Memory B cell responses induced by pneumococcal conjugate vaccine schedules with fewer doses: analysis of a randomised-controlled trial in Viet Nam.

The use of pneumococcal conjugate vaccine (PCV) schedules with fewer doses are being considered to reduce costs and improve access, particularly in low- and middle-income countries. While several studies have assessed their immunogenicity, there are limited data on their potential for long-term immune protection, as assessed by pneumococcal serotype-specific memory B cell (Bmem) responses. This current study reports secondary outcome data that aims to compare Bmem responses following reduced-dose (0 + 1 and 1 + 1) schedules of PCV10 and PCV13 in Vietnamese infants from our randomised-controlled trial (trial registration number NCT03098628). Following vaccination at 12 months of age, Bmem levels for most serotypes peaked seven days post-vaccination and were higher in magnitude for the 1 + 1 than 0 + 1 schedules and for PCV13 than PCV10. Furthermore, Bmem did not wane as rapidly as IgG levels by 24 months of age. Further studies are needed to assess the use of Bmem as markers of long-term protection against pneumococcal carriage and disease, which is crucial to generate data for immunisation program decision-making.

Prevalence and associated factors of bacterial vaginosis among pregnant women in Hue, Vietnam.

INTRODUCTION: Bacterial vaginosis (BV) is the most frequent vaginal infection affecting women of childbearing age worldwide. It is associated with significant adverse healthcare outcomes, especially during pregnancy. Although screening for BV could reduce potential pregnancy-related obstetric complications, there is no routine screening of pregnant women for BV in Vietnam. We aimed to identify the prevalence of BV among pregnant women and the associated factors in two tertiary hospitals in Hue, Vietnam. METHODOLOGY: This cross-sectional descriptive study included 885 pregnant women in third trimester, who received routine antenatal care in the Hue Central Hospital and Hue University Hospital of Medicine and Pharmacy, Hue city, Thua Thien Hue province, Vietnam. Gram-stained vaginal smears were used for calculating the Nugent score and recording the fungal elements. RESULTS: In total, 435 (49.1%) women had a normal BV score, 352 (39.8%) had intermediate vaginal microbiota, and 98 (11.1%) had BV. Among the 98 women with BV, 71 (72.4%) also had fungal infection. There was a significant association of BV with discharge (p = 0.004) and abnormal cervix (p = 0.014). BV was significantly more frequent among the women who reported previous abortion or miscarriage (p = 0.007). CONCLUSIONS: About a tenth of women in Thua Thien Hue province have BV in the third trimester of pregnancy being associated with previous adverse outcome. Discharge with fishy odour is still a characteristic feature among subtle clinical presentations of BV. Better awareness about this disease and routine test-and-treat management during pregnancy may improve pregnancy outcome.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

A deep learning model for brain segmentation across pediatric and adult populations.

Automated quantification of brain tissues on MR images has greatly contributed to the diagnosis and follow-up of neurological pathologies across various life stages. However, existing solutions are specifically designed for certain age ranges, limiting their applicability in monitoring brain development from infancy to late adulthood. This retrospective study aims to develop and validate a brain segmentation model across pediatric and adult populations. First, we trained a deep learning model to segment tissues and brain structures using T1-weighted MR images from 390 patients (age range: 2-81 years) across four different datasets. Subsequently, the model was validated on a cohort of 280 patients from six distinct test datasets (age range: 4-90 years). In the initial experiment, the proposed deep learning-based pipeline, icobrain-dl, demonstrated segmentation accuracy comparable to both pediatric and adult-specific models across diverse age groups. Subsequently, we evaluated intra- and inter-scanner variability in measurements of various tissues and structures in both pediatric and adult populations computed by icobrain-dl. Results demonstrated significantly higher reproducibility compared to similar brain quantification tools, including childmetrix, FastSurfer, and the medical device icobrain v5.9 (p-value< 0.01). Finally, we explored the potential clinical applications of icobrain-dl measurements in diagnosing pediatric patients with Cerebral Visual Impairment and adult patients with Alzheimer's Disease.

Comparison of Dual Antiplatelet Therapies for Minor, Nondisabling, Acute Ischemic Stroke: A Bayesian Network Meta-Analysis.

Importance: Dual antiplatelet therapy (DAPT) appears to be an effective treatment option for minor (nondisabling) acute ischemic stroke. This conclusion is based on trials that include both transient ischemic attack (TIA) and minor stroke; however, these 2 conditions may differ. Objective: To compare DAPT regimens specifically for minor stroke. Data Sources: PubMed was searched for randomized clinical trials published up to November 4, 2023. Search terms strategy included TIA, transient ischemic attack, minor stroke, or moderate stroke, with the filter randomized controlled trial. Unpublished data on minor stroke were sourced from authors and/or institutions. Study Selection: Trials testing DAPT within the first 24 hours of a minor stroke (defined as a National Institutes of Health Stroke Scale score ≤5) were included by consensus. Of 1508 studies screened, 6 (0.3%) initially met inclusion criteria and were reviewed. Data Extraction and Synthesis: The study was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by multiple observers. Bayesian fixed-effect network meta-analysis was conducted. Secondary analysis performed for high-risk TIA alone. Main Outcomes and Measures: Treatments were ranked using a probability measure called surface under the cumulative rank curve (SUCRA). The primary outcome was subsequent ischemic stroke at 90 days. Secondary outcomes included major hemorrhage, mortality, and hemorrhagic stroke. The number needed to treat (NNT) and number needed to harm (NNH) were obtained. Results: Five trials were included that described 28 148 patients, of whom 22 203 (78.9%) had a minor stroke. Of these, 13 995 (63.0%) were in DAPT groups and 8208 (37.0%) in aspirin (acetylsalicylic acid) groups. Aspirin and ticagrelor had a 94% probability of being the superior treatment for minor stroke (SUCRA, 0.94) for the primary outcome. Both aspirin and ticagrelor (NNT, 40; 95% CI, 31-64) and aspirin and clopidogrel (NNT, 58; 95% CI, 39-136) were superior to aspirin alone in the prevention of recurrent ischemic stroke at 90 days. Both treatments had higher rates of major hemorrhage than aspirin alone (NNH for aspirin and ticagrelor, 284; 95% CI, 108-1715 vs NNH for aspirin and clopidogrel, 330; 95% CI, 118-3430), but neither had increased risk of hemorrhagic stroke or death. For high-risk TIA, ticagrelor and aspirin had a 60% probability (SUCRA, 0.60) and clopidogrel and aspirin had a 40% probability (SUCRA 0.40) of being a superior treatment; neither was optimum, but both were superior to aspirin alone for the primary outcome. Conclusions and Relevance: These findings suggest that DAPT with aspirin and ticagrelor has higher probability of being the superior treatment among patients with minor stroke when presence of CYP2C19 loss-of-function alleles has not been excluded. For patients with TIA, the superiority of aspirin and ticagrelor vs aspirin and clopidogrel was not demonstrated.

Osteoporosis and fracture risk assessment in adults with ischaemic stroke.

PURPOSE: To study the prevalence of osteoporosis, falls and fractures in adults with ischaemic stroke. METHODS: Observational cohort study of adults aged ≥ 50 years admitted with ischaemic stroke over a 12-month period were invited to participate in a telephone interview one-year post-stroke to ascertain falls and fracture. A Fracture Risk After Ischaemic Stroke (FRAC-stroke) score was calculated. RESULTS: Of the 1267 patients admitted to the stroke unit between 1 January 2020 and 31 December 2020, 624 had a modified Rankin Score documented. Of these, 316 adults ≥ 50 years had ischaemic stroke and 131 consented to a telephone interview. Mean age was 72.4 ± 10.7 years and 36.6% were female. 34 patients (25.9%) had a FRAC-stroke score of ≥ 15, equating to ≥ 5% risk of fracture in the year following stroke. Eleven (8.4%) patients (6 female) had a minimal trauma fracture in the 12 months post-stroke. There was a significant difference in patients experiencing falls pre- and post-stroke (19.8% vs 31.3%, p = 0.04). FRAC-stroke score was higher in those who had a fracture post stroke compared those who did not (20.4 vs 8.9, p < 0.001). Receiver operating characteristic analysis found an area under the curve of 0.867 for FRAC-stroke score (95% CI 0.785-0.949, p < 0.005). The optimal cutoff value for FRAC-stroke score predicting fracture was 12 with a sensitivity of 90.9% and specificity of 70%. CONCLUSION: The FRAC-stroke score is a simple clinical tool that can be used to identify patients at high risk of fracture post-stroke who would most benefit from osteoporosis therapy. Stroke is a risk factor for fracture due to immobilisation, vitamin D deficiency and increased falls risk. This study found that a simple bedside tool, the FRAC-stroke score, can predict fracture after ischaemic stroke. This will allow clinicians to plan treatment of osteoporosis prior to discharge from a stroke unit.

Use of the phrase 'pyramidal weakness' within the past 100 years.

The concept of 'pyramidal weakness' denotes that neurological examination findings can be localised to the central nervous system (CNS), and implying a specific pattern of motor weakness involving upper limb extensors and lower limb flexors. However, other weakness patterns have been observed in CNS lesions. We aim to investigate the pattern of weakness observed in CNS lesions and explore the use of the phrase 'pyramidal weakness' over time. We searched Medline, PubMed, and Google Scholar up to January 1st, 2022, using keywords such as 'distal weakness,' 'upper limb flexion,' 'lower limb extension,' 'pyramidal weakness,' and related terms. The inclusion criteria were papers relating to brain or spinal cord lesions and terms inferring their presence or the description of a motor weakness pattern. We identified 117 studies since 1889, of which 29.9% of publications described weakness in upper limb extensors and lower limb flexors, and 26.5% reported distal weakness. We found an early reference to 'pyramidal weakness' in 1922 in the context of unilateral weakness in encephalitis with no description of the upper limb extensor and lower limb flexor pattern. Since 1988, 'pyramidal weakness' has become associated with weakness in upper limb extensors and lower limb flexors. The phrase 'pyramidal weakness', used in its current format, has been more frequent since the 1980s. Distal weakness and upper limb extensor and lower limb flexor weakness have been associated with CNS lesions.

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.

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.

Personalised prediction of maintenance dialysis initiation in patients with chronic kidney disease stages 3-5: a multicentre study using the machine learning approach.

BACKGROUND: Optimal timing for initiating maintenance dialysis in patients with chronic kidney disease (CKD) stages 3-5 is challenging. This study aimed to develop and validate a machine learning (ML) model for early personalised prediction of maintenance dialysis initiation within 1-year and 3-year timeframes among patients with CKD stages 3-5. METHODS: Retrospective electronic health record data from the Taipei Medical University clinical research database were used. Newly diagnosed patients with CKD stages 3-5 between 2008 and 2017 were identified. The observation period spanned from the diagnosis of CKD stages 3-5 until the maintenance dialysis initiation or a maximum follow-up of 3 years. Predictive models were developed using patient demographics, comorbidities, laboratory data and medications. The dataset was divided into training and testing sets to ensure robust model performance. Model evaluation metrics, including area under the curve (AUC), sensitivity, specificity, positive predictive value, negative predictive value and F1 score, were employed. RESULTS: A total of 6123 and 5279 patients were included for 1 year and 3 years of the model development. The artificial neural network demonstrated better performance in predicting maintenance dialysis initiation within 1 year and 3 years, with AUC values of 0.96 and 0.92, respectively. Important features such as baseline estimated glomerular filtration rate and albuminuria significantly contributed to the predictive model. CONCLUSION: This study demonstrates the efficacy of an ML approach in developing a highly predictive model for estimating the timing of maintenance dialysis initiation in patients with CKD stages 3-5. These findings have important implications for personalised treatment strategies, enabling improved clinical decision-making and potentially enhancing patient outcomes.

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.

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.

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.

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.

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.

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.

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.