Ninety-Day Stroke Recurrence in Minor Stroke: Systematic Review and Meta-Analysis of Trials and Observational Studies.

BACKGROUND: Risk of recurrence after minor ischemic stroke is usually reported with transient ischemic attack. No previous meta-analysis has focused on minor ischemic stroke alone. The objective was to evaluate the pooled proportion of 90-day stroke recurrence for minor ischemic stroke, defined as a National Institutes of Health Stroke Scale severity score of ≤5. METHODS AND RESULTS: Published papers found on PubMed from 2000 to January 12, 2021, reference lists of relevant articles, and experts in the field were involved in identifying relevant studies. Randomized controlled trials and observational studies describing minor stroke cohort with reported 90-day stroke recurrence were selected by 2 independent reviewers. Altogether 14 of 432 (3.2%) studies met inclusion criteria. Multilevel random-effects meta-analysis was performed. A total of 6 randomized controlled trials and 8 observational studies totaling 45 462 patients were included. The pooled 90-day stroke recurrence was 8.6% (95% CI, 6.5-10.7), reducing by 0.60% (95% CI, 0.09-1.1; P=0.02) with each subsequent year of publication. Recurrence was lowest in dual antiplatelet trial arms (6.3%, 95% CI, 4.5-8.0) when compared with non-dual antiplatelet trial arms (7.2%, 95% CI, 4.7-9.6) and observational studies 10.6% (95% CI, 7.0-14.2). Age, hypertension, diabetes, ischemic heart disease, or known atrial fibrillation had no significant association with outcome. Defining minor stroke with a lower National Institutes of Health Stroke Scale threshold made no difference - score ≤3: 8.6% (95% CI, 6.0-11.1), score ≤4: 8.4% (95% CI, 6.1-10.6), as did excluding studies with n<500%-7.3% (95% CI, 5.5-9.0). CONCLUSIONS: The risk of recurrence after minor ischemic stroke is declining over time but remains important.

Heparanase promotes the onset and progression of atherosclerosis in apolipoprotein E gene knockout mice.

BACKGROUND AND AIMS: Atherosclerosis is the primary underlying cause of myocardial infarction and stroke, which are the major causes of death globally. Heparanase (Hpse) is a pro-inflammatory extracellular matrix degrading enzyme that has been implicated in atherogenesis. However, to date the precise roles of Hpse in atherosclerosis and its mechanisms of action are not well defined. This study aims to provide new insights into the contribution of Hpse in different stages of atherosclerosis in vivo. METHODS: We generated Hpse gene-deficient mice on the atherosclerosis-prone apolipoprotein E gene knockout (ApoE-/-) background to investigate the impact of Hpse gene deficiency on the initiation and progression of atherosclerosis after 6 and 14 weeks high-fat diet feeding, respectively. Atherosclerotic lesion development, blood serum profiles, lesion composition and aortic immune cell populations were evaluated. RESULTS: Hpse-deficient mice exhibited significantly reduced atherosclerotic lesion burden in the aortic sinus and aorta at both time-points, independent of changes in plasma cholesterol levels. A significant reduction in the necrotic core size and an increase in smooth muscle cell content were also observed in advanced atherosclerotic plaques of Hpse-deficient mice. Additionally, Hpse deficiency reduced circulating and aortic levels of VCAM-1 at the initiation and progression stages of disease and circulating MCP-1 levels in the initiation but not progression stage. Moreover, the aortic levels of total leukocytes and dendritic cells in Hpse-deficient ApoE-/- mice were significantly decreased compared to control ApoE-/-mice at both disease stages. CONCLUSIONS: This study identifies Hpse as a key pro-inflammatory enzyme driving the initiation and progression of atherosclerosis and highlighting the potential of Hpse inhibitors as novel anti-inflammatory treatments for cardiovascular disease.

Miliutine C methyl ester, a new drimane sesquiterpene and bioactive alkaloids from the stems of Miliusa velutina.

Previous results from the our research group have isolated numerous compounds, including novel ones, but the anticancer activity of Miliusa velutina has not been demonstrated. In this study, from the most active ethyl acetate extract of the stems of Miliusa velutina, seven compounds were isolated and determined structures, including a new drimane sesquiterpenoid compound named miliutine C methyl ester (1) and three bioactive alkaloids (5-7). These three alkaloids (5-7) exhibited strong anticancer activities against various cancer cell lines such as MCF-7, HepG2, HeLa, NCI H460 and normal fibroblasts. Especially, on MCF-7 and normal fibroblasts with values of IC50 (µM) in order for compounds 5 (3.38, 31.15), 6 (21.96, 102.00), 7 (7.90, greater than 300), to compare with positive control camptothecin (0.020, 4.51); which is highly noteworthy. These results contribute to elucidating and confirming the value of Miliusa velutina, similar to other published and folkloric findings.

Urban-rural inequalities in IV thrombolysis for acute ischemic stroke: A nationwide study.

INTRODUCTION: Rural residency has been associated with lower reperfusion treatment rates for acute ischemic stroke in many countries. We aimed to explore urban-rural differences in IV thrombolysis rates in a small country with universal health care, and short transport times to stroke units. PATIENTS AND METHODS: In this nationwide cohort study, adult ischemic stroke patients registered in the Danish Stroke Registry (DSR) between 2015 and 2020 were included. The exposure was defined by residence rurality. Data from the DSR, Statistics Denmark, and the Danish Health Data Authority, were linked on the individual level using the Civil Registration Number. Adjusted treatment rates were calculated by balancing baseline characteristics using inverse probability of treatment weights. RESULTS: Among the included 56,175 patients, prehospital delays were shortest for patients residing in capital municipalities (median 4.7 h), and longest for large town residents (median 7.1 h). Large town residents were predominantly admitted directly to a comprehensive stroke center (98.5%), whereas 30.9% of capital residents were admitted to a hospital with no reperfusion therapy available (non-RT unit). Treatment rates were similar among all non-rural residents (18.5%-18.7%), but slightly lower among rural residents (17.2% [95% CI 16.5-17.8]). After adjusting for age, sex, immigrant status, and educational attainment, rural residents reached treatment rates comparable to capital and large town residents at 18.5% (95% CI 17.7-19.4). DISCUSSION AND CONCLUSION: While treatment rates varied minimally by urban-rural residency, substantial differences in median prehospital delay and admission to non-RT units underscored marked urban-rural differences in potential obstacles to reperfusion therapies.

Introducing the Concept of Sanctuary Sites in Ischemic Stroke.

BACKGROUND: The topography of arterial territories has been defined using digital maps of supratentorial infarcts. Regions with a high probability of infarction (Pi) exist in the deep compartment due to a paucity of collaterals. However, less attention has been given to regions with a low Pi. METHODS: Using published digital maps, patients with cortical stroke and documented vessel occlusion were included. Infarcts from T2-weighted magnetic resonance images were segmented and registered onto a standard brain template (Montreal Neurological Institute 152). Segmented magnetic resonance images were averaged to yield the Pi at a voxel level. The overall Pi for the combined arterial territories was calculated to ensure that Pi was in the range of 0 to 1. Sanctuary sites were identified as regions with Pi <0.1. RESULTS: There were 154 patients (63% men; median age, 69 years; and interquartile range, 57-78 years). The magnetic resonance imaging scan used for segmentation was performed at a median interval of 35 (interquartile range, 3-66) days after stroke onset. Sanctuary sites were present in the frontal (gyrus rectus, the paracentral lobule, and orbitofrontal and precentral gyrus), parietal (postcentral, supramarginal, and angular gyrus, superior and inferior parietal lobule, and precuneus and posterior cingulate), and occipital cortex (cuneus, middle, and superior occipital gyrus). CONCLUSIONS: We propose that following vessel occlusion, there are cortical regions with a low Pi, which we termed sanctuary sites. The anatomic basis for this observation is the compensatory capacity of leptomeningeal collaterals.

Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Prevalence of primary aldosteronism in acute stroke or transient ischemic attack: a systematic review and meta-analysis.

Background and purpose: Primary aldosteronism (PA) is the most common endocrine cause of secondary hypertension with a prevalence of 14% in patients with newly diagnosed hypertension. Patients with PA experience a higher rate of cardiovascular events including stroke when compared to those with blood pressure matched essential hypertension. This systematic review and meta-analysis summarize current evidence on the prevalence of PA in patients with acute stroke or transient ischemic attack (TIA). Methods: Two reviewers independently reviewed the literature for observational studies on the prevalence of PA in patients with acute stroke or TIA. MEDLINE and Embase were searched for studies up to December 13, 2023. Results: Three single center studies conducted in Japan, Singapore and China were found to meet the inclusion criteria. The reported prevalence of PA in two cohort studies of adults with stroke or TIA were 3.1% and 4.0% and a third cross-sectional study in adults under 45 years old revealed a prevalence rate of 12.9%. Following a meta-analysis, the pooled prevalence of PA in adults with stroke or TIA is 5.8% [95% CI 1.6%-12.3%]. Conclusions: A considerable proportion of patients with stroke or TIA may have PA as the underlying cause of their hypertension. Given the increased risk of stroke associated with PA, clinicians should consider screening for PA in hypertensive patients with stroke or TIA. Further research is needed to evaluate the effect of timing and interfering medications on test results, which will inform an evidence-based approach to testing for PA following TIA or stroke. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022328644.

Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.

Enhanced photoelectrochemical performance of quantum dot-sensitized solar cell using Cu2+ co-doped CdS and CdSe nanoscrystals.

Today, nanoscrystals are researched and developed very quickly because of their advantages in many areas of life. One of the potential applications is quantum dot-sensitized solar cells. This is a green, clean, environmentally friendly cell, and has been studied by scientists since 2000. In this study, we fabricated photoanodes with Cu2+ ions co-doped into cadmium sulfide (CdS) and cadmium selenide (CdSe) nanoscrystals by successive ionic layer adsorption and reaction, and chemical bath deposition methods to improve absorption spectral intensity of films. The results showed that the absorption intensity increased by eight times compared with our previous results on Cu2+ ions doped with CdSe nanoscrystals. The CdS:Cu2+ film is optimized at 2% doping, the efficiency is 4.6819%, and the current density is 27.3501 mA.cm-2, which is higher when compared with the Cu2+ ion only doped into the CdSe quantum dot (19.915 mA.cm-2). In addition, the composition of the photoanode was determined by surface and cross-sectional field-emission scanning electron microscope images, and the structure of the film was determined by X-ray diffraction, energy-dispersive X-ray spectroscopy mapping and X-ray photoelectron spectroscopy. Finally, the film's optical properties were studied by ultraviolet-visible spectroscopy, photoluminescence spectroscopy and electrochemical properties by electrochemical impedance spectroscopy. The results obtained have been discussed and presented in great detail.

Third harmonic generation due to free carrier in InSb using a terahertz free electron laser.

We report on the third harmonic generation (THG) in InSb semiconductor irradiated by a terahertz (THz) free electron laser (FEL). The conversion of 4 THz (wavelength 70 µm) FEL outputs into its third harmonic 12 THz was observed. We found that by tuning the sample temperature to 360 K, high conversion efficiency up to 1% can be obtained and is the highest in the THz and FIR regions below 10 THz. We also discuss the observed intensity dependence of the THG with the nonlinear order lower than 3 when the pumping intensity was high.

Cost-effectiveness of an individualised management program after stroke: a trial-based economic evaluation.

INTRODUCTION: Evidence on the cost-effectiveness of comprehensive post-stroke programs is limited. We assessed the cost-effectiveness of an individualised management program (IMP) for stroke or transient ischaemic attack (TIA). METHODS: A cost-utility analysis alongside a randomised controlled trial with a 2-year follow-up, from both societal and health system perspectives, was conducted. Adults with stroke/TIA discharged from hospitals were randomised by primary care practice to receive either usual care (UC) or an IMP in addition to UC. An IMP included at-home stroke-specific nurse-led education and a specialist review of care plans at baseline, 3, and 12 months, and telephone reviews by nurses at 6 and 18 months. Costs in 2021 Australian dollars (AUD) and quality-adjusted life years (QALYs) were discounted by 5%. The probability of cost-effectiveness of the intervention was determined by quantifying 10,000 bootstrapped iterations of incremental costs and QALYs below the threshold of AUD50,000/QALY. RESULTS: Among the 502 participants (65% male, median age 69 years), 251 (50%) were in the intervention group. From a health system perspective, the incremental cost per QALY gained was AUD53,175 with an IMP compared to UC alone. At a willingness-to-pay threshold of AUD50,000/QALY, an IMP was preferred in 46.7% of iterations. From a societal perspective, the intervention was dominant in 52.7% of iterations with mean per-patient costs of AUD49,045 and 1.352 QALYs compared to mean per-patient costs of AUD51,394 and 1.324 QALYs in the UC group. The probability of cost-effectiveness of an IMP, from a societal perspective, was 60.5%. CONCLUSIONS: Care for people with stroke/TIA using an IMP was cost-effective from a societal perspective over two years. Economic evaluations of prevention programs need sufficient time horizons and consideration of costs beyond direct health care utilisation to demonstrate their value to society.

Artificial Intelligence Assistive Software Tool for Automated Detection and Quantification of Amyloid-Related Imaging Abnormalities.

Importance: Amyloid-related imaging abnormalities (ARIA) are brain magnetic resonance imaging (MRI) findings associated with the use of amyloid-ß-directed monoclonal antibody therapies in Alzheimer disease (AD). ARIA monitoring is important to inform treatment dosing decisions and might be improved through assistive software. Objective: To assess the clinical performance of an artificial intelligence (AI)-based software tool for assisting radiological interpretation of brain MRI scans in patients monitored for ARIA. Design, Setting, and Participants: This diagnostic study used a multiple-reader multiple-case design to evaluate the diagnostic performance of radiologists assisted by the software vs unassisted. The study enrolled 16 US Board of Radiology-certified radiologists to perform radiological reading with (assisted) and without the software (unassisted). The study encompassed 199 retrospective cases, where each case consisted of a predosing baseline and a postdosing follow-up MRI of patients from aducanumab clinical trials PRIME, EMERGE, and ENGAGE. Statistical analysis was performed from April to July 2023. Exposures: Use of icobrain aria, an AI-based assistive software for ARIA detection and quantification. Main Outcomes and Measures: Coprimary end points were the difference in diagnostic accuracy between assisted and unassisted detection of ARIA-E (edema and/or sulcal effusion) and ARIA-H (microhemorrhage and/or superficial siderosis) independently, assessed with the area under the receiver operating characteristic curve (AUC). Results: Among the 199 participants included in this study of radiological reading performance, mean (SD) age was 70.4 (7.2) years; 105 (52.8%) were female; 23 (11.6%) were Asian, 1 (0.5%) was Black, 157 (78.9%) were White, and 18 (9.0%) were other or unreported race and ethnicity. Among the 16 radiological readers included, 2 were specialized neuroradiologists (12.5%), 11 were male individuals (68.8%), 7 were individuals working in academic hospitals (43.8%), and they had a mean (SD) of 9.5 (5.1) years of experience. Radiologists assisted by the software were significantly superior in detecting ARIA than unassisted radiologists, with a mean assisted AUC of 0.87 (95% CI, 0.84-0.91) for ARIA-E detection (AUC improvement of 0.05 [95% CI, 0.02-0.08]; P = .001]) and 0.83 (95% CI, 0.78-0.87) for ARIA-H detection (AUC improvement of 0.04 [95% CI, 0.02-0.07]; P = .001). Sensitivity was significantly higher in assisted reading compared with unassisted reading (87% vs 71% for ARIA-E detection; 79% vs 69% for ARIA-H detection), while specificity remained above 80% for the detection of both ARIA types. Conclusions and Relevance: This diagnostic study found that radiological reading performance for ARIA detection and diagnosis was significantly better when using the AI-based assistive software. Hence, the software has the potential to be a clinically important tool to improve safety monitoring and management of patients with AD treated with amyloid-ß-directed monoclonal antibody therapies.

Asymptomatic coronary artery disease in ischaemic stroke survivors: A systematic review and meta-analysis.

BACKGROUND: Ischaemic stroke and coronary artery disease share risk factors and stroke survivors experience a high rate of cardiac events. Recent work suggests a high burden of asymptomatic coronary artery disease (CAD) in ischaemic stroke survivors. Thus, we performed this systematic review and meta-analysis to A) estimate the prevalence of CAD in ischaemic stroke survivors without known CAD and B) evaluate the association between coronary atherosclerosis and future major adverse cardiovascular events (MACE) in stroke survivors. PATIENTS AND METHODS: We conducted a systematic review and meta-analysis according to the PRISMA statement. We included studies investigating acute ischaemic stroke or transient ischaemic attack where participants underwent anatomical assessment of all coronary arteries. For objective B) we included studies that reported an association between coronary atherosclerosis and MACE. Two reviewers used the Newcastle-Ottawa Scale to assess risk of bias. We used random-effects modelling for our analyses. RESULTS: We identified 2983 studies of which 17 were included. These studies had a total of 6862 participants between 2008 and 2022. The pooled prevalence of any coronary atherosclerosis was 66.8% (95% CI 57.2%-75.1%) with substantial heterogeneity (I2 = 95.2%). The pooled prevalence of obstructive (>50%) stenosis was 29.3% with substantial heterogeneity (I2 = 91%). High-risk coronary anatomy (triple vessel disease or left main stenosis) was found in 7.0% (95% CI 4%-12%) with high heterogeneity I2 = 72%. One study examined high-risk plaques and found a prevalence of 5.9%. Five studies reported the association of coronary atherosclerosis with future MACE. The presence of obstructive CAD confers a HR of 8.0 (95% CI 1.7-37.1, p = 0.007) for future MACE. DISCUSSION AND CONCLUSIONS: Asymptomatic CAD is common in ischaemic stroke survivors. The presence and severity of asymptomatic CAD strongly associates with the risk of future MACE. Further evaluation of the benefits of routine coronary assessment in ischaemic stroke is warranted.

Estimating the cost of visiting hospital outpatient.

Objectives: This study aims to investigate the cost incurred by people travelling to the neurology outpatient clinic of a large metropolitan hospital. As outpatients are a substantial portion of a hospital's demographic, we aimed to understand the patient experience of various commuters. Methods: We conducted an observational study collecting demographic details and travel information for how people attended the neurology clinic of Monash Medical Centre. Statistical analysis was performed using R. 165 participants were randomly selected and interviewed in-person. Data were collected via an anonymous questionnaire. The study was approved by the Monash Health Human Ethics Research Committee. Results: 155 responses were included in the analysis. Patients paid an average of $A16.64 to travel to Monash Medical Centre. Drivers paid on average $A16.70 and those taking public transport paid on average $A9.64, with the maximum cost overall being $A120.00. For patients driving to hospital, parking accounted for 60% of their travel costs. The average to Monash Medical centre was 20.82 km with the maximum being 190.88 km. Distance from hospital was correlated with a higher cost of travel (p<0.001, Spearman's rank correlation coefficient=0.48). There was also an inverse association between distance from hospital and socioeconomic status (p<0.001, Spearman's rank correlation coefficient=-0.26). Conclusion: Travelling to hospital can be a costly endeavour. Driving is the most popular form of transport, but a large portion of the cost involved is hospital parking. Further research should be conducted at other tertiary centres with larger samples.

LAMA: Lesion-Aware Mixup Augmentation for Skin Lesion Segmentation.

Deep learning can exceed dermatologists' diagnostic accuracy in experimental image environments. However, inaccurate segmentation of images with multiple skin lesions can be seen with current methods. Thus, information present in multiple-lesion images, available to specialists, is not retrievable by machine learning. While skin lesion images generally capture a single lesion, there may be cases in which a patient's skin variation may be identified as skin lesions, leading to multiple false positive segmentations in a single image. Conversely, image segmentation methods may find only one region and may not capture multiple lesions in an image. To remedy these problems, we propose a novel and effective data augmentation technique for skin lesion segmentation in dermoscopic images with multiple lesions. The lesion-aware mixup augmentation (LAMA) method generates a synthetic multi-lesion image by mixing two or more lesion images from the training set. We used the publicly available International Skin Imaging Collaboration (ISIC) 2017 Challenge skin lesion segmentation dataset to train the deep neural network with the proposed LAMA method. As none of the previous skin lesion datasets (including ISIC 2017) has considered multiple lesions per image, we created a new multi-lesion (MuLe) segmentation dataset utilizing publicly available ISIC 2020 skin lesion images with multiple lesions per image. MuLe was used as a test set to evaluate the effectiveness of the proposed method. Our test results show that the proposed method improved the Jaccard score 8.3% from 0.687 to 0.744 and the Dice score 5% from 0.7923 to 0.8321 over a baseline model on MuLe test images. On the single-lesion ISIC 2017 test images, LAMA improved the baseline model's segmentation performance by 0.08%, raising the Jaccard score from 0.7947 to 0.8013 and the Dice score 0.6% from 0.8714 to 0.8766. The experimental results showed that LAMA improved the segmentation accuracy on both single-lesion and multi-lesion dermoscopic images. The proposed LAMA technique warrants further study.

I don't feel sick: Cognitive and affective processing of self-health associations using the Implicit Association Test.

Measuring implicit associations of self-concept with health or illness attributes may offer valuable insight into the mechanisms entailing the perception of one's own health, as explicit measures of self-reported health are usually influenced by social desirability or response bias. In this study, healthy participants performed a modified version of the implicit association test (IAT) investigating implicit associations between the self and either health or illness related representations. Behaviorally, implicit associations dominated for self-health pairing, and their strength was inversely correlated with depressive traits. Neurally, concomitant EEG recording showed significant modulations of the P1, LPP, and N4 components evoked by such pairings, suggesting a facilitation of sensory responses to self-related stimuli and differential emotional processes engaged to integrate health versus illness information into self-related representations. These data offer new clues to better understand the cognitive and affective mechanisms underlying unrealistic optimism and pathological awareness of health conditions in various clinical populations.

The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity.

Discovery of new small molecules that can activate distinct programmed cell death pathway is of significant interest as a research tool and for the development of novel therapeutics for pathological conditions such as cancer and infectious diseases. The small molecule raptinal was discovered as a pro-apoptotic compound that can rapidly trigger apoptosis by promoting the release of cytochrome c from the mitochondria and subsequently activating the intrinsic apoptotic pathway. As raptinal is very effective at inducing apoptosis in a variety of different cell types in vitro and in vivo, it has been used in many studies investigating cell death as well as the clearance of dying cells. While examining raptinal as an apoptosis inducer, we unexpectedly identified that in addition to its pro-apoptotic activities, raptinal can also inhibit the activity of caspase-activated Pannexin 1 (PANX1), a ubiquitously expressed transmembrane channel that regulates many cell death-associated processes. By implementing numerous biochemical, cell biological and electrophysiological approaches, we discovered that raptinal can simultaneously induce apoptosis and inhibit PANX1 activity. Surprisingly, raptinal was found to inhibit cleavage-activated PANX1 via a mechanism distinct to other well-described PANX1 inhibitors such as carbenoxolone and trovafloxacin. Furthermore, raptinal also interfered with PANX1-regulated apoptotic processes including the release of the 'find-me' signal ATP, the formation of apoptotic cell-derived extracellular vesicles, as well as NLRP3 inflammasome activation. Taken together, these data identify raptinal as the first compound that can simultaneously induce apoptosis and inhibit PANX1 channels. This has broad implications for the use of raptinal in cell death studies as well as in the development new PANX1 inhibitors.

Rapid outpatient transient ischemic attack clinic and stroke service activity during the SARS-CoV-2 pandemic: a multicenter time series analysis.

Background and aim: Rapid outpatient evaluation and treatment of TIA in structured clinics have been shown to reduce stroke recurrence. It is unclear whether short-term downtrends in TIA incidence and admissions have had enduring impact on TIA clinic activity. This study aims to measure the impact of the pandemic on hospitals with rapid TIA clinics. Methods: Relevant services were identified by literature search and contacted. Three years of monthly data were requested - a baseline pre-COVID period (April 2018 to March 2020) and an intra-COVID period (April 2020 to March 2021). TIA presentations, ischemic stroke presentations, and reperfusion trends inclusive of IV thrombolysis (IVT) and endovascular thrombectomy (EVT) were recorded. Pandemic impact was measured with interrupted time series analysis, a segmented regression approach to test an effect of an intervention on a time-dependent outcome using a defined impact model. Results: Six centers provided data for a total of 6,231 TIA and 13,191 ischemic stroke presentations from Australia (52.1%), Canada (35.0%), Italy (7.6%), and England (5.4%). TIA clinic volumes remained constant during the pandemic (2.9, 95% CI -1.8 to 7.6, p = 0.24), as did ischemic stroke (2.9, 95% CI -7.8 to 1.9, p = 0.25), IVT (-14.3, 95% CI -36.7, 6.1, p < 0.01), and EVT (0, 95% CI -16.9 to 16.9, p = 0.98) counts. Proportion of ischemic strokes requiring IVT decreased from 13.2 to 11.4% (p < 0.05), but those requiring EVT did not change (16.0 to 16.7%, p = 0.33). Conclusion: This suggests that the pandemic has not had an enduring effect on TIA clinic or stroke service activity for these centers. Furthermore, the disproportionate decrease in IVT suggests that patients may be presenting outside the IVT window during the pandemic - delays in seeking treatment in this group could be the target for public health intervention.

Clinical Associations and Prognostic Value of MRI-Visible Perivascular Spaces in Patients With Ischemic Stroke or TIA: A Pooled Analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Type 2 Diabetes and Biomarkers of Brain Structure, Perfusion, Metabolism, and Function in Late Mid-Life: A Multimodal Discordant Twin Study.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of dementia and early features may become evident even in mid-life. Characterizing these early features comprehensively requires multiple measurement modalities and careful selection of participants with and without T2D. OBJECTIVE: We conducted a cross-sectional multimodal imaging study of T2D-discordant twins in late mid-life to provide insights into underlying mechanisms. METHODS: Measurements included computerized cognitive battery, brain MRI (including arterial spin labelling, diffusion tensor, resting state functional), fluorodeoxyglucose (FDG)-PET, and retinal optical coherence tomography. RESULTS: There were 23 pairs, mean age 63.7 (±6.1) years. In global analyses, T2D was associated with poorer attention (ß= -0.45, p <0.001) and with reduced FDG uptake (ß= -5.04, p = 0.02), but not with cortical thickness (p = 0.71), total brain volume (p = 0.51), fractional anisotropy (p = 0.15), mean diffusivity (p = 0.34), or resting state activity (p = 0.4). Higher FDG uptake was associated with better attention (ß= 3.19, p = 0.01) but not with other cognitive domains. In regional analyses, T2D was associated with lower accumbens volume (ß= -44, p = 0.0004) which was in turn associated with poorer attention. CONCLUSION: T2D-related brain dysfunction in mid-life manifests as attentional loss accompanied by evidence of subtle neurodegeneration and global reduction in cerebral metabolism, in the absence of overt cerebrovascular disease.