Objectives Since low insulin-like growth factor (IGF) 1 is often linked to inflammation, we analyze whether serum levels of IGF1 are associated with cardiovascular disease (CVD) in rheumatoid arthritis (RA) in a longitudinal observational study. Methods A CVD risk was estimated (eCVR) in 184 female RA patients (mean age 52 years) and in 132 female patients after ischemic stroke (mean age 56 years) with no rheumatic disease, using the Framingham algorithm. The median level of IGF1 divided the cohorts in IGF1 high and IGF1 low groups. A 5-year prospective follow-up for new CVD events was completed in all RA patients. The Mantel-Cox analysis and event-free survival curves were prepared. Unsupervised clustering of proteins within the IGF1 signaling pathway was employed to identify their association with eCVR. Results Low IGF1 resulted in a higher eCVR in RA patients (7.2% and 3.3%, p = 0.0063) and in stroke (9.3% and 7.1%, p = 0.033). RA had higher rate for new CVD events at prospective follow-up (OR 4.96, p = 0.028). Hypertension was the major risk factor associated with low IGF1 in RA and stroke. In hypertension, IGF1 was no longer responsible for intracellular activation and lost its correlation to IRS1/2 adaptor proteins. The clustering analysis confirmed that combination of low IGF1 and IRS1/2 with high IL6, insulin, and glucose predisposed to high eCVR and emphasized the functional role of serum IGF1. Conclusions Low serum IGF1 precedes and predicts development of early CVD events in female RA patients. Hypertension and aberrant IGF1 receptor signaling are highlighted as the important contributors to IGF1-related CVD events.

Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was affected by lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischemic patients (age: 64.7[15.0], 39% women) originating from the multi-center MRI-GENIE study to model unfavorable outcomes (modified Rankin Scale > 2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men (mean difference of Bayesian posterior distributions (men-women)=-0.295 (90%-highest posterior density interval=-0.556 to -0.068)). Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.

Aims This study aims to estimate the cost-effectiveness of percutaneous left atrial appendage occlusion (LAAO) compared to standard stroke prevention care for patients with atrial fibrillation (AF) and contraindication to oral anticoagulation (OAC) in a Swedish healthcare and public sector perspective. Methods and results We used a combined decision tree and cohort Markov model to estimate costs and quality-adjusted life-years (QALYs) over a lifetime horizon with LAAO compared to standard of care where the treatment effect is based on a recent meta-analysis. According to our analysis, LAAO gives more QALYs than standard of care (7.11 vs. 6.12). Furthermore, LAAO treatment is related to the first-year cost of 14 984 Euro (EUR) and higher average healthcare costs over the lifetime by about 4010 EUR, which gives an incremental cost-effectiveness ratio of LAAO vs. standard of care at 4047 EUR per gained QALY. From a public sector perspective, LAAO reduces average costs due to substantial reductions in long-term care and, thus, implies that LAAO is dominant from a public sector perspective (lower average costs and better health outcomes). Conclusion From both Swedish healthcare and public sector perspectives, LAAO can be considered cost-effective compared to standard of care for individuals with AF and contraindication to OAC. However, these results must be confirmed in health economic evaluations alongside the ongoing randomized clinical trials. Key Question Is left atrial appendage occlusion (LAAO) cost-effective for patients with atrial fibrillation (AF) and contraindication to oral anticoagulation (OAC) compared to the standard of care from a Swedish healthcare and public sector perspective? Key Finding LAAO is associated with lower cost than the standard of care from a public sector perspective and an incremental cost of 4010 Euro from a healthcare perspective. Furthermore, LAAO is related to better health outcomes than the standard of care. Take Home Message Treatment with LAAO among individuals with AF and contraindication to OAC can be considered as cost-effective compared to the standard of care from a Swedish healthcare and public sector perspective.

Background: Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). Remarkably, cases of cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) have rarely been reported from LMICs. Aims: We studied the frequency, manifestations, treatment, and outcomes of CVST-VITT in LMICs. Methods: We report data from an international registry on CVST after COVID-19 vaccination. VITT was classified according to the Pavord criteria. We compared CVST-VITT cases from LMICs to cases from high-income countries (HICs). Results: Until August 2022, 228 CVST cases were reported, of which 63 from LMICs (all middle-income countries [MICs]: Brazil, China, India, Iran, Mexico, Pakistan, Turkey). Of these, 32/63 (51%) met the VITT criteria, compared to 103/165 (62%) from HICs. Only 5/32 (16%) CVST-VITT cases from MICs had definite VITT, mostly because anti-PF4 antibodies were often not tested. Median age was 26 (IQR 20-37) vs 47 (IQR 32-58) years, and proportion of women was 25/32 (78%) vs 77/103 (75%) in MICs vs HICs, respectively. Patients from MICs were diagnosed later than patients from HICs (1/32 [3%] vs 65/103 [63%] diagnosed before May 2021). Clinical manifestations, including intracranial hemorrhage, were largely similar as was intravenous immunoglobulin use. In-hospital mortality was lower in MICs (7/31 [23%, 95%CI 11-40]) than HICs (44/102 [43%, 95%CI 34-53], p=0.039). Conclusions: The number of CVST-VITT cases reported from LMICs was small despite widespread use of adenoviral vaccines. Clinical manifestations and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs.

While chronological age is one of the most influential determinants of post-stroke outcomes, little is known of the impact of neuroimaging-derived biological brain age. We here first examine whether radiomics analysis of the texture of brain T2-FLAIR MRI images can be used to predict brain age in stroke patients. We then assess the clinical determinants of accelerated brain aging and, finally, its impact on post-stroke functional outcomes. Leveraging a multisite cohort of 4,163 ischemic stroke patients, we show that older-appearing patients have more hypertension, diabetes mellitus, prior strokes, and smoking history and are more likely to develop worse post-stroke outcomes than their younger-appearing counterparts. Our results strengthen the importance of preventive medicine for maintaining brain health in stroke patients as they age and suggest a novel methodology to capture previously undescribed prognostic information available on commonly acquired MRI sequences during routine stroke care.

Background The forced transition to emergency remote teaching (ERT) during the COVID-19 pandemic has significantly impacted health professions education worldwide. In Sweden, the need for alternative solutions for the training of junior doctors became urgent, as many of the mandatory onsite courses required for residents to qualify as specialists were canceled. The purpose of this study was to understand course leaders' perceptions and experiences of using digital technologies, such as video conferencing, to teach medical residents (ST) during the pandemic and beyond. Methods A qualitative study using semi-structured interviews was conducted with seven course leaders responsible for residency courses during the first year of the pandemic to capture their perceptions and experiences. The interviews were transcribed verbatim and analyzed using thematic analysis, drawing on the technology affordances and constraints theory (TACT) as a framework to explore pedagogical strategies and new teaching practices emerging from the forced use of digital technologies for remote teaching. Results The data analysis revealed affordances of, as well as constraints to, teaching specialist medical training during the pandemic. The findings show that the use of digital conference technologies for ERT can both enable and inhibit social interactions, the interactive learning environment and the utilization of technological features, depending on the individual course leaders’ goals of using the technology and the situated context of the teaching. Conclusions The study reflects the course leaders' pedagogical response to the pandemic, as remote teaching became the only way to provide residency education. Initially, the sudden shift was perceived as constraining, but over time they found new affordances through the enforced use of digital technology that helped them not only to cope with the transition but also to innovate their pedagogical methods. After a rapid, forced shift from on-site to digital courses, it is crucial to utilize experiences to create better preconditions for digital technology to facilitate learning in the future.

IntroductionComprehensive studies mapping domain-specific trajectories of recovery after stroke and biomarkers reflecting these processes are scarce. We, therefore, initiated an exploratory prospective observational study of stroke cases with repeated evaluation, theFIND Stroke Recovery Study. We aim to capture trajectories of recovery from different impairments, including cognition, in combination with broad profiling of blood and imaging biomarkers of the recovery.Methods and analysisWe recruit individuals with first-ever stroke at the stroke unit at the Sahlgrenska University Hospital, Sweden, to FIND. The inclusion started early 2018 and we aim to enrol minimum 500 patients. Neurological and cognitive impairments across multiple domains are assessed using validated clinical assessment methods, advanced neuroimaging is performed and blood samples for biomarker measuring (protein, RNA and DNA) at inclusion and follow-up visits at 3 months, 6 months, 1 year, 2 years and 5 years poststroke. At baseline and at each follow-up visit, we also register clinical variables known to influence outcomes such as prestroke functioning, stroke severity, acute interventions, rehabilitation, other treatments, socioeconomic status, infections (including COVID-19) and other comorbidities. Recurrent stroke and other major vascular events are identified continuously in national registers.Ethics and disseminationFIND composes a unique stroke cohort with detailed phenotyping, repetitive assessments of outcomes across multiple neurological and cognitive domains and patient-reported outcomes as well as blood and imaging biomarker profiling. Ethical approval for the FIND study has been obtained from the Regional Ethics Review Board in Gothenburg and the Swedish Ethics Review Board. The results of this exploratory study will provide novel data on the time course of recovery and biomarkers after stroke. The description of this protocol will inform the stroke research community of our ongoing study and facilitate comparisons with other data sets.Trial registration numberThe protocol is registered athttp://www.clinicaltrials.gov, Study ID:NCT05708807.

This study aimed to investigate the influence of stroke lesions in pre-defined highly interconnected (rich club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke (AIS) enrolled in the multisite MRI-GENIE study. Structural stroke lesions were spatially normalized and parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS>2) was modeled in a Bayesian logistic regression framework that relied on both lesion location, as well as the covariates: age, sex, total DWI lesion volume and comorbidities. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. Via model comparisons, we first tested whether the rich club region model was superior to a baseline model considering clinical covariates and lesion volume only. In spatial specificity analyses, we randomized the split into rich club and non-rich club regions and compared the effect of the actual rich club regions to the distribution of effects from 1,000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club region effects. A total of 822 patients (age: 64.7 (standard deviation: 15.0), 39% women, 27.7% with mRS>2) were analyzed. The rich club model substantially outperformed the baseline model (weights of model comparison: rich club model: 0.96; baseline: 0.04). Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations (15/1,000 random constellations with higher mean posterior values). Among the these 15 random constellations with higher means, the most frequently selected regions were the inferior temporal gyrus (posterior division, 8/15), the putamen (8/15), the cingulate gyrus (7/15) and the superior parietal lobule (6/15). Rich club regions were substantially more important in explaining long-term outcome in women than in men (mean of the difference distribution:-0.107, 90%-HDPI:-0.193 to -0.0124). Lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific, i.e., the majority of random combinations of six regions had comparably smaller effects on long-term outcome. Effects were substantially more pronounced in women.