Detailed Analysis of Prebiotic Fructo- and Galacto-Oligosaccharides in the Human Small Intestine.

Galacto-oligosaccharides (GOS) and fructo-oligosaccharides (FOS) are food ingredients that improve human health, but their degradation throughout the human small intestine is not well understood. We studied the breakdown kinetics of FOS and GOS in the intestines of seven healthy Dutch adults. Subjects were equipped with a catheter in the distal ileum or proximal colon and consumed 5 g of chicory-derived FOS (degree of polymerization (DP) DP2-10), and 5 g of GOS (DP2-6). Postprandially, intestinal content was frequently collected until 350 min and analyzed for mono-, di-, and oligosaccharides. FOS and GOS had recoveries of 96 ± 25% and 76 ± 28%, respectively. FOS DP ≥ 2 and GOS DP ≥ 3 abundances in the distal small intestine or proximal colon matched the consumed doses, while GOS dimers (DP2) had lower recoveries, namely 22.8 ± 11.1% for ß-D-gal-(1↔1)-α-D-glc+ß-D-gal-(1↔1)-ß-D-glc, 19.3 ± 19.1% for ß-D-gal-(1 → 2)-D-glc+ß-D-gal-(1 → 3)-D-glc, 43.7 ± 24.6% for ß-D-gal-(1 → 6)-D-gal, and 68.0 ± 38.5% for ß-D-gal-(1 → 4)-D-gal. Lactose was still present in the distal small intestine of all of the participants. To conclude, FOS DP ≥ 2 and GOS DP ≥ 3 were not degraded in the small intestine of healthy adults, while most prebiotic GOS DP2 was hydrolyzed in a structure-dependent manner. We provide evidence on the resistances of GOS with specific ß-linkages in the human intestine, supporting the development of GOS prebiotics that resist small intestine digestion.

Supramolecular architecture of theophylline polymorphs, monohydrate and co-crystals with iodine: study from the energetic viewpoint.

The regularities of crystal structure organization were thoroughly studied in all to date known polymorphic modifications of theophylline (THP) using an energetic approach. The monohydrate and a co-crystal of theophylline with one half equivalent of an iodine molecule were similarly investigated. The calculations of pairwise interaction energies have showed that the crystals studied can be divided into two groups according to their basic structural motifs: columnar-layered or columnar. The energetic approach also allows the role of different interactions in the crystal structure formation to be estimated. It was found that strong N-H⋯N, N-H⋯O hydrogen bonds and stacking interactions play the most important roles in polymorphic modifications of THP and the THP monohydrate. In the case of the co-crystal with iodine, N-H⋯O hydrogen bond participates in the dimeric building unit formation. However, instead of a stacking interaction the π⋯π interaction between carbonyl groups of neighboring molecules plays the highest role in the supramolecular architecture of this crystal. The lattice energies calculations in periodic conditions for polymorphic structures have shown that polymorph with the most anisotropic energetic structure may be considered as stable and all others forms metastable. In the polymorphic modification 1 of THP a zwitter-ionic resonance form is predominant, which affects significantly the solubility and the intermolecular interactions of this modification.

Knee Pain, Joint Loading, and Structural Abnormalities on MRI in 13-Year-Old Children in a Population-Based Birth Cohort.

BACKGROUND: Knee pain is a common problem in children and adolescents, and it often has a chronic character. PURPOSE: To examine the prevalence of knee pain in 13-year-old children and assess associations of knee pain with physical factors and the presence of structural abnormalities on magnetic resonance imaging (MRI). STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Data from the Generation R Study, a population-based birth cohort, were used. Prevalence and characteristics of knee pain were assessed, using a pain mannequin, in children 13 years of age (N = 1849). Patient characteristics and data on physical activity were extracted from questionnaires. The body mass index standard deviation score and waist-hip ratio were calculated from objectively measured weight and height. Structural abnormalities were assessed by MRI. The differences between children with and without knee pain were also analyzed. RESULTS: A prevalence of 8.0% was found for knee pain in children, of which 92.3% persisted for >3 months (ie, chronic); 37.5% of the children experienced pain daily, and the pain was almost always located on the anterior side of the knee (98.6%). Higher body mass index standard deviation scores were seen in children with knee pain than in the children without knee pain. No differences in physical activity were seen between children with and without knee pain. Moreover, in children with knee pain compared with children without knee pain, characteristics of Osgood-Schlatter disease (6.8% vs 1.9%) and bipartite patella type 3 (4.7% vs 0.3%) were more often seen on MRI. CONCLUSION: This study shows that knee pain is a relatively frequent problem in children. It is almost always located on the anterior aspect, has a chronic character, and is often experienced daily. However, the possible implication of structural abnormalities on MRI in children with knee pain and the possible relationship with the development of future knee complaints are still unclear.

Brain Health Outcomes in Sexual and Gender Minority Groups: Results From the All of Us Research Program.

BACKGROUND AND OBJECTIVES: Sexual and gender minority (SGM) groups have been historically underrepresented in neurologic research, and their brain health disparities are unknown. We aim to evaluate whether SGM persons are at higher risk of adverse brain health outcomes compared with cisgender straight (non-SGM) individuals. METHODS: We conducted a cross-sectional study in the All of Us Research Program, a US population-based study, including all participants with information on gender identity and sexual orientation. We used baseline questionnaires to identify sexual minority (lesbian, gay, bisexual, diverse sexual orientation; nonstraight sexual orientation) and gender minority (gender diverse and transgender; gender identity different from sex assigned at birth) participants. The primary outcome was a composite of stroke, dementia, and late-life depression, assessed using electronic health record data and self-report. Secondarily, we evaluated each disease separately. Furthermore, we evaluated all subgroups of gender and sexual minorities stratified by sex assigned at birth. We used multivariable logistic regression (adjusted for age, sex assigned at birth, race/ethnicity, cardiovascular risk factors, other relevant comorbidities, and neighborhood deprivation index) to assess the relationship between SGM groups and the outcomes. RESULTS: Of 413,457 US adults enrolled between May 31, 2017, and June 30, 2022, we included 393,041 participants with available information on sexual orientation and gender identity (mean age 51 [SD 17] years), of whom 39,632 (10%) belonged to SGM groups. Of them, 38,528 (97%) belonged to a sexual minority and 4,431 (11%) to a gender minority. Compared with non-SGM, SGM persons had 15% higher odds of the brain health composite outcome (odds ratio [OR] 1.15, 95% CI 1.08-1.22). In secondary analyses, these results persisted across sexual and gender minorities separately (all 95% CIs > 1). Assessing individual diseases, all SGM groups had higher odds of dementia (SGM vs non-SGM: OR 1.14, 95% CI 1.00-1.29) and late-life depression (SGM vs non-SGM: OR 1.27, 95% CI 1.17-1.38) and transgender women had higher odds of stroke (OR 1.68, 95% CI 1.04-2.70). DISCUSSION: In a large US population study, SGM persons had higher odds of adverse brain health outcomes. Further research should explore structural causes of inequity to advance inclusive and diverse neurologic care.

White matter hyperintensity on MRI and plasma Aß42/40 ratio additively increase the risk of cognitive impairment in hypertensive adults.

INTRODUCTION: Dementia often involves comorbid Alzheimer's and vascular pathology, but their combined impact warrants additional study. METHODS: We analyzed the Systolic Blood Pressure Intervention Trial and categorized white matter hyperintensity (WMH) volume into highest versus lowest/mid tertile and the amyloid beta (Aß)42/40 ratio into lowest versus mid/highest ratio tertile. Using these binary variables, we created four exposure categories: (1) combined low risk, (2) Aß risk, (3) WMH risk, and (4) combined high risk. RESULTS: In the cohort of 467 participants (mean age 69.7 ± 7.1, 41.8% female, 31.9% nonwhite or Hispanic) during 4.8 years of follow-up and across the four exposure categories the rates of cognitive impairment were 5.3%, 7.8%, 11.8%, and 22.6%. Compared to the combined low-risk category, the adjusted hazard ratio for cognitive impairment was 4.12 (95% confidence interval, 1.71 to 9.94) in the combined high-risk category. DISCUSSION: This study emphasizes the potential impact of therapeutic approaches to dementia prevention that target both vascular and amyloid pathology. HIGHLIGHTS: White matter hyperintensity (WMH) and plasma amyloid (Aß42/40) are additive risk factors for the development of cognitive impairment in the SPRINT MIND trial. Individuals in the high-risk categories of both WMH and Aß42/40 had a near fivefold increase in risk of cognitive impairment during 4.8 years of follow-up on average. These findings suggest that treatment strategies targeting both vascular health and amyloid burden warrant further research.

Genetics of posttraumatic stress disorder and cardiovascular conditions using Life's Essential 8, Electronic Health Records, and Heart Imaging.

BACKGROUND: Patients with post-traumatic stress disorder (PTSD) experience higher risk of adverse cardiovascular (CV) outcomes. This study explores shared loci, and genes between PTSD and CV conditions from three major domains: CV diagnoses from electronic health records (CV-EHR), cardiac and aortic imaging, and CV health behaviors defined in Life's Essential 8 (LE8). METHODS: We used genome-wide association study (GWAS) of PTSD (N=1,222,882), 246 CV diagnoses based on EHR data from Million Veteran Program (MVP; N=458,061), UK Biobank (UKBB; N=420,531), 82 cardiac and aortic imaging traits (N=26,893), and GWAS of traits defined in the LE8 (N = 282,271 ~ 1,320,016). Shared loci between PTSD and CV conditions were identified using local genetic correlations (rg), and colocalization (shared causal variants). Overlapping genes between PTSD and CV conditions were identified from genetically regulated proteome expression in brain and blood tissues, and subsequently tested to identify functional pathways and gene-drug targets. Epidemiological replication of EHR-CV diagnoses was performed in AllofUS cohort (AoU; N=249,906). RESULTS: Among the 76 PTSD-susceptibility risk loci, 33 loci exhibited local rg with 45 CV-EHR traits (|rg|≥0.4), four loci with eight heart imaging traits(|rg|≥0.5), and 44 loci with LE8 factors (|rg|≥0.36) in MVP. Among significantly correlated loci, we found shared causal variants (colocalization probability > 80%) between PTSD and 17 CV-EHR (in MVP) at 11 loci in MVP, that also replicated in UKBB and/or other cohorts. Of the 17 traits, the observational analysis in the AoU showed PTSD was associated with 13 CV-EHR traits after accounting for socioeconomic factors and depression diagnosis. PTSD colocalized with eight heart imaging traits on 2 loci and with LE8 factors on 31 loci. Leveraging blood and brain proteome expression, we found 33 and 122 genes, respectively, shared between PTSD and CVD. Blood proteome genes were related to neuronal and immune processes, while the brain proteome genes converged on metabolic and calcium-modulating pathways (FDR p <0.05). Drug repurposing analysis highlighted DRD2, NOS1, GFAP, and POR as common targets of psychiatric and CV drugs. CONCLUSION: PTSD-CV comorbidities exhibit shared risk loci, and genes involved in tissue-specific regulatory mechanisms.

The predictive validity of a Brain Care Score for late-life depression and a composite outcome of dementia, stroke, and late-life depression: data from the UK Biobank cohort.

Introduction: The 21-point Brain Care Score (BCS) is a novel tool designed to motivate individuals and care providers to take action to reduce the risk of stroke and dementia by encouraging lifestyle changes. Given that late-life depression is increasingly recognized to share risk factors with stroke and dementia, and is an important clinical endpoint for brain health, we tested the hypothesis that a higher BCS is associated with a reduced incidence of future depression. Additionally, we examined its association with a brain health composite outcome comprising stroke, dementia, and late-life depression. Methods: The BCS was derived from the United Kingdom Biobank baseline evaluation in participants with complete data on BCS items. Associations of BCS with the risk of subsequent incident late-life depression and the composite brain health outcome were estimated using multivariable Cox proportional hazard models. These models were adjusted for age at baseline and sex assigned at birth. Results: A total of 363,323 participants were included in this analysis, with a median BCS at baseline of 12 (IQR: 11-14). There were 6,628 incident cases of late-life depression during a median follow-up period of 13 years. Each five-point increase in baseline BCS was associated with a 33% lower risk of incident late-life depression (95% CI: 29%-36%) and a 27% lower risk of the incident composite outcome (95% CI: 24%-30%). Discussion: These data further demonstrate the shared risk factors across depression, dementia, and stroke. The findings suggest that a higher BCS, indicative of healthier lifestyle choices, is significantly associated with a lower incidence of late-life depression and a composite brain health outcome. Additional validation of the BCS is warranted to assess the weighting of its components, its motivational aspects, and its acceptability and adaptability in routine clinical care worldwide.

Deep learning for prediction of post-thrombectomy outcomes based on admission CT angiography in large vessel occlusion stroke.

Purpose: Computed Tomography Angiography (CTA) is the first line of imaging in the diagnosis of Large Vessel Occlusion (LVO) strokes. We trained and independently validated end-to-end automated deep learning pipelines to predict 3-month outcomes after anterior circulation LVO thrombectomy based on admission CTAs. Methods: We split a dataset of 591 patients into training/cross-validation (n = 496) and independent test set (n = 95). We trained separate models for outcome prediction based on admission "CTA" images alone, "CTA + Treatment" (including time to thrombectomy and reperfusion success information), and "CTA + Treatment + Clinical" (including admission age, sex, and NIH stroke scale). A binary (favorable) outcome was defined based on a 3-month modified Rankin Scale ≤ 2. The model was trained on our dataset based on the pre-trained ResNet-50 3D Convolutional Neural Network ("MedicalNet") and included CTA preprocessing steps. Results: We generated an ensemble model from the 5-fold cross-validation, and tested it in the independent test cohort, with receiver operating characteristic area under the curve (AUC, 95% confidence interval) of 70 (0.59-0.81) for "CTA," 0.79 (0.70-0.89) for "CTA + Treatment," and 0.86 (0.79-0.94) for "CTA + Treatment + Clinical" input models. A "Treatment + Clinical" logistic regression model achieved an AUC of 0.86 (0.79-0.93). Conclusion: Our results show the feasibility of an end-to-end automated model to predict outcomes from admission and post-thrombectomy reperfusion success. Such a model can facilitate prognostication in telehealth transfer and when a thorough neurological exam is not feasible due to language barrier or pre-existing morbidities.

Dual TTK/PLK1 inhibition has potent anticancer activity in TNBC as monotherapy and in combination.

Background: Threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the in vitro and in vivo characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891). Methods: Mechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed in vitro using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC). Results: BAL0891 elicits a prolonged effect on TTK, with a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis with faster kinetics than observed with a TTK-specific inhibitor. Broad anti-proliferative activity was demonstrated across solid tumor cell lines in vitro. Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent. Conclusions: Dual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations.

PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality by disrupting mitochondrial pathways.

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.

Enabling Effective Implementation of Occupational Safety and Health Interventions.

Background: The design, implementation, and evaluation are three important stages of occupational safety and health (OSH) interventions. Historically, there has been a tendency to prioritize implementation, often neglecting detailed design and rigorous outcome evaluation. Currently, much has changed, and contemporary approaches recognize the interdependence of these stages, considering them integral to the success of any intervention. This work presents a comprehensive procedure for implementing interventions, not only to ensure short-term effectiveness but also their long-term sustainability through continuous monitoring. The focus is on a national OSH project introducing a near-miss management system (NMS) in Italy. Methods: Initial meetings were convened among project partners, complemented by interviews with diverse stakeholders, to plan implementation steps and test the NMS. Tailored questionnaires were designed for diverse stakeholder groups - initial promoters, company managers and employers, and employees - facilitating targeted implementation, and three case studies were started in Italian regions to assess the structured implementation, involving intervention promoters and collaborating companies. Results: The primary outcome is the development of practical tools, specifically three questionnaires, which are considered valuable for establishing an effective human-centered implementation strategy, meticulously designed to facilitate ongoing monitoring of processes and continual enhancement of instruments intended for NMS integration within companies. Conclusions: This work lays the foundation for successful NMS implementation in Italy and, although the outlined procedure had specific objectives, it also provides valuable insights applicable in enhancing the effectiveness and sustainability of interventions across diverse contexts. It underscores the importance of comprehensive planning, stakeholder engagement, and continuous evaluation in achieving lasting OSH interventions.

Brain Care Score and Neuroimaging Markers of Brain Health in Asymptomatic Middle-Age Persons.

OBJECTIVES: To investigate associations between health-related behaviors as measured using the Brain Care Score (BCS) and neuroimaging markers of white matter injury. METHODS: This prospective cohort study in the UK Biobank assessed the BCS, a novel tool designed to empower patients to address 12 dementia and stroke risk factors. The BCS ranges from 0 to 21, with higher scores suggesting better brain care. Outcomes included white matter hyperintensities (WMH) volume, fractional anisotropy (FA), and mean diffusivity (MD) obtained during 2 imaging assessments, as well as their progression between assessments, using multivariable linear regression adjusted for age and sex. RESULTS: We included 34,509 participants (average age 55 years, 53% female) with no stroke or dementia history. At first and repeat imaging assessments, every 5-point increase in baseline BCS was linked to significantly lower WMH volumes (25% 95% CI [23%-27%] first, 33% [27%-39%] repeat) and higher FA (18% [16%-20%] first, 22% [15%-28%] repeat), with a decrease in MD (9% [7%-11%] first, 10% [4%-16%] repeat). In addition, a higher baseline BCS was associated with a 10% [3%-17%] reduction in WMH progression and FA decline over time. DISCUSSION: This study extends the impact of the BCS to neuroimaging markers of clinically silent cerebrovascular disease. Our results suggest that improving one's BCS could be a valuable intervention to prevent early brain health decline.

APOE epsilon variants and composite risk of dementia, disability, and death in the health and retirement study.

BACKGROUND: Clinical trials in older adults are increasingly focused on functional outcomes, and the composite outcome of dementia, disability, and death is gaining pivotal importance. Genetic variation, particularly the APOE epsilon(ε) variants, may modify responses to new treatments. Although APOE ε4 is known to influence these outcomes separately, the magnitude of its effect on this composite outcome remains unknown. We tested the hypothesis that APOE ε4 increases, whereas APOE ε2 decreases, the risk of a composite outcome of dementia, disability, and death. METHODS: We evaluated clinical and genomic data from the Health and Retirement Study collected from 1992 to 2020. We used variants rs429358 and rs7412 to determine APOE genotypes, modeled dominantly (carriers/noncarriers). We conducted survival analysis, using multivariable Cox proportional hazards models with a composite endpoint of dementia, disability, and death. Our primary analysis evaluated participants with genetic data and no previous dementia or disability. In secondary analyses, we focused on persons aged > = 75 years without heart disease or stroke, a subpopulation increasingly important in clinical trials of older adults. RESULTS: We included 14,527 participants in the primary analysis. Over a median of 18 (Interquartile Range [IQR] 12-24) years, 6711 (46%) participants developed the composite outcome. In Cox analyses, APOE ε4 associated with higher risk (HR:1.15, 95%CI:1.09-1.22) of the composite outcome, whereas APOE ε2 associated with lower risk (HR:0.92, 95%CI:0.86-0.99). In the secondary analysis, we included 3174 participants. Over a median of 7 (IQR 4-11) years, 1326 participants (42%) developed the composite outcome. In Cox analyses, APOE ε4 associated with higher risk (HR:1.25, 95%CI:1.10-1.41) of the composite outcome, whereas APOE ε2 associated with lower risk (HR:0.84, 95%CI:0.71-0.98). CONCLUSIONS: APOE ε variants are linked to the risk of dementia, disability, and death in older adults. By examining these variants in clinical trials, we can better elucidate how they might alter the effectiveness of tested interventions. Importantly, this genetic information could help identify participants who may have greater absolute benefit from such interventions.

Automated detection of early signs of irreversible ischemic change on CTA source images in patients with large vessel occlusion.

PURPOSE: To create and validate an automated pipeline for detection of early signs of irreversible ischemic change from admission CTA in patients with large vessel occlusion (LVO) stroke. METHODS: We retrospectively included 368 patients for training and 143 for external validation. All patients had anterior circulation LVO stroke, endovascular therapy with successful reperfusion, and follow-up diffusion-weighted imaging (DWI). We devised a pipeline to automatically segment Alberta Stroke Program Early CT Score (ASPECTS) regions and extracted their relative Hounsfield unit (rHU) values. We determined the optimal rHU cut points for prediction of final infarction in each ASPECT region, performed 10-fold cross-validation in the training set, and measured the performance via external validation in patients from another institute. We compared the model with an expert neuroradiologist for prediction of final infarct volume and poor functional outcome. RESULTS: We achieved a mean area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity of 0.69±0.13, 0.69±0.09, 0.61±0.23, and 0.72±0.11 across all regions and folds in cross-validation. In the external validation cohort, we achieved a median [interquartile] AUC, accuracy, sensitivity, and specificity of 0.71 [0.68-0.72], 0.70 [0.68-0.73], 0.55 [0.50-0.63], and 0.74 [0.73-0.77], respectively. The rHU-based ASPECTS showed significant correlation with DWI-based ASPECTS (rS = 0.39, p<0.001) and final infarct volume (rS = -0.36, p<0.001). The AUC for predicting poor functional outcome was 0.66 (95%CI: 0.57-0.75). The predictive capabilities of rHU-based ASPECTS were not significantly different from the neuroradiologist's visual ASPECTS for either final infarct volume or functional outcome. CONCLUSIONS: Our study demonstrates the feasibility of an automated pipeline and predictive model based on relative HU attenuation of ASPECTS regions on baseline CTA and its non-inferior performance in predicting final infarction on post-stroke DWI compared to an expert human reader.

Deep learning survival model predicts outcome after intracerebral hemorrhage from initial CT scan.

BACKGROUND: Predicting functional impairment after intracerebral hemorrhage (ICH) provides valuable information for planning of patient care and rehabilitation strategies. Current prognostic tools are limited in making long term predictions and require multiple expert-defined inputs and interpretation that make their clinical implementation challenging. This study aimed to predict long term functional impairment of ICH patients from admission non-contrast CT scans, leveraging deep learning models in a survival analysis framework. METHODS: We used the admission non-contrast CT scans from 882 patients from the Massachusetts General Hospital ICH Study for training, hyperparameter optimization, and model selection, and 146 patients from the Yale New Haven ICH Study for external validation of a deep learning model predicting functional outcome. Disability (modified Rankin scale [mRS] > 2), severe disability (mRS > 4), and dependent living status were assessed via telephone interviews after 6, 12, and 24 months. The prediction methods were evaluated by the c-index and compared with ICH score and FUNC score. RESULTS: Using non-contrast CT, our deep learning model achieved higher prediction accuracy of post-ICH dependent living, disability, and severe disability by 6, 12, and 24 months (c-index 0.742 [95% CI -0.700 to 0.778], 0.712 [95% CI -0.674 to 0.752], 0.779 [95% CI -0.733 to 0.832] respectively) compared with the ICH score (c-index 0.673 [95% CI -0.662 to 0.688], 0.647 [95% CI -0.637 to 0.661] and 0.697 [95% CI -0.675 to 0.717]) and FUNC score (c-index 0.701 [95% CI- 0.698 to 0.723], 0.668 [95% CI -0.657 to 0.680] and 0.727 [95% CI -0.708 to 0.753]). In the external independent Yale-ICH cohort, similar performance metrics were obtained for disability and severe disability (c-index 0.725 [95% CI -0.673 to 0.781] and 0.747 [95% CI -0.676 to 0.807], respectively). Similar AUC of predicting each outcome at 6 months, 1 and 2 years after ICH was achieved compared with ICH score and FUNC score. CONCLUSION: We developed a generalizable deep learning model to predict onset of dependent living and disability after ICH, which could help to guide treatment decisions, advise relatives in the acute setting, optimize rehabilitation strategies, and anticipate long-term care needs.

Effectiveness of Occupational Safety and Health interventions: a long way to go.

Background: Occupational Safety and Health (OSH) has become an area of increasing concern for organizations and institutions. As it evolves, it has gradually posed ongoing challenges, becoming more complex, for organizations. Consequently, more comprehensive studies are required to advance academic and institutional research. From this perspective, this study aims to gather research contributions on the effectiveness of existing interventions for OSH improvement and identify areas for further exploration. Methods: According to the nature of scientific literature, the overall process of a literature review was investigated following an integrative approach, which involved searching for, selecting, and analyzing various literature in a creative and integrated manner, without a predefined structure. Results: The analysis suggests that there is room for improvement in understanding the effectiveness of OSH interventions and more concrete guidance is still desirable. Based on the literature, some research areas for future developments in OSH interventions are identified. One potential area to explore further is fostering human-centered technological development and a more conscious network of stakeholders, with higher coordination, shared knowledge, and open communication. Implications: Focusing on the proposed directions will support scholars and practitioners in pursuing continuous OSH improvement through more effective and well-grounded workplace interventions and encourage organizations to be proactive in daily OSH management.

Contemporary Prestroke Dual Antiplatelet Use and Symptomatic Intracerebral Hemorrhage Risk After Thrombolysis.

Importance: Intravenous alteplase (IV-tPA) can be administered to patients with acute ischemic stroke but is associated with symptomatic intracerebral hemorrhage (sICH). It is unclear if patients taking prestroke dual antiplatelet therapy (DAPT) are at higher risk of sICH. Objective: To determine the associated risk of sICH in patients taking prestroke dual antiplatelet therapy receiving alteplase for acute ischemic stroke using propensity score matching analysis. Design, Setting, and Participants: This cohort study used data from the American Heart Association and American Stroke Association Get With The Guidelines-Stroke (GWTG-Stroke) registry between 2013 and 2021. Data were obtained from hospitals in the GWTG-Stroke registry. This study included patients hospitalized with acute ischemic stroke and treated with IV-tPA. Data were analyzed from January 2013 to December 2021. Exposures: Prestroke DAPT before treatment with IV-tPA for acute ischemic stroke. Main Outcome Measures: sICH, In-hospital death, discharge modified Rankin scale score, and other life-threatening systemic hemorrhages. Results: Of 409 673 participants, 321 819 patients (mean [SD] age, 68.6 [15.1] years; 164 587 female [51.1%]) who were hospitalized with acute ischemic stroke and treated with IV-tPA were included in the analysis. The rate of sICH was 2.9% (5200 of 182 344), 3.8% (4457 of 117 670), and 4.1% (893 of 21 805) among patients treated with no antiplatelet therapy, single antiplatelet therapy (SAPT), and DAPT, respectively (P < .001). In adjusted analyses after propensity score subclassification, both SAPT (odds ratio [OR], 1.13; 95% CI, 1.07-1.19) and DAPT (OR, 1.28; 95% CI, 1.14-1.42) were associated with increased risks of sICH. Prestroke antiplatelet medications were associated with lower odds of discharge mRS score of 2 or less compared with no medication (SAPT OR, 0.92; 95% CI, 0.90-0.95; DAPT OR, 0.94; 95% CI, 0.88-0.98). Results of a subgroup analysis of patients taking DAPT exposed to aspirin-clopidogrel vs aspirin-ticagrelor combination therapy were not significant (OR, 1.35; 95% CI, 0.84-1.86). Conclusions and Relevance: Prestroke DAPT was associated with a significantly elevated risk of sICH among patients with ischemic stroke who were treated with thrombolysis; however, the absolute increase in risk was small. Patients exposed to antiplatelet medications did not have excess sICH compared with landmark trials, which demonstrated overall clinical benefit of thrombolysis therapy for acute ischemic stroke.

Radiomic Features of Acute Cerebral Hemorrhage on Non-Contrast CT Associated with Patient Survival.

The mortality rate of acute intracerebral hemorrhage (ICH) can reach up to 40%. Although the radiomics of ICH have been linked to hematoma expansion and outcomes, no research to date has explored their correlation with mortality. In this study, we determined the admission non-contrast head CT radiomic correlates of survival in supratentorial ICH, using the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) trial dataset. We extracted 107 original radiomic features from n = 871 admission non-contrast head CT scans. The Cox Proportional Hazards model, Kaplan-Meier Analysis, and logistic regression were used to analyze survival. In our analysis, the "first-order energy" radiomics feature, a metric that quantifies the sum of squared voxel intensities within a region of interest in medical images, emerged as an independent predictor of higher mortality risk (Hazard Ratio of 1.64, p < 0.0001), alongside age, National Institutes of Health Stroke Scale (NIHSS), and baseline International Normalized Ratio (INR). Using a Receiver Operating Characteristic (ROC) analysis, "the first-order energy" was a predictor of mortality at 1-week, 1-month, and 3-month post-ICH (all p < 0.0001), with Area Under the Curves (AUC) of >0.67. Our findings highlight the potential role of admission CT radiomics in predicting ICH survival, specifically, a higher "first-order energy" or very bright hematomas are associated with worse survival outcomes.

Clinical, neuroimaging and genetic findings in Brazilian patients with neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) encompasses a clinically and genetically heterogeneous group of rare disorders. Here, we report clinical, neuroimaging and genetic studies in twenty three Brazilian NBIA patients. In thirteen subjects, deleterious variants were detected in known NBIA-causing genes (PANK2, PLA2G6, C9ORF12, WDR45 and FA2H), including previously unreported variants in PANK2 and PLA2G6. Two patients carried rare, likely pathogenic variants in genes not previously associated with NBIA: KMT2A c.11785A > C (p.Ile3929Leu), and TIMM8A c.127T > C (p.Cys43Arg), suggesting an expansion of their associated phenotypes to include NBIA. In eight patients the etiology remains unsolved, suggesting variants undetectable by the adopted methods, or the existence of additional NBIA-causing genes.