Rescue therapy for vasospasm following aneurysmal subarachnoid hemorrhage:a propensity score-matched analysis with machine learning

OBJECTIVE Rescue therapies have been recommended for patients with angiographic vasospasm (aVSP) and delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). However, there is little evidence from randomized clinical trials that these therapies are safe and effective. The primary aim of this study was to apply game theory-based methods in explainable machine learning (ML) and propensity score matching to determine if rescue therapy was associated with better 3-month outcomes following post-SAH aVSP and DCI. The authors also sought to use these explainable ML methods to identify patient populations that were more likely to receive rescue therapy and factors associated with better outcomes after rescue therapy. METHODS Data for patients with aVSP or DCI after SAH were obtained from 8 clinical trials and 1 observational study in the Subarachnoid Hemorrhage International Trialists repository. Gradient boosting ML models were constructed for each patient to predict the probability of receiving rescue therapy and the 3-month Glasgow Outcome Scale (GOS) score. Favorable outcome was defined as a 3-month GOS score of 4 or 5. Shapley Additive Explanation (SNAP) values were calculated for each patient-derived model to quantify feature importance and interaction effects. Variables with high S HAP importance in predicting rescue therapy administration were used in a propensity score-matched analysis of rescue therapy and 3-month GOS scores. RESULTS The authors identified 1532 patients with aVSP or DCI. Predictive, explainable ML models revealed that aneurysm characteristics and neurological complications, but not admission neurological scores, carried the highest relative importance rankings in predicting whether rescue therapy was administered. Younger age and absence of cerebral ischemia/ infarction were invariably linked to better rescue outcomes, whereas the other important predictors of outcome varied by rescue type (interventional or noninterventional). In a propensity score-matched analysis guided by SHAP-based variable selection, rescue therapy was associated with higher odds of 3-month GOS scores of 4-5 (OR 1.63, 95% CI 1.22-2.17). CONCLUSIONS Rescue therapy may increase the odds of good outcome in patients with aVSP or DCI after SAH. Given the strong association between cerebral ischemia/infarction and poor outcome, trials focusing on preventative or therapeutic interventions in these patients may be most able to demonstrate improvements in clinical outcomes. Insights developed from these models may be helpful for improving patient selection and trial design

SNP based heritability estimates of common and specific variance in self and informant reported neuroticism scales

Objective. Our study aims to estimate the proportion of the phenotypic variance of Neuroticism and its facet scales that can be attributed to common SNPs in two adult populations from Estonia (EGCUT; N = 3,292) and the Netherlands (Lifelines; N = 13,383). Method. Genomic-Relatedness-Matrix Restricted Maximum Likelihood (GREML) using Genome-wide Complex Trait Analysis (GCTA) software was employed. To build upon previous research, we used self- and informant-reports of the 30-facet NEO personality inventories and analyzed both the usual sum scores and the residual facet scores of Neuroticism. Results. In the EGCUT cohort, the proportion of phenotypic variance explained by the additive effects of common genetic variants in self- and informant-reported Neuroticism domain scores was 15.2% (p = .070, SE = .11) and 6.2% (p = .293, SE = .12), respectively. The SNP-based heritability estimates at the level of Neuroticism facet scales differed greatly across cohorts and modes of measurement but were generally higher (a) for self- than for informant-reports, and (b) for sum than for residual scores. Conclusions. Our findings indicate that a large proportion of the heritability of Neuroticism is not captured by additive genetic effects of common SNPs with some evidence for gene-environment interaction across cohorts. This article is protected by copyright. All rights reserved

Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage:the SAHIT multinational cohort study

Objective To develop and validate a set of practical prediction tools that reliably estimate the outcome of subarachnoid haemorrhage from ruptured intracranial aneurysms (SAH). Design Cohort study with logistic regression analysis to combine predictors and treatment modality. Setting Subarachnoid Haemorrhage International Trialists' (SAHIT) data repository, including randomised clinical trials, prospective observational studies, and hospital registries. Participants Researchers collaborated to pool datasets of prospective observational studies, hospital registries, and randomised clinical trials of SAH from multiple geographical regions to develop and validate clinical predicti

Reversible molecular pathology of skeletal muscle in spinal muscular atrophy

Low levels of full-length survival motor neuron (SMN) protein cause the motor neuron disease, spinal muscular atrophy (SMA). Although motor neurons undoubtedly contribute directly to SMA pathogenesis, the role of muscle is less clear. We demonstrate significant disruption to the molecular composition of skeletal muscle in pre-symptomatic severe SMA mice, in the absence of any detectable degenerative changes in lower motor neurons and with a molecular profile distinct from that of denervated muscle. Functional cluster analysis of proteomic data and phospho-histone H2AX labelling of DNA damage revealed increased activity of cell death pathways in SMA muscle. Robust upregulation of voltage-dependent anion-selective channel protein 2 (Vdac2) and downregulation of parvalbumin in severe SMA mice was confirmed in a milder SMA mouse model and in human patient muscle biopsies. Molecular pathology of skeletal muscle was ameliorated in mice treated with the FDA-approved histone deacetylase inhibitor, suberoylanilide hydroxamic acid. We conclude that intrinsic pathology of skeletal muscle is an important and reversible event in SMA and also suggest that muscle proteins have the potential to act as novel biomarkers in SMA

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Symptomatic low-grade carotid stenosis with intraplaque hemorrhage and expansive arterial remodeling is associated with a high relapse rate refractory to medical treatment.

[BACKGROUND]: Carotid plaque characteristics influence future risk of stroke considerably. However, the severity of stenosis does not accurately reflect plaque burden in patients with expansive arterial remodeling. [OBJECTIVE]: To determine the therapeutic outcome of symptomatic carotid low-grade stenosis with vulnerable plaque based on magnetic resonance imaging (MRI) characterization. [METHODS]: We studied 25 (male, n = 23; age, 74.2 ± 5.6 years) of 29 consecutive patients with symptomatic carotid low-grade stenosis (<50%) and both high-signal plaque and expansive remodeling on T1-weighted MRIs. The remaining 4 were excluded because of impending stroke. A single antithrombotic and statin were administered, and recurrent ischemic stroke was treated with dual antithrombotics. We considered carotid endarterectomy when recurrence was refractory to aggressive medical treatment. [RESULTS]: During a 31.3 ± 16.4-month follow-up, 11 of the 25 patients developed a total of 30 recurrent ischemic events (46.0% per patient-year). The patients' characteristics did not differ significantly between the groups with and without recurrence (n = 11 and n = 14, respectively). Seven of 11 patients in the recurrence group treated with carotid endarterectomy remained free of ischemic events during a postoperative follow-up of 19.1 ± 14.6 months. [CONCLUSION]: Symptomatic low-grade carotid stenosis with vulnerable plaque confirmed by MRI was associated with a high rate of stroke recurrence that was refractory to aggressive medical treatment. However, carotid endarterectomy was safe and effective for such patients. Plaque characterization by MRI has the potential for more accurate stroke risk stratification in the management of carotid low-grade stenosis