesis would support follow-up research focused on using hypertension-related genomic information to risk-stratify middle-aged adults before hypertension develops., Methods: We conducted a nested cross-sectional genetic study within the UK Biobank (UKB). Study participants with a history of dementia or stroke were excluded. We categorized participants as having low (≤20th percentile), intermediate, or high (≥80th percentile) PSH according to results of 2 polygenic risk scores for systolic and diastolic blood pressure (BP) generated with data on 732 genetic risk variants. A general cognitive ability score was calculated as the first component of an analysis that included the results of 5 cognitive tests. Primary analyses focused on Europeans, and secondary analyses included all race/ethnic groups., Results: Of the 502,422 participants enrolled in the UKB, 48,118 (9.6%) completed the cognitive evaluation, including 42,011 (8.4%) of European ancestry. Multivariable regression models using systolic BP-related genetic variants indicated that compared with study participants with a low PSH, those with intermediate and high PSH had reductions of 3.9% (β -0.039, SE 0.012) and 6.6% (β -0.066, SE 0.014), respectively, in their general cognitive ability score ( p < 0.001). Secondary analyses including all race/ethnic groups and using diastolic BP-related genetic variants yielded similar results ( p < 0.05 for all tests). Analyses evaluating each cognitive test separately indicated that reaction time, numeric memory, and fluid intelligence drove the association between PSH and general cognitive ability score (all individual tests, p < 0.05)., Discussion: Among nondemented, community-dwelling, middle-aged Britons, a higher PSH is associated with worse cognitive performance. These findings suggest that genetic predisposition to hypertension influences brain health in persons who have not yet developed dementia. Because information on genetic risk variants for elevated BP is available long before the development of hypertension, these results lay the foundation for further research focused on using genomic data for the early identification of high-risk middle-aged adults., (© 2023 American Academy of Neurology.)

Background: Frailty is a prevalent state associated with several aging-related traits and conditions. The relationship between frailty and stroke remains understudied. Here we aim to investigate whether the hospital frailty risk score (HFRS) is associated with the risk of stroke and determine whether a significant association between genetically determined frailty and stroke exists., Design: Observational study using data from All of Us research program and Mendelian Randomization analyses., Methods: Participants from All of Us with available electronic health records were selected for analysis. All of Us began national enrollment in 2018 and is expected to continue for at least 10 years. All of Us is recruiting members of groups that have traditionally been underrepresented in research. All participants provided informed consent at the time of enrollment, and the date of consent was recorded for each participant. Incident stroke was defined as stroke event happening on or after the date of consent to the All of Us study HFRS was measured with a 3-year look-back period before the date of consent for stroke risk. The HFRS was stratified into 4 categories: no-frailty (HFRS=0), low (HFRS ≥1 and <5), intermediate (≥5 and <15), and high (HFRS ≥15). Last, we implemented Mendelian Randomization analyses to evaluate whether genetically determined frailty is associated with stroke risk., Results: Two hundred fifty-three thousand two hundred twenty-six participants were at risk of stroke. In multivariable analyses, frailty status was significantly associated with risk of any (ischemic or hemorrhagic) stroke following a dose-response way: not-frail versus low HFRS (HR, 4.9 [CI, 3.5-6.8]; P <0.001), not-frail versus intermediate HFRS (HR, 11.4 [CI, 8.3-15.7]; P <0.001) and not-frail versus high HFRS (HR, 42.8 [CI, 31.2-58.6]; P <0.001). We found similar associations when evaluating ischemic and hemorrhagic stroke separately ( P value for all comparisons <0.05). Mendelian Randomization confirmed this association by indicating that genetically determined frailty was independently associated with risk of any stroke (OR, 1.45 [95% CI, 1.15-1.84]; P =0.002)., Conclusions: Frailty, based on the HFRS was associated with higher risk of any stroke. Mendelian Randomization analyses confirmed this association providing evidence to support a causal relationship., Competing Interests: Disclosures None.

Importance: Aside from widely known cardiovascular implications, higher weight in children may have negative associations with brain microstructure and neurodevelopment., Objective: To evaluate the association of body mass index (BMI) and waist circumference with imaging metrics that approximate brain health., Design, Setting, and Participants: This cross-sectional study used data from the Adolescent Brain Cognitive Development (ABCD) study to examine the association of BMI and waist circumference with multimodal neuroimaging metrics of brain health in cross-sectional and longitudinal analyses over 2 years. From 2016 to 2018, the multicenter ABCD study recruited more than 11 000 demographically representative children aged 9 to 10 years in the US. Children without any history of neurodevelopmental or psychiatric disorders were included in this study, and a subsample of children who completed 2-year follow-up (34%) was included for longitudinal analysis., Exposures: Children's weight, height, waist circumference, age, sex, race and ethnicity, socioeconomic status, handedness, puberty status, and magnetic resonance imaging scanner device were retrieved and included in the analysis., Main Outcomes and Measures: Association of preadolescents' BMI z scores and waist circumference with neuroimaging indicators of brain health: cortical morphometry, resting-state functional connectivity, and white matter microstructure and cytostructure., Results: A total of 4576 children (2208 [48.3%] female) at a mean (SD) age of 10.0 years (7.6 months) were included in the baseline cross-sectional analysis. There were 609 (13.3%) Black, 925 (20.2%) Hispanic, and 2565 (56.1%) White participants. Of those, 1567 had complete 2-year clinical and imaging information at a mean (SD) age of 12.0 years (7.7 months). In cross-sectional analyses at both time points, higher BMI and waist circumference were associated with lower microstructural integrity and neurite density, most pronounced in the corpus callosum (fractional anisotropy for BMI and waist circumference at baseline and second year: P < .001; neurite density for BMI at baseline: P < .001; neurite density for waist circumference at baseline: P = .09; neurite density for BMI at second year: P = .002; neurite density for waist circumference at second year: P = .05), reduced functional connectivity in reward- and control-related networks (eg, within the salience network for BMI and waist circumference at baseline and second year: P < .002), and thinner brain cortex (eg, for the right rostral middle frontal for BMI and waist circumference at baseline and second year: P < .001). In longitudinal analysis, higher baseline BMI was most strongly associated with decelerated interval development of the prefrontal cortex (left rostral middle frontal: P = .003) and microstructure and cytostructure of the corpus callosum (fractional anisotropy: P = .01; neurite density: P = .02)., Conclusions and Relevance: In this cross-sectional study, higher BMI and waist circumference among children aged 9 to 10 years were associated with imaging metrics of poorer brain structure and connectivity as well as hindered interval development. Future follow-up data from the ABCD study can reveal long-term neurocognitive implications of excess childhood weight. Imaging metrics that had the strongest association with BMI and waist circumference in this population-level analysis may serve as target biomarkers of brain integrity in future treatment trials of childhood obesity.

Background and Objectives: Blood pressure (BP) is often not at goal in stroke survivors, leaving individuals vulnerable to additional vascular events. Given that BP is a highly heritable trait, we hypothesize that a higher polygenic susceptibility to hypertension (PSH) leads to worse BP control in stroke survivors., Methods: We conducted a study within the UK Biobank evaluating persons of European ancestry who survived an ischemic or hemorrhagic stroke. To model the PSH, we created polygenic risk scores (PRSs) for systolic and diastolic BP using 732 genetic variants. We divided the PRSs into quintiles and used linear/logistic regression to test whether higher PSH led to higher observed BP, uncontrolled BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg), and resistant BP (uncontrolled BP despite being on ≥3 antihypertensive drugs). We conducted an independent replication using data from the Vitamin Intervention for Stroke Prevention (VISP) trial., Results: We analyzed 5,940 stroke survivors. When comparing stroke survivors with very low vs very high PSH, the mean systolic BP was 137 (SD 18) vs 143 (SD 20, p < 0.001), the mean diastolic BP was 81 (SD 10) vs 84 (SD 11, p < 0.001), the prevalence of uncontrolled BP was 42.8% vs 57.2% ( p < 0.001), and the prevalence of resistant hypertension was 3.9% vs 11% ( p < 0.001). Results remained significant using multivariable models ( p < 0.001) and were replicated in the VISP study (all tests with p < 0.05)., Discussion: A higher PSH is associated with worse BP control in stroke survivors. These findings point to genetic predisposition as an important determinant of poorly controlled BP in this population., (© 2023 American Academy of Neurology.)

Background: Ischemic stroke (IS) is a highly heritable trait, and genome-wide association studies have identified several commonly occurring susceptibility risk loci for this condition. However, there are limited data on the contribution of rare genetic variation to IS., Methods: We conducted an exome-wide study using whole-exome sequencing data from 152 058 UK Biobank participants, including 1777 IS cases. We performed single-variant analyses for rare variants and gene-based analyses for loss-of-function and deleterious missense rare variants. We validated these results through (1) gene-based testing using summary statistics from MEGASTROKE-a genome-wide association study of IS that included 67 162 IS cases and 454 450 controls, (2) gene-based testing using individual-level data from 1706 IS survivors, including 142 recurrent IS cases, enrolled in the VISP trial (Vitamin Intervention for Stroke Prevention); and (3) gene-based testing against neuroimaging phenotypes related to cerebrovascular disease using summary-level data from 42 310 UK Biobank participants with available magnetic resonance imaging data., Results: In single-variant association analyses, none of the evaluated variants were associated with IS at genome-wide significance levels ( P <5×10 -8 ). In the gene-based analysis focused on loss-of-function and deleterious missense variants, rare genetic variation at CYP2R1 was significantly associated with IS risk ( P =2.6×10 -6 ), exceeding the Bonferroni-corrected threshold for 16 074 tests ( P <3.1×10 -6 ). Validations analyses indicated that CYP2R1 was associated with IS risk in MEGASTROKE (gene-based test, P =0.003), with IS recurrence in the VISP trial (gene-based test, P =0.001) and with neuroimaging traits (white matter hyperintensity, mean diffusivity, and fractional anisotropy) in the UK Biobank neuroimaging study (all gene-based tests, P <0.05)., Conclusions: Because CYP2R1 plays an important role in vitamin D metabolism and existing observational evidence suggests an association between vitamin D levels and cerebrovascular disease, our results support a role of this pathway in the occurrence of IS.

Background: Andexanet alfa (AA), a factor Xa-inhibitor (FXi) reversal agent, is given as a bolus followed by a 2-hour infusion. This long administration time can delay EVD placement in intracerebral hemorrhage (ICH) patients. We sought to evaluate the safety of EVD placement immediately post-AA bolus compared to post-AA infusion., Methods: We conducted a retrospective study that included adult patients admitted with FXi-associated ICH who received AA and underwent EVD placement The primary outcome was the occurrence of a new hemorrhage (tract, extra-axial, or intraventricular hemorrhage). Secondary outcomes included mortality, intensive care unit and hospital length of stay, and discharge modified Rankin Score. The primary safety outcome was documented thrombotic events., Results: Twelve patients with FXi related ICH were included (EVD placement post-AA bolus, N = 8; EVD placement post-AA infusion, N = 4). Each arm included one patient with bilateral EVD placed. There was no difference in the incidence of new hemorrhages, with one post-AA bolus patient had small, focal, nonoperative extra-axial hemorrhage. Morbidity and mortality were higher in post-AA infusion patients (mRS, post-AA bolus, 4 [4-6] vs. post-AA infusion 6 [5,6], p = 0.24 and post-AA bolus, 3 (37.5 %) vs. post-AA infusion, 3 (75 %), p = 0.54, respectively). One patient in the post-AA bolus group had thrombotic event. There was no difference in hospital LOS (post-AA bolus, 19 days [12-26] vs. post-AA infusion, 14 days [9-22], p = 0.55) and ICU LOS (post-AA bolus, 10 days [6-13] vs. post-AA infusion, 11 days [5-21], p = 0.86)., Conclusion: We report no differences in the incidence of tract hemorrhage, extra-axial hemorrhage, or intraventricular hemorrhage post-AA bolus versus post-AA infusion. Larger prospective studies to validate these results are warranted., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: The evidence linking chronic kidney disease (CKD) to spontaneous intracerebral hemorrhage (ICH) is inconclusive owing to possible confounding by comorbidities that frequently coexist in patients with these 2 diseases., Objective: To determine whether there is an association between CKD and ICH risk., Design, Setting, and Participants: A 3-stage study that combined observational and genetic analyses was conducted. First, the association between CKD and ICH risk was tested in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, a multicenter case-control study in the US. All participants with available data on CKD from ERICH were included. Second, this analysis was replicated in the UK Biobank (UKB), an ongoing population study in the UK. All participants in the UKB were included in this study. Third, mendelian randomization analyses were implemented in the UKB using 27 CKD-related genetic variants to test for genetic associations. ERICH was conducted from August 1, 2010, to August 1, 2017, and observed participants for 1 year. The UKB enrolled participants between 2006 and 2010 and will continue to observe them for 30 years. Data analysis was performed from November 11, 2019, to May 10, 2022., Exposures: CKD stages 1 to 5., Main Outcomes and Measures: The outcome of interest was ICH, ascertained in ERICH via expert review of neuroimages and in the UKB via a combination of self-reported data and International Statistical Classification of Diseases, Tenth Revision, codes., Results: In the ERICH study, a total of 2914 participants with ICH and 2954 controls who had available data on CKD were evaluated (mean [SD] age, 61.6 [14.0] years; 2433 female participants [41.5%]; 3435 male participants [58.5%]); CKD was found to be independently associated with higher risk of ICH (odds ratio [OR], 1.95; 95% CI, 1.35-2.89; P < .001). This association was not modified by race and ethnicity. Replication in the UKB with 1341 participants with ICH and 501 195 controls (mean [SD] age, 56.5 [8.1] years; 273 402 female participants [54.4%]; 229 134 male participants [45.6%]) confirmed this association (OR, 1.28; 95% CI, 1.01-1.62; P = .04). Mendelian randomization analyses indicated that genetically determined CKD was associated with ICH risk (OR, 1.56; 95% CI, 1.13-2.16; P = .007)., Conclusions and Relevance: In this 3-stage study that combined observational and genetic analyses among study participants enrolled in 2 large observational studies with different characteristics and study designs, CKD was consistently associated with higher risk of ICH. Mendelian randomization analyses suggest that this association was causal. Further studies are needed to identify the specific biological pathways that mediate this association.

The increasing availability of biomedical data from large biobanks, electronic health records, medical imaging, wearable and ambient biosensors, and the lower cost of genome and microbiome sequencing have set the stage for the development of multimodal artificial intelligence solutions that capture the complexity of human health and disease. In this Review, we outline the key applications enabled, along with the technical and analytical challenges. We explore opportunities in personalized medicine, digital clinical trials, remote monitoring and care, pandemic surveillance, digital twin technology and virtual health assistants. Further, we survey the data, modeling and privacy challenges that must be overcome to realize the full potential of multimodal artificial intelligence in health., (© 2022. Springer Nature America, Inc.)

Importance: Patients who survive severe intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) typically have poor functional outcome in the short term and understanding of future recovery is limited., Objective: To describe 1-year recovery trajectories among ICH and IVH survivors with initial severe disability and assess the association of hospital events with long-term recovery., Design, Setting, and Participants: This post hoc analysis pooled all individual patient data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 trial (CLEAR-III) and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE-III) phase 3 trial in multiple centers across the US, Canada, Europe, and Asia. Patients were enrolled from August 1, 2010, to September 30, 2018, with a follow-up duration of 1 year. Of 999 enrolled patients, 724 survived with a day 30 modified Rankin Scale score (mRS) of 4 to 5 after excluding 13 participants with missing day 30 mRS. An additional 9 patients were excluded because of missing 1-year mRS. The final pooled cohort included 715 patients (71.6%) with day 30 mRS 4 to 5. Data were analyzed from July 2019 to January 2022., Exposures: CLEAR-III participants randomized to intraventricular alteplase vs placebo. MISTIE-III participants randomized to stereotactic thrombolysis of hematoma vs standard medical care., Main Outcomes and Measures: Primary outcome was 1-year mRS. Patients were dichotomized into good outcome at 1 year (mRS 0 to 3) vs poor outcome at 1 year (mRS 4 to 6). Multivariable logistic regression models assessed associations between prospectively adjudicated hospital events and 1-year good outcome after adjusting for demographic characteristics, ICH and IVH severity, and trial cohort., Results: Of 715 survivors, 417 (58%) were male, and the overall mean (SD) age was 60.3 (11.7) years. Overall, 174 participants (24.3%) were Black, 491 (68.6%) were White, and 49 (6.9%) were of other races (including Asian, Native American, and Pacific Islander, consolidated owing to small numbers); 98 (13.7%) were of Hispanic ethnicity. By 1 year, 129 participants (18%) had died and 308 (43%) had achieved mRS 0 to 3. In adjusted models for the combined cohort, diabetes (adjusted odds ratio [aOR], 0.50; 95% CI, 0.26-0.96), National Institutes of Health Stroke Scale (aOR, 0.93; 95% CI, 0.90-0.96), severe leukoaraiosis (aOR, 0.30; 95% CI, 0.16-0.54), pineal gland shift (aOR, 0.87; 95% CI, 0.76-0.99]), acute ischemic stroke (aOR, 0.44; 95% CI, 0.21-0.94), gastrostomy (aOR, 0.30; 95% CI, 0.17-0.50), and persistent hydrocephalus by day 30 (aOR, 0.37; 95% CI, 0.14-0.98) were associated with lack of recovery. Resolution of ICH (aOR, 1.82; 95% CI, 1.08-3.04) and IVH (aOR, 2.19; 95% CI, 1.02-4.68) by day 30 were associated with recovery to good outcome. In the CLEAR-III model, cerebral perfusion pressure less than 60 mm Hg (aOR, 0.30; 95% CI, 0.13-0.71), sepsis (aOR, 0.05; 95% CI, 0.00-0.80), and prolonged mechanical ventilation (aOR, 0.96; 95% CI, 0.92-1.00 per day), and in MISTIE-III, need for intracranial pressure monitoring (aOR, 0.35; 95% CI, 0.12-0.98), were additional factors associated with poor outcome. Thirty-day event-based models strongly predicted 1-year outcome (area under the receiver operating characteristic curve [AUC], 0.87; 95% CI, 0.83-0.90), with significantly improved discrimination over models using baseline severity factors alone (AUC, 0.76; 95% CI, 0.71-0.80; P < .001)., Conclusions and Relevance: Among survivors of severe ICH and IVH with initial poor functional outcome, more than 40% recovered to good outcome by 1 year. Hospital events were strongly associated with long-term functional recovery and may be potential targets for intervention. Avoiding early pessimistic prognostication and delaying prognostication until after treatment may improve ability to predict future recovery.

Competing Interests: Conflicts of interest None disclosed.

The use of artificial intelligence (AI) has grown dramatically in the past few years in the United States and worldwide, with more than 300 AI-enabled devices approved by the U.S. Food and Drug Administration (FDA). Most of these AI-enabled applications focus on helping radiologists with detection, triage, and prioritization of tasks by using data from a single point, but clinical practice often encompasses a dynamic scenario wherein physicians make decisions on the basis of longitudinal information. Unfortunately, benchmark data sets incorporating clinical and radiologic data from several points are scarce, and, therefore, the machine learning community has not focused on developing methods and architectures suitable for these tasks. Current AI algorithms are not suited to tackle key image interpretation tasks that require comparisons to previous examinations. Focusing on the curation of data sets and algorithm development that allow for comparisons at different points will be required to advance the range of relevant tasks covered by future AI-enabled FDA-cleared devices., (© RSNA, 2022.)

Background: Among prognostic imaging variables, the hematoma volume on admission computed tomography (CT) has long been considered the strongest predictor of outcome and mortality in intracerebral hemorrhage., Aims: To examine whether different features of hematoma shape are associated with functional outcome in deep intracerebral hemorrhage., Methods: We analyzed 790 patients from the ATACH-2 trial, and 14 shape features were quantified. We calculated Spearman's Rho to assess the correlation between shape features and three-month modified Rankin scale (mRS) score, and the area under the receiver operating characteristic curve (AUC) to quantify the association between shape features and poor outcome defined as mRS>2 as well as mRS > 3., Results: Among 14 shape features, the maximum intracerebral hemorrhage diameter in the coronal plane was the strongest predictor of functional outcome, with a maximum coronal diameter >∼3.5 cm indicating higher three-month mRS scores. The maximum coronal diameter versus hematoma volume yielded a Rho of 0.40 versus 0.35 ( p  = 0.006), an AUC [mRS>2] of 0.71 versus 0.68 ( p  = 0.004), and an AUC [mRS>3] of 0.71 versus 0.69 ( p  = 0.029). In multiple regression analysis adjusted for known outcome predictors, the maximum coronal diameter was independently associated with three-month mRS (p < 0.001)., Conclusions: A coronal-plane maximum diameter measurement offers greater prognostic value in deep intracerebral hemorrhage than hematoma volume. This simple shape metric may expedite assessment of admission head CTs, offer a potential biomarker for hematoma size eligibility criteria in clinical trials, and may substitute volume in prognostic intracerebral hemorrhage scoring systems.

Background The evidence linking vitamin D (VitD) levels and spontaneous intracerebral hemorrhage (ICH) remains inconclusive. We tested the hypothesis that lower genetically determined VitD levels are associated with higher risk of ICH. Methods and Results We conducted a 2 sample Mendelian Randomization (MR) study using publicly available summary statistics from published genome-wide association studies of VitD levels (417 580 study participants) and ICH (1545 ICH cases and 1481 matched controls). We used the inverse-variance weighted approach to generate causal estimates and the MR Pleiotropy Residual Sum and Outlier and MR-Egger approaches to assess for horizontal pleiotropy. To account for known differences in their underlying mechanism, we implemented stratified analysis based on the location of the hemorrhage within the brain (lobar or nonlobar). Our primary analysis indicated that each SD decrease in genetically instrumented VitD levels was associated with a 60% increased risk of ICH (odds ratio [OR], 1.60; [95% CI, 1.05-2.43]; P =0.029). We found no evidence of horizontal pleiotropy (MR-Egger intercept and MR Pleiotropy Residual Sum and Outlier global test with P >0.05). Stratified analyses indicated that the association was stronger for nonlobar ICH (OR, 1.87; [95% CI, 1.18-2.97]; P =0.007) compared with lobar ICH (OR, 1.43; [95% CI, 0.86-2.38]; P =0.17). Conclusions Lower levels of genetically proxied VitD levels are associated with higher ICH risk. These results provide evidence for a causal role of VitD metabolism in ICH.

Importance: The American Heart Association (AHA) Life's Simple 7 (LS7) score captures 7 biological and lifestyle factors associated with promoting cardiovascular health., Objectives: To test whether healthier LS7 profiles are associated with significant brain health benefits in persons without stroke or dementia, and to evaluate whether genomic information can recapitulate the observed LS7., Design, Setting, and Participants: This genetic association study was a nested neuroimaging study within the UK Biobank, a large population-based cohort study in the United Kingdom. Between March 2006 and October 2010, the UK Biobank enrolled 502 480 community-dwelling persons aged 40 to 69 years at recruitment. This study focused on a subset of 35 914 participants without stroke or dementia who completed research brain magnetic resonance imaging (MRI) and had available genome-wide data. All analyses were conducted between March 2021 and March 2022., Exposures: The LS7 (blood pressure, low-density lipoprotein cholesterol, hemoglobin A1c, smoking, exercise, diet, and body mass index) profiles were ascertained clinically and genomically. Independent genetic variants known to influence each of the traits included in the LS7 were assessed. The total LS7 score ranges from 0 (worst) to 14 (best) and was categorized as poor (≤4), average (>4 to 9) and optimal (>9)., Main Outcomes and Measures: The outcomes of interest were 2 neuroimaging markers of brain health: white matter hyperintensity (WMH) volume and brain volume (BV)., Results: The final analytical sample included 35 914 participants (mean [SD] age 64.1 [7.6] years; 18 830 [52.4%] women). For WMH, compared with persons with poor observed LS7 profiles, those with average profiles had 16% (β = -0.18; SE, 0.03; P < .001) lower mean volume and those with optimal profiles had 39% (β = -0.39; SE, 0.03; P < .001) lower mean volume. Similar results were obtained using the genomic LS7 for WMH (average LS7 profile: β = -0.06; SE, 0.014; P < .001; optimal LS7 profile: β = -0.08; SE, 0.018; P < .001). For BV, compared with persons with poor observed LS7 profiles, those with average LS7 profiles had 0.55% (β = 0.09; SE, 0.02; P < .001) higher volume, and those with optimal LS7 profiles had 1.9% (β = 0.14; SE, 0.02; P < .001) higher volume. The genomic LS7 profiles were not associated with BV., Conclusions and Relevance: These findings suggest that healthier LS7 profiles were associated with better profiles of 2 neuroimaging markers of brain health in persons without stroke or dementia, indicating that cardiovascular health optimization was associated with improved brain health in asymptomatic persons. Genomic information appropriately recapitulated 1 of these associations, confirming the feasibility of modeling the LS7 genomically and pointing to an important role of genetic predisposition in the observed association among cardiometabolic and lifestyle factors and brain health.

We evaluated whether genetically elevated low-density lipoprotein cholesterol (LDL-C) levels are associated with lower risk of intracranial aneurysms and subarachnoid hemorrhage (IA/SAH). We conducted a 2-sample Mendelian randomization (MR) study. Our primary analysis used the inverse-variance weighted method. In secondary analyses, we implemented the MR-PRESSO method, restricted our analysis to LDL-C-specific instruments, and performed multivariate MR. A 1-mmol/l increase in genetically instrumented LDL-C levels was associated with a 17% lower risk of IA/SAH (odds ratio = 0.83, 95% confidence interval = 0.73-0.94, p = 0.004). Results remained consistent in secondary and multivariate analyses (all p < 0.05). Our results provide evidence for an inverse causal relationship between LDL-C levels and risk of IA/SAH. ANN NEUROL 2022;91:145-149., (© 2021 American Neurological Association.)

Background All of Us is a novel research program that aims to accelerate research in populations traditionally underrepresented in biomedical research. Our objective was to evaluate the burden of cardiovascular disease (CVD) in broadly defined underrepresented groups. Methods and Results We evaluated the latest data release of All of Us. We conducted a cross-sectional analysis combining survey and electronic health record data to estimate the prevalence of CVD upon enrollment in underrepresented groups defined by race, ethnicity, age (>75 years), disability (not able to carry out everyday physical activities), sexual orientation and gender identity lesbian, gay, bisexual, transgender, queer, intersex, and asexual (LGBTQIA+), income (annual household income <$35 000 US dollars) and education (less than a high school degree). We used multivariate logistic regression to estimate the adjusted odds ratio (OR) and product terms to test for interaction. The latest All of Us data release includes 315 297 participants. Of these, 230 577 (73%) had information on CVD and 17 958 had CVD (overall prevalence, 7.8%; 95% CI, 7.7-7.9). Multivariate analyses adjusted by hypertension, hyperlipidemia, type 2 diabetes mellitus, body mass index, and smoking indicated that, compared with White participants, Black participants had a higher adjusted odds of CVD (OR, 1.21; 95% CI, 1.16-1.27). Higher adjusted odds of CVD were also observed in underrepresented groups defined by other factors, including age >75 years (OR, 1.90; 95% CI, 1.81-1.99), disability (OR, 1.60; 95% CI, 1.53-1.68), and income <$35 000 US dollars (OR, 1.22; 95% CI, 1.17-1.27). Sex significantly modified the odds of CVD in several of the evaluated groups. Conclusions Among participants enrolled in All of Us, underrepresented groups defined based on race, ethnicity and other factors have a disproportionately high burden of CVD. The All of Us research program constitutes a powerful platform to accelerate research focused on individuals in underrepresented groups.

Background and Purpose: Radiomics provides a framework for automated extraction of high-dimensional feature sets from medical images. We aimed to determine radiomics signature correlates of admission clinical severity and medium-term outcome from intracerebral hemorrhage (ICH) lesions on baseline head computed tomography (CT)., Methods: We used the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage II) trial dataset. Patients included in this analysis (n = 895) were randomly allocated to discovery (n = 448) and independent validation (n = 447) cohorts. We extracted 1130 radiomics features from hematoma lesions on baseline noncontrast head CT scans and generated radiomics signatures associated with admission Glasgow Coma Scale (GCS), admission National Institutes of Health Stroke Scale (NIHSS), and 3-month modified Rankin Scale (mRS) scores. Spearman's correlation between radiomics signatures and corresponding target variables was compared with hematoma volume., Results: In the discovery cohort, radiomics signatures, compared to ICH volume, had a significantly stronger association with admission GCS (0.47 vs. 0.44, p = 0.008), admission NIHSS (0.69 vs. 0.57, p < 0.001), and 3-month mRS scores (0.44 vs. 0.32, p < 0.001). Similarly, in independent validation, radiomics signatures, compared to ICH volume, had a significantly stronger association with admission GCS (0.43 vs. 0.41, p = 0.02), NIHSS (0.64 vs. 0.56, p < 0.001), and 3-month mRS scores (0.43 vs. 0.33, p < 0.001). In multiple regression analysis adjusted for known predictors of ICH outcome, the radiomics signature was an independent predictor of 3-month mRS in both cohorts., Conclusions: Limited by the enrollment criteria of the ATACH-2 trial, we showed that radiomics features quantifying hematoma texture, density, and shape on baseline CT can provide imaging correlates for clinical presentation and 3-month outcome. These findings couldtrigger a paradigm shift where imaging biomarkers may improve current modelsfor prognostication, risk-stratification, and treatment triage of ICH patients., (© 2021 European Academy of Neurology.)

Stroke is a leading cause of death and disability worldwide. However, our understanding of its underlying biology and the number of available treatment options remain limited. Mendelian randomization (MR) offers a powerful approach to identify novel biological pathways and therapeutic targets for this disease. Around ~100 MR studies have been conducted so far to explore, confirm, and quantify causal relationships between several exposures and risk of stroke. In this review, we summarize the current evidence arising from these studies, including those investigating ischemic stroke, hemorrhagic stroke, or both. We highlight the different types of exposures that are currently under study, ranging from well-known cardiovascular risk factors to less established inflammation-related mechanisms. Finally, we provide an overview of future avenues of research and novel approaches, including drug target validation MR, which is poised to have a substantial impact on drug development and drug repurposing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Acosta, Szejko and Falcone.)

Background/objective: There are limited data on the risks and benefits of using andexanet alfa (AA) in comparison with four-factor prothrombin complex concentrate (4F-PCC) to reverse factor Xa inhibitors (FXi) associated intracranial hemorrhage (ICH). We sought to describe our experience with AA or 4F-PCC in patients with oral FXi-related traumatic and spontaneous ICH., Methods: We conducted a retrospective review of consecutive adult patients with FXi-related ICH who received AA or 4F-PCC. FXi-related ICH cases included traumatic and spontaneous intracranial hemorrhages. Our primary analysis evaluated ICH stability on head computed tomography scan (CT), defined as a similar amount of blood from the initial scan at the onset of ICH to subsequent scans, at 6-h and 24-h post-administration of AA or 4F-PCC. For the subset of spontaneous intraparenchymal hemorrhages, volume was measured at 6-h and 24-h post-reversal. In secondary analyses, we evaluated good functional outcome at discharge, defined as a Modified Rankin Score of less than 3, and the incidence of thrombotic events after AA or 4F-PCC adminstration, during hospitalization., Results: A total of 44 patients (16 traumatic and 28 spontaneous ICH) with median age of 79 years [72-86], 36% females, with a FXi-related ICH, were included in this study. The majority of spontaneous ICHs were intraparenchymal 19 (68%). Twenty-eight patients (64%) received AA and 16 patients (36%) received 4F-PCC. There was no difference between AA and 4F-PCC in terms of CT stability at 6 h (21 [78%] vs 10 [71%], p = 0.71) and 24 h (15 [88%] vs 6 [60%], p = 0.15). In a subgroup of patients with spontaneous intraparenchymal hemorrhage, there was no difference in the degree of achieved hemostasis based on hematoma volume between AA and 4F-PCC at 6 h (9.3 mL [6.9-26.4] vs 10 mL [9.4-22.1], adjusted p = 0. 997) and 24-h (9.2 mL [6.1-18.8] vs 9.9 [9.4-21.1], adjusted p = 1). The number of patients with good outcome based on mRS on discharge were 10 (36%) and 6 (38%) in the AA and 4F-PCC groups, respectively (adjusted p = 0.81). The incidence of thromboembolic events was similar in the AA and 4F-PCC groups (2 [7%] vs 0, p = 0.53)., Conclusion: In this limited sample of patients, we found no difference in neuroimaging stability, functional outcome and thrombotic events when comparing AA and 4F-PCC in patients with FXi-related ICH. Since our analysis is likely underpowered, a multi-center collaborative network devoted to this question is warranted., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Objectives: To test the hypothesis that admission hemoglobin levels are associated with outcome in primary, nontraumatic intracerebral hemorrhage., Design: Individual patient data meta-analysis of three studies of intracerebral hemorrhage., Setting: Two randomized clinical trials and one multiethnic observational study., Patients: Patients with spontaneous, nontraumatic intracerebral hemorrhage., Interventions: None., Measurements and Main Results: Our exposure of interest was admission hemoglobin levels and the primary outcome was 3-month postintracerebral hemorrhage-dichotomized modified Rankin Scale (0-3 vs 4-6). Intermediate outcomes were admission hematoma volume and hematoma expansion defined as 6 mL or 33% increase in hemorrhage size on repeat CT. A total of 4,172 intracerebral hemorrhage patients were included in the study (mean age 63 [sd = 14]; female sex 1,668 [40%]). Each additional g/dL of admission hemoglobin was associated with 14% (odds ratio, 0.86; 95% CI, 0.82-0.91) and 7% (odds ratio, 0.93; 95% CI, 0.88-0.98) reductions in the risk of poor outcome in unadjusted and adjusted analyses, respectively. Dose-response analyses indicated a linear relationship between admission hemoglobin levels and poor outcome across the entire evaluated range (test-for-trend p < 0.001). No consistent associations were found between the admission hemoglobin levels and hematoma volume or hematoma expansion., Conclusions: Higher hemoglobin levels are associated with better outcome in intracerebral hemorrhage. Further research is needed to evaluate admission hemoglobin levels as both a therapeutic target and predictor of outcome., Competing Interests: Ms. Leasure is supported by the National Institutes of Health (NIH) (R03NS112859). Dr. Sansing is supported by the NIH (R01NS095993, R01NS097728, U01NS113445). Dr. Kamel is supported by the NIH (R01NS097443, U01NS095869, R01HL144541, U01NS106513). Dr. Murthy is supported by the NIH (K23NS105948) and the Leon Levy Foundation. Dr. Sheth is supported by the NIH (U24NS107136, U24NS107215, R01NR018335, U01NS106513, R03NS112859) and the American Heart Association (18TPA34170180,17CSA33550004). Dr. Falcone is supported by the National Institute on Aging (K76AG59992), the National Institute of Neurological Disorders and Stroke (R03NS112859), the American Heart Association (18IDDG34280056), a Yale Pepper Scholar Award (P30AG021342), and the Neurocritical Care Society Research Fellowship. Drs. Acosta, Sansing, Langefeld, Woo, Sheth, and Falcone received support for article research from the NIH. Drs. Langefeld’s and Woo’s institutions received funding from the NIH. Dr. Kamel serves as a principal investigator for the NIH-funded AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA) trial (National Institute of Nuerological Disoders and Stroke U01NS095869), which receives in-kind study drug from the Bristol-Myers-Squibb-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics, serves as Deputy Editor for JAMA Neurology, serves as a steering committee member of Medtronic’s Stroke atrial fibrillation trial (uncompensated), serves on an end point adjudication committee for a trial of empagliflozin for Boehringer-Ingelheim, and has served on an advisory board for Roivant Sciences related to Factor XI inhibition. Dr. Mayer recieved funding from Idorsia, MaxQ AI, Bayer, Brain Cool, Biogen, and Nestle. Dr. Sheth’s institution received funding from Biogen, Novartis, and Bard, and he recieved funding from Hyperfine and Zoll. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background and Purpose: Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to nontraumatic subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and the risk of SAH has not been established. Using Mendelian randomization (MR) analyses, we tested the hypothesis that smoking is causally linked to the risk of SAH., Methods: We conducted a 1-sample MR study using data from the UK Biobank, a large cohort study that enrolled over 500 000 Britons aged 40 to 69 from 2006 to 2010. Participants of European descent were included. SAH cases were ascertained using a combination of self-reported, electronic medical record, and death registry data. As the instrument, we built a polygenic risk score using independent genetic variants known to associate ( P <5 ×10 - 8 ) with smoking behavior. This polygenic risk score represents the genetic susceptibility to smoking initiation. The primary MR analysis utilized the ratio method. Secondary MR analyses included the inverse variance weighted and weighted median methods., Results: A total of 408 609 study participants were evaluated (mean age, 57 [SD 8], female sex, 220 937 [54%]). Among these, 132 566 (32%) ever smoked regularly, and 904 (0.22%) had a SAH. Each additional SD of the smoking polygenic risk score was associated with 21% increased risk of smoking (odds ratio [OR], 1.21 [95% CI, 1.20-1.21]; P <0.001) and a 10% increased risk of SAH (OR, 1.10 [95% CI, 1.03-1.17]; P =0.006). In the primary MR analysis, genetic susceptibility to smoking was associated with a 63% increase in the risk of SAH (OR, 1.63 [95% CI, 1.15-2.31]; P =0.006). Secondary analyses using the inverse variance weighted method (OR, 1.57 [95% CI, 1.13-2.17]; P =0.007) and the weighted median method (OR, 1.74 [95% CI, 1.06-2.86]; P =0.03) yielded similar results. There was no significant pleiotropy (MR-Egger intercept P =0.39; MR Pleiotropy Residual Sum and Outlier global test P =0.69)., Conclusions: These findings provide evidence for a causal link between smoking and the risk of SAH.

Objective: To determine the leading causes of death in intracerebral hemorrhage (ICH) survivors, we used administrative data from 3 large US states to identify adult survivors of a first-time spontaneous ICH and track all hospital readmissions resulting in death., Methods: We performed a longitudinal analysis of prospectively collected claims data from hospitalizations in California (2005-2011), New York (2005-2014), and Florida (2005-2014). Adult residents admitted with a nontraumatic ICH who survived to discharge were included. Patients were followed for a primary outcome of any readmission resulting in death. The cause of death was defined as the primary diagnosis assigned at discharge. Multivariable Cox proportional hazards and multinomial logistic regression were used to determine factors associated with the risk for and cause of death., Results: Of 72,432 ICH survivors (mean age 68 years [SD 16], 48% female), 12,753 (18%) died during a median follow-up period of 4.0 years (interquartile range 2.3-6.3). The leading causes of death were infection (34%), recurrent intracranial hemorrhage (14%), cardiac disease (8%), respiratory failure (8%), and ischemic stroke (5%). Death in patients with atrial fibrillation (AF) was more likely to be caused by ischemic stroke (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.9-2.9, p < 0.001) and less likely to be caused by recurrent intracranial hemorrhage (OR 0.7, 95% CI 0.6-0.8, p < 0.001) compared to patients without AF., Conclusions: Infection is the leading cause of death in all ICH survivors. Survivors with AF were at increased risk for death from ischemic stroke. These findings will help prioritize interventions aimed to improve long-term survival and recovery in ICH survivors., (© 2020 American Academy of Neurology.)

Objective: The aim of this retrospective cohort study was to analyze responses to intravenous (IV) phenytoin (PHT) for trigeminal neuralgia (TN) crisis in a group of patients treated at our institution., Background: TN is one of the most common causes of facial pain. Its treatment relies on preventive therapy with either carbamazepine or oxcarbazepine. During severe pain episodes, patients may be unable to eat, drink, or even swallow oral medication, requiring in-hospital treatment. There is scarce evidence to support IV medication use for TN, making management of this condition difficult., Methods: We reviewed clinical records of patients with TN crisis consulting the emergency department at a tertiary neurological referral center in Buenos Aires, Argentina, treated with IV PHT as analgesic strategy, and with at least 1-month posttreatment follow-up. Demographic features, magnetic resonance imaging findings, and therapeutic management were analyzed., Results: Thirty-nine patients with TN were included, 18 (46.2%) receiving IV PHT more than once (total number of infusions administered, 65). Immediate pain relief was observed in 89.2% (58/65) and 15.4% (10/65) presented side effects., Conclusions: We recommend IV PHT as acute rescue treatment in TN crisis., (© 2020 American Headache Society.)

Objective: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH., Methods: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses., Results: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10 -100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively., Interpretation: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66., (© 2020 American Neurological Association.)

Disease-specific therapeutic options for critically ill neurological patients are limited. The identification of new preventive, therapeutic, and rehabilitation strategies is of the utmost importance in the field of neurocritical care research. Population genetics offers powerful tools to identify and prioritize biological pathways to be targeted by novel interventions. New treatments with supportive genetic evidence have twice the chances of obtaining final FDA approval compared to those without this support. Large collaborations, public access to data, reproducible science, and innovative analytical methods have exponentially increased the pace of discoveries related to neurocritical care genetics.

Introduction: Rapidly progressive dementia (RPD) is a broadly defined clinical syndrome. Our aim was to describe clinical and ancillary study findings in patients with RPD and evaluate their diagnostic performance for the identification of nonchronic neurodegenerative rapidly progressive dementia (ncnRPD)., Methods: We reviewed clinical records and ancillary methods of patients evaluated for RPD at our institution in Buenos Aires, Argentina from 2011 to 2017. We compared findings between chronic neurodegenerative RPD and ncnRPD and evaluated the diagnostic metrics using receiver operating characteristic curves., Results: We included 104 patients with RPD, 29 of whom were chronic neurodegenerative RPD and 75 of whom were ncnRPD. The 6-month time to dementia cutpoint had a sensitivity of 89% and specificity of 100% for ncnRPD, with an area under the receiver operating characteristic curve of 0.965 (95% confidence interval=0.935-0.99; P<0.001). A decision tree that included time to dementia, brain magnetic resonance imaging, and cerebrospinal fluid analysis identified ncnRPD patients with a sensitivity of 100%, specificity of 79%, positive predictive value of 93%, and negative predictive value of 100% overall., Discussion: RPD is a clinical syndrome that comprises different diagnoses, many of them for treatable diseases. Using the time to dementia, brain magnetic resonance imaging, and cerebrospinal fluid analysis when triaging these patients could help identify those diseases that need to be studied more aggressively.

As the number of stroke survivors continues to increase, identification of therapeutic targets for stroke recovery has become a priority in stroke genomics research. The introduction of high-throughput genotyping technologies and novel analytical tools has significantly advanced our understanding of the genetic underpinnings of stroke recovery.

Introduction: To assess clinical and/or imaging features useful to distinguish between Susac syndrome (SuS) and primary angiitis of central nervous system (PACNS)., Methods: Multicenter retrospective analysis of two cohorts of Argentine patients diagnosed with SuS and PACNS., Results: 13 patients diagnosed with SuS (6 women and 7 men, mean age 35 ± 10 years) and 15 with PACNS (10 women and 5 men, mean age 44 ± 18 years) were analyzed. Cognitive impairment (11 out of 13 patients vs. 5 out of 15, p = .006), ataxia (7 out of 13 vs. 2 out of 15, p = .042) and auditory disturbances (7 out of 13 vs. 0 out of 15, p = .003) were more frequent in SuS patients; whereas seizures were more frequent in PACNS patients (8 out of 15 vs. 1 out of 13, p = .035). On MRI, corpus callosum (CC) involvement was observed more often in SuS, with abnormalities in CC genu, in 13 out of 13 SuS patients vs. only 2 out of 15 PACNS patients (p < .001); in CC body these were present in 13 out of 13 SuS patients vs. 1 out of 15 PACNS patients, (p < .001); and in CC splenium in 12 out of 13 Sus patients vs. 1 of 15 PACNS, p < .001). Cortical lesions were more frequent in PACNS patients (10 out of 15 vs. 3 out of 13 SuS patients, p = .02), as were hemorrhages (5 out of 15 vs. 0 out of 13 SuS, p = .04) and multiple basal ganglia infarcts (7 out of 15 vs. 1 out of 13 Sus, p = .037)., Conclusion: Specific clinical and/or MRI findings may help distinguish SuS from PACNS with potential therapeutic implications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Acute inflammatory demyelinating polyneuropathy (AIDP) and acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) are conditions presenting overlapping clinical features during early stages (first 4 weeks), although the latter may progress after 8 weeks. The aim of this study was to identify predictive factors contributing to their differential diagnosis. Clinical records of adult patients with AIDP or A-CIDP diagnosed at our institution between January 2006 and July 2017 were retrospectively reviewed. Demographic characteristics, clinical manifestations, cerebrospinal-fluid (CSF) findings, treatment and clinical evolution were analyzed. Nerve conduction studies were performed in all patients with at least 12 months follow-up. A total of 91 patients were included (AIDP, n = 77; A-CIDP, n = 14). The median age was 55.5 years in patients with A-CIDP vs 43 years in AIDP (P = .07). The history of diabetes mellitus was more frequent in A-CIDP (29% vs 8%, P = .04). No significant differences between groups were observed with respect to: human immunodeficiency virus (HIV) status, presence of auto-immune disorder or oncologic disease. Cranial, motor and autonomic nerve involvement rates were similar in both groups. Patients in the A-CIDP group showed higher frequency of proprioceptive disturbances (83% vs 28%; P < .001), sensory ataxia (46% vs 16%; P = .01), and the use of combined immunotherapy with corticoids (29% vs 3%; P = .005). There were no significant differences in CSF findings, intensive care unit (ICU) admission, or mortality rates. During the first 8 weeks both entities are practically indistinguishable. Alterations in proprioception could suggest A-CIDP. Searching for markers that allow early differentiation could favor the onset of corticotherapy without delay., (© 2018 Peripheral Nerve Society.)