A Multicentre Prospective Cohort Study to Identify High-Risk Transient Ischemic Attack/Minor Stroke Patients Benefiting from Echocardiography.

BACKGROUND: We aimed to derive a clinical decision rule to identify transient ischemic attack (TIA)/minor stroke patients most likely to benefit from echocardiography. METHODS: This multicentre prospective cohort study enrolled adults diagnosed with TIA/minor stroke in the emergency department who underwent a echocardiogram within 90 days, from 13 Canadian academic emergency departments from October 2006 to May 2017. Our outcome was clinically significant echocardiogram findings. RESULTS: In 7,149 eligible patients, a clinically significant finding was found in 556 (7.8%). There were a further 2,421 (33.9%) with a potentially significant finding. History of heart failure (adjusted odds ratio [OR] 3.9) or coronary artery disease (OR 2.7) were the factors most strongly associated with clinically significant echocardiogram findings, while young age, male sex, valvular heart disease and infarct (any age) on neuroimaging were modestly associated (OR between 1.3 and 1.9). The model combining these predictors into a score (range 0 to 15), had a C-statistic of 0.67 (95%CI 0.65-0.70). A cut point of 6 points or more classified 6.6% of cases as high likelihood, defined as >15% for clinically significant echocardiogram findings. CONCLUSION: Echocardiography is a very useful test in the investigations of TIA/minor stroke patients. We identified high risk clinical features, combined to create a clinical decision rule, to identify which TIA/minor stroke patients are likely to have clinically significant echocardiogram findings requiring an immediate change in management. These patients should have echocardiography prioritized while others may continue to have echocardiography conducted in a less urgent fashion.

Evaluation of Salivary Immunoglobulin A Level and Its Correlation with Severity of Early Childhood Caries: An Original Research.

Background and objectives: Early childhood caries (ECC) remains one of the most prevalent diseases mutilating the primary dentition. It is a multifactorial disease that severely affects the quality of life of affected children. One of the risk indicators reported in the literature is the presence of viable mutans streptococci (MS) and protective factors such as salivary immunoglobulin A (SIgA). Hence, it is important to identify such risks and protective factors associated with ECC using simple yet reliable methods supported by advanced technology and a fully automated platform to improve the results. Materials and methods: A retrospective analysis was done on 40 children who were divided into two groups: group I (experimental) and group II (control). Group I comprised 30 healthy children who were further divided into three subgroups of 10 children each. Group IA with decayed, missing, filled teeth/decayed, extracted, filled teeth (dmft/deft) = 1-2, group IB with dmft/deft = 3-4, group IC with dmft/deft ≥5, and group II, comprising 10 healthy children having no caries by using World Health Organization (WHO) 2013 Oral Health Survey criteria. Unstimulated saliva was collected by drooling saliva into a sterile container. The samples were transported to the central research laboratory for SIgA by the immunoturbidimetry method by a fully automated Abbott Architect c system. The data obtained was subjected to statistical analysis. Results: On comparison of SIgA in between varying severities of dental caries and caries-free children between age-group of 3 and 6 years, it was found to be below the grand median 0.20 mg/mL for subgroups IA and control group II. A significant negative statistical correlation (r = -0.948) was present between the SIgA and varying severities of ECC and the control group. Interpretation and conclusion: The low dmft/deft group was found to be relatively closer to the caries-free groups as their mean dmft was 1.50, standard deviation (SD) ± 0.53. A slight change in dmft/deft score and SIgA could be used as a potential biomarker for assessing the severity of ECC in children between age-group of 3 and 6 years. How to cite this article: Sharma V, Bagchi A, Dutta B, et al. Evaluation of Salivary Immunoglobulin A Level and Its Correlation with Severity of Early Childhood Caries: An Original Research. Int J Clin Pediatr Dent 2024;17(3):316-320.

Derivation of a clinical prediction score for the diagnosis of clinically significant symptomatic carotid artery disease.

OBJECTIVES: Emergent vascular imaging identifies a subset of patients requiring immediate specialized care (i.e. carotid stenosis > 50%, dissection or free-floating thrombus). However, most TIA patients do not have these findings, so it is inefficient to image all TIA patients in crowded emergency departments (ED). Our objectives were to derive and internally validate a clinical prediction score for clinically significant carotid artery disease in TIA patients. METHODS: This was a planned secondary analysis of a prospective cohort study from 14 Canadian EDs. Among 11555 consecutive adult ED patients with TIA/minor stroke symptoms over 12 years, 9882 had vascular imaging and were included in the analysis. Our main outcome was clinically significant carotid artery disease, defined as extracranial internal carotid stenosis ≥ 50%, dissection, or thrombus in the internal carotid artery, with contralateral symptoms. RESULTS: Of 9882 patients, 888 (9.0%) had clinically significant carotid artery disease. Logistic regression was used to derive a 13-variable reduced model. We simplified the model into a score (Symcard [Symptomatic carotid artery disease] Score), with suggested cut-points for high, medium, and low-risk stratification. A substantial portion (38%) of patients were classified as low-risk, 33.8% as medium risk, and 28.2% as high risk. At the low-risk cut-point, sensitivity was 92.9%, specificity 41.1%, and diagnostic yield 1.7%. CONCLUSIONS: This simple score can predict carotid artery disease in TIA patients using readily available information. It identifies low-risk patients who can defer vascular imaging to an outpatient or specialty clinic setting. Medium-risk patients may undergo imaging immediately or with slight delay, depending on local resources. High-risk patients should undergo urgent vascular imaging.

RéSUMé: OBJECTIFS: L'imagerie vasculaire émergente permet d'identifier un sous-ensemble de patients nécessitant des soins spécialisés immédiats (c.-à-d. sténose carotidienne >50 %, dissection ou thrombus flottant). Cependant, la plupart des patients atteints de RTI ne présentent pas ces résultats, il est donc inefficace d'effectuer une imagerie de tous les patients atteints de RTI dans les services d'urgence (ER) surpeuplés. Nos objectifs étaient de calculer et de valider en interne un score de prédiction clinique pour la maladie carotide cliniquement significative chez les patients atteints d'une AIT MéTHODES: Il s'agissait d'une analyse secondaire planifiée d'une étude de cohorte prospective menée auprès de 14 DE canadiens. Parmi les 11555 patients adultes consécutifs atteints d'un EI présentant des symptômes d'AIT/AVC mineur au cours des 12 dernières années, 9882 ont reçu une imagerie vasculaire et ont été inclus dans l'analyse. Notre principal critère de jugement était la maladie carotide cliniquement significative, définie comme une sténose extracrânienne de la carotide interne à 50 %, une dissection ou un thrombus dans l'artère carotide interne, avec des symptômes contralatéraux. RéSULTATS: Sur 9882 patients, 888 (9,0 %) présentaient une maladie de l'artère carotide cliniquement significative. La régression logistique a été utilisée pour obtenir un modèle réduit à 13 variables. Nous avons simplifié le modèle en un score (Symcard [Symptomatic carotid artery disease] Score), avec des points de coupure suggérés pour la stratification à risque élevé, moyen et faible. Une proportion importante (38,0 %) des patients ont été classés à faible risque, 33,8 % à risque moyen et 28,2 % à risque élevé. Au seuil de faible risque, la sensibilité était de 92,9 %, la spécificité de 41,1 % et le rendement diagnostique de 1,7 %. CONCLUSIONS: Ce score simple permet de prédire la maladie de l'artère carotide chez les patients atteints d'AIT en utilisant des informations facilement disponibles. Il identifie les patients à faible risque qui peuvent reporter l'imagerie vasculaire à un établissement de consultation externe ou de spécialité. Les patients à risque moyen peuvent subir une imagerie immédiatement ou avec un léger délai, selon les ressources locales. Les patients à haut risque doivent subir une imagerie vasculaire urgente.

Comparative host transcriptomics as a tool to identify candidate biomarkers for immune reactions in leprosy using meta-analysis.

Background Leprosy is no longer considered an imprecation, as an effective multidrug therapy regimen is available worldwide for its cure. However, its diverse clinical manifestations sometimes involve acute inflammatory reactions. These complications result in irreversible nerve damage, neuritis and anatomical deformities that emerge before, during the treatment or after the completion of treatment. Reversal reaction (Type-I) and erythema nodosum leprosum (Type-II) are the leprosy reactions generally seen in patients with lepromatous and borderline forms of leprosy. At present, there is no accurate diagnostic test available to detect these leprosy reactions. Objectives To identify potential biomarkers indicative of Type-I and Type-II leprosy reactions that could help in their early diagnosis. Methods and Results Host-transcriptomics investigations have been utilised in this study to decipher a correlation between host-gene expression-based biomarkers and exacerbation of leprosy reactions. We present a comparative analysis of publicly available host transcriptomics datasets (from Gene Expression Omnibus) related to leprosy reactions. Individual datasets were analysed and integration of results was carried out using meta-analysis. Common differentially expressed genes (DEGs) were identified using the frequentist and Bayesian ratio association test methods. We have identified several genes - ADAMTS5, ADAMTS9, IFITM2, IFITM3, KIRREL, ANK3, CD1E, CTSF, DOCK9 and KRT73 to name a few - which can serve as potential biomarkers for Type-II reaction. Similarly, ACP5, APOC1, CCL17, S100B, SLC11A1 among others may likely serve as biomarkers for Type-I reaction. Limitations The number of datasets related to leprosy reactions found after the systematic search is less (n = 4) and may limit the accuracy of identified biomarker genes. This could be resolved by including more studies in the data analysis. Conclusion We provide a comprehensive list of gene candidates which could be prioritised further in research focusing on immune reactions in leprosy, as they are likely important in understanding its complexities and could be useful in its early diagnosis.

Interhospital Transfer for Endovascular Stroke Treatment in Canada: Results From the OPTIMISE Registry.

BACKGROUND: Interhospital transfer for patients with stroke due to large vessel occlusion for endovascular thrombectomy (EVT) has been associated with treatment delays. METHODS: We analyzed data from Optimizing Patient Treatment in Major Ischemic Stroke With EVT, a quality improvement registry to support EVT implementation in Canada. We assessed for unadjusted differences in baseline characteristics, time metrics, and procedural outcomes between patients with large vessel occlusion transferred for EVT and those directly admitted to an EVT-capable center. RESULTS: Between January 1, 2018, and December 31, 2021, a total of 6803 patients received EVT at 20 participating centers (median age, 73 years; 50% women; and 50% treated with intravenous thrombolysis). Patients transferred for EVT (n=3376) had lower rates of M2 occlusion (22% versus 27%) and higher rates of basilar occlusion (9% versus 5%) compared with those patients presenting directly at an EVT-capable center (n=3373). Door-to-needle times were shorter in patients receiving intravenous thrombolysis before transfer compared with those presenting directly to an EVT center (32 versus 36 minutes). Patients transferred for EVT had shorter door-to-arterial access times (37 versus 87 minutes) but longer last seen normal-to-arterial access times (322 versus 181 minutes) compared with those presenting directly to an EVT-capable center. No differences in arterial access-to-reperfusion times, successful reperfusion rates (85% versus 86%), or adverse periprocedural events were found between the 2 groups. Patients transferred to EVT centers had a similar likelihood for good functional outcome (modified Rankin Scale score, 0-2; 41% versus 43%; risk ratio, 0.95 [95% CI, 0.88-1.01]; adjusted risk ratio, 0.98 [95% CI, 0.91-1.05]) and a higher risk for all-cause mortality at 90 days (29% versus 25%; risk ratio, 1.15 [95% CI, 1.05-1.27]; adjusted risk ratio, 1.14 [95% CI, 1.03-1.28]) compared with patients presenting directly to an EVT center. CONCLUSIONS: Patients transferred for EVT experience significant delays from the time they were last seen normal to the initiation of EVT.

Using 30-day modified rankin scale score to predict 90-day score in patients with intracranial hemorrhage: Derivation and validation of prediction model.

Whether 30-day modified Rankin Scale (mRS) scores can predict 90-day scores is unclear. This study derived and validated a model to predict ordinal 90-day mRS score in an intracerebral hemorrhage (ICH) population using 30-day mRS values and routinely available baseline variables. Adults enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage-2 (ATACH-2) trial between May 2011 and September 2015 with acute ICH, who were alive at 30 days and had mRS scores reported at both 30 and 90 days were included in this post-hoc analysis. A proportional odds regression model for predicting ordinal 90-day mRS scores was developed and internally validated using bootstrapping. Variables in the model included: mRS score at 30 days, age (years), hematoma volume (cm3), hematoma location (deep [basal ganglia, thalamus], lobar, or infratentorial), presence of intraventricular hemorrhage (IVH), baseline Glasgow Coma Scale (GCS) score, and National Institutes of Health Stroke Scale (NIHSS) score at randomization. We assessed model fit, calibration, discrimination, and agreement (ordinal, dichotomized functional independence), and EuroQol-5D ([EQ-5D] utility weighted) between predicted and observed 90-day mRS. A total of 898/1000 participants were included. Following bootstrap internal validation, our model (calibration slope = 0.967) had an optimism-corrected c-index of 0.884 (95% CI = 0.873-0.896) and R2 = 0.712 for 90-day mRS score. The weighted ĸ for agreement between observed and predicted ordinal 90-day mRS score was 0.811 (95% CI = 0.787-0.834). Agreement between observed and predicted functional independence (mRS score of 0-2) at 90 days was 74.3% (95% CI = 69.9-78.7%). The mean ± SD absolute difference between predicted and observed EQ-5D-weighted mRS score was negligible (0.005 ± 0.145). This tool allows practitioners and researchers to utilize clinically available information along with the mRS score 30 days after ICH to reliably predict the mRS score at 90 days.

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Genetic diversity of Mycobacterium leprae: Need to move towards genome-wide approaches.

ABSTRACT: Leprosy, an ancient disease, continues to be a public health concern as it remains endemic in several countries. After reaching the elimination target (1/10,000) as a public health problem in 2005 in India, around 1.2 lakh cases have been detected every year over the last decade indicating active transmission of leprosy bacillus (Mycobacterium leprae). Single-nucleotide polymorphisms (SNPs), genomic insertions/deletions and variable-number tandem repeats (VNTRs) have been identified as genetic markers for tracking M. leprae transmission. As the leprosy bacilli cannot be cultured in vitro, molecular testing of M. leprae genotypes is done by polymerase chain reaction-based sequencing which provides a practical alternative for the identification of strains as well as drug resistance-associated mutations. Whole-genome sequencing (WGS) of M. leprae directly from clinical samples has also proven to be an effective tool for identifying genetic variations which can further help refine the molecular epidemiological schemes based on SNPs and VNTRs. However, the WGS data of M. leprae strains from India are scarce, being responsible for a gross under-representation of the genetic diversity of M. leprae strains present in India and need to be addressed suitably. Molecular studies of leprosy can provide better insight into phylogeographic markers to monitor the transmission dynamics and emergence of antimicrobial resistance. An improved understanding of M. leprae transmission is essential to guide efficient leprosy control strategies. Therefore, this review compiles and discusses the current status of molecular epidemiology, genotyping and the potential of genome-wide analysis of M. leprae strains in the Indian context.

Recent Advances in Carbon Nanotube Utilization in Perovskite Solar Cells: A Review.

Due to their exceptional optoelectronic properties, halide perovskites have emerged as prominent materials for the light-absorbing layer in various optoelectronic devices. However, to increase device performance for wider adoption, it is essential to find innovative solutions. One promising solution is incorporating carbon nanotubes (CNTs), which have shown remarkable versatility and efficacy. In these devices, CNTs serve multiple functions, including providing conducting substrates and electrodes and improving charge extraction and transport. The next iteration of photovoltaic devices, metal halide perovskite solar cells (PSCs), holds immense promise. Despite significant progress, achieving optimal efficiency, stability, and affordability simultaneously remains a challenge, and overcoming these obstacles requires the development of novel materials known as CNTs, which, owing to their remarkable electrical, optical, and mechanical properties, have garnered considerable attention as potential materials for highly efficient PSCs. Incorporating CNTs into perovskite solar cells offers versatility, enabling improvements in device performance and longevity while catering to diverse applications. This article provides an in-depth exploration of recent advancements in carbon nanotube technology and its integration into perovskite solar cells, serving as transparent conductive electrodes, charge transporters, interlayers, hole-transporting materials, and back electrodes. Additionally, we highlighted key challenges and offered insights for future enhancements in perovskite solar cells leveraging CNTs.

Sequential trypsin and ProAlanase digestions unearth immunological protein biomarkers shrouded by skeletal collagen.

This study investigates the efficacy of proteomic analysis of human remains to identify active infections in the past through the detection of pathogens and the host response to infection. We advance leprosy as a case study due to the sequestering of sufferers in leprosaria and the suggestive skeletal lesions that can result from the disease. Here we present a sequential enzyme extraction protocol, using trypsin followed by ProAlanase, to reduce the abundance of collagen peptides and in so doing increase the detection of non-collagenous proteins. Through our study of five individuals from an 11th to 18th century leprosarium, as well as four from a contemporaneous non-leprosy associated cemetery in Barcelona, we show that samples from 2 out of 5 leprosarium individuals extracted with the sequential digestion methodology contain numerous host immune proteins associated with modern leprosy. In contrast, individuals from the non-leprosy associated cemetery and all samples extracted with a trypsin-only protocol did not. Through this study, we advance a palaeoproteomic methodology to gain insights into the health of archaeological individuals and take a step toward a proteomics-based method to study immune responses in past populations.

Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial.

Importance: Atrial cardiopathy is associated with stroke in the absence of clinically apparent atrial fibrillation. It is unknown whether anticoagulation, which has proven benefit in atrial fibrillation, prevents stroke in patients with atrial cardiopathy and no atrial fibrillation. Objective: To compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy. Design, Setting, and Participants: Multicenter, double-blind, phase 3 randomized clinical trial of 1015 participants with cryptogenic stroke and evidence of atrial cardiopathy, defined as P-wave terminal force greater than 5000 µV × ms in electrocardiogram lead V1, serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m2 or greater on echocardiogram. Participants had no evidence of atrial fibrillation at the time of randomization. Enrollment and follow-up occurred from February 1, 2018, through February 28, 2023, at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium. Interventions: Apixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508). Main Outcomes and Measures: The primary efficacy outcome in a time-to-event analysis was recurrent stroke. All participants, including those diagnosed with atrial fibrillation after randomization, were analyzed according to the groups to which they were randomized. The primary safety outcomes were symptomatic intracranial hemorrhage and other major hemorrhage. Results: With 1015 of the target 1100 participants enrolled and mean follow-up of 1.8 years, the trial was stopped for futility after a planned interim analysis. The mean (SD) age of participants was 68.0 (11.0) years, 54.3% were female, and 87.5% completed the full duration of follow-up. Recurrent stroke occurred in 40 patients in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (hazard ratio, 1.00 [95% CI, 0.64-1.55]). Symptomatic intracranial hemorrhage occurred in 0 patients taking apixaban and 7 patients taking aspirin (annualized rate, 1.1%). Other major hemorrhages occurred in 5 patients taking apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (hazard ratio, 1.02 [95% CI, 0.29-3.52]). Conclusions and Relevance: In patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.

Transcranial Doppler ultrasound to evaluate the risk of hyperperfusion after endovascular stroke thrombectomy.

BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) has been reported in up to 50% of acute ischemic stroke (AIS) patients with a large vessel occlusion (LVO) treated with endovascular thrombectomy (EVT). HT may be driven by postrecanalization hyperperfusion injury and is independently associated with worse functional outcomes. Strategies to identify patients at risk for HT may assist in developing preventive therapies. METHODS: We prospectively included adult AIS patients with an anterior circulation LVO achieving successful recanalization after EVT. Consenting participants received transcranial Doppler ultrasound (TCD) within 18 hours of procedure completion. We compared flow velocities according to the presence of HT on the computed tomography scan performed within the first 24±12 hours from the end of EVT. We also evaluated the association of flow velocities with systemic blood pressure (BP) readings at the time of insonation. RESULTS: A total of 48 patients consented to participate in the study. Six (12%) were excluded due to the absence of temporal windows. HT was detected in 20 participants (48%). Those with HT had higher peak systolic velocities on the middle cerebral arteries compared to those without HT for both the symptomatic (107±42 vs. 82±25 cm/second, p = .024) and asymptomatic (97±21 vs. 81±25 cm/second, p = .040) sides. No correlation of flow velocities on either the symptomatic or asymptomatic side and BP measurements at the time of insonation was detected. CONCLUSION: TCD can identify patients at risk of HT following successful EVT. TCD could serve as an inexpensive ancillary test to guide participant selection for clinical trials targeting postprocedural reperfusion injury.

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Novel mutations found in Mycobacterium leprae DNA repair gene nth from central India.

INTRODUCTION: The importance of DNA repair enzymes in maintaining genomic integrity is highlighted by the hypothesis that DNA damage by reactive oxygen/nitrogen species produced inside the host cell is essential for the mutagenesis process. Endonuclease III (Nth), formamidopyrimide (Fpg) and endonuclease VIII (Nei) DNA glycosylases are essential components of the bacterial base excision repair process. Mycobacterium leprae lost both fpg/nei genes during the reductive evolution event and only has the nth (ML2301) gene. This study aims to characterize the mutations in the nth gene of M. leprae strains and explore its correlation with drug-resistance. METHOD: A total of 91 M. leprae positive DNA samples extracted from skin biopsy samples of newly diagnosed leprosy patients from NSCB Hospital Jabalpur were assessed for the nth gene as well as drug resistance-associated loci of the rpoB, gyrA and folP1 genes through PCR followed by Sanger sequencing. RESULTS: Of these 91 patients, a total of two insertion frameshift mutations, two synonymous and seven nonsynonymous mutations were found in nth in seven samples. Sixteen samples were found to be resistant to ofloxacin and one was found to be dapsone resistant as per the known DRDR mutations. No mutations were found in the rpoB region. Interestingly, none of the nth mutations were identified in the drug-resistant associated samples. CONCLUSION: The in-silico structural analysis of the non-synonymous mutations in the Nth predicted five of them were to be deleterious. Our results suggest that the mutations in the nth gene may be potential markers for phylogenetic and epidemiological studies.

Cognitive performance following stroke, transient ischaemic attack, myocardial infarction, and hospitalisation: an individual participant data meta-analysis of six randomised controlled trials.

BACKGROUND: Survivors of stroke are often concerned about cognitive problems, and information on the risk of cognitive problems often comes from small studies. We aimed to estimate years of cognitive ageing associated with stroke compared with transient ischaemic attack, myocardial infarction, and other hospitalisations in a large population. METHODS: Using data from six randomised controlled trials (ORIGIN, ONTARGET, TRANSCEND, COMPASS, HOPE-3, and NAVIGATE ESUS), we completed an individual participant data meta-analysis using data requested from the Public Health Research Institute to estimate the association of stroke (by type and severity), transient ischaemic attack, myocardial infarction, and other hospitalisations with cognitive performance measured at the end of each trial. We included participants in any of these randomised controlled trials with a cognitive assessment at baseline and at least one other timepoint. Cognitive performance was measured with the Mini-Mental State Examination or the Montreal Cognitive Assessment, transformed into Z scores. We estimated Z score differences in end of trial cognitive performance between people with and without events and calculated corresponding years of cognitive ageing in these trials, and additionally calculated using a population representative cohort-the Cognitive Function and Ageing Study. FINDINGS: In 64 106 participants from 55 countries, compared with no event, stroke was associated with 18 years of cognitive ageing (1487 strokes included in the model, 95% CI 10 to 28; p<0·0001) and transient ischaemic attack with 3 years (660 transient ischaemic attacks included in the model, 0 to 6; p=0·021). Myocardial infarction (p=0·60) and other hospitalisations (p=0·26) were not associated with cognitive ageing. The mean difference in SD compared with people without an event was -0·84 (95% CI -0·91 to -0·76; p<0·0001) for disabling stroke, and -0·12 (-0·19 to -0·05; p=0·0012) for non-disabling stroke. Haemorrhagic stroke was associated with worse cognition (-0·75, -0·95 to -0·55; p<0·0001) than ischaemic stroke (-0·42, -0·48 to -0·36; p <0·0001). INTERPRETATION: Stroke has a substantial effect on cognition. The effects of transient ischaemic attack were small, whereas myocardial infarction and hospitalisation had a neutral effect. Prevention of stroke could lead to a reduction in cognitive ageing in those at greatest risk. FUNDING: Population Health Research Institute and Chief Scientist Office of Scotland.

Multiplex PCR-based RFLP assay for early identification of prevalent Mycobacterium leprae genotypes.

Mycobacterium leprae is classified into four SNP genotypes and 16 subtypes (from 1A to 4P) that exhibit phylogeographical association reported from around the world. Among them, genotypes 1D and 3I represent more than 60% of M. leprae strains. Here, we report a new method for M. leprae genotyping which identifies the genotypes 1D and 3I by combining multiplex PCR amplification and restriction fragment length polymorphism (RFLP) of a M. leprae DNA amplicons using AgeI restriction enzyme. Agarose gel electrophoresis showed a deletion of 11 bp only among 3I genotypes by electrophoresis. When this multiplex PCR reaction is subjected to AgeI digestion, successful restriction digestion shows three bands for all the genotypes except 1D where only two bands were observed due to loss of restriction site. This method gives us the advantage of 1-step identification of the two most prevalent strains of M. leprae without using specialized equipments such as the Sanger sequencing system or quantitative PCR.

Efficacy and Safety of Oral Factor XIa Inhibitors in Stroke Prevention: A Systematic Review and Meta-Analysis.

INTRODUCTION: Despite preventive measures, stroke rates remain high in the primary and secondary prevention settings. Factor XIa inhibition may offer a novel, safe and effective antithrombotic option for stroke prevention. METHODS: We conducted a systematic review and meta-analysis including all available randomized controlled clinical trials (RCTs) that investigated the efficacy and safety of factor XIa inhibitors versus controls in primary or secondary stroke prevention. The primary efficacy and safety outcomes of interest were symptomatic ischemic stroke (IS) and the composite of major bleeding and clinically relevant non-major bleeding. RESULTS: Four phase II dose-finding RCTs were included, comprising a total of 4732 patients treated with factor XIa inhibitors versus 1798 controls. Treatment with factor XIa inhibitors did not reduce the risk of IS compared to controls (RR: 0.89; 95% CI: 0.67-1.17). The composite of symptomatic IS and covert infarcts on brain MRI (RR: 1.01; 95% CI: 0.87-1.18), the composite of symptomatic IS and transient ischemic attack (TIA; RR: 0.78; 95% CI: 0.61-1.01), and the composite of major adverse cardiovascular events (RR: 1.07; 95% CI: 0.87-1.31) did not differ between the treatment groups. Treatment with factor XIa inhibitors did not increase the risk of the composite of major bleeding and clinically relevant non-major bleeding (RR: 1.19; 95% CI: 0.65-2.16), major bleeding alone (RR: 1.19; 95% CI: 0.64-2.22), intracranial bleeding (RR: 0.91; 95% CI: 0.26-3.19) or all-cause mortality (RR: 1.21; 95% CI: 0.77-1.90). CONCLUSION: This meta-analysis provides reassuring evidence regarding the safety of factor XIa inhibitors. These findings, coupled with potential signals of efficacy in reducing IS (and TIA), underscore the importance of ongoing phase III RCTs for providing definitive data regarding the effect of factor XIa inhibition on stroke prevention.

Perkinsus olseni in green-lipped mussels Perna canaliculus: diagnostic evaluation, prevalence, and distribution.

Perkinsus olseni (Perkinsidae) is a molluscan parasite notifiable to the World Organisation for Animal Health that is reported in several shellfish hosts in New Zealand, including the native green-lipped mussel Perna canaliculus. Green-lipped mussels comprise over half of New Zealand's aquaculture export value and have historically been considered free of serious diseases based on extensive histology-based surveillance. The discovery of P. olseni in green-lipped mussels has raised questions about future disease threats to green-lipped mussels, particularly under changing ocean climatic conditions. Using mussels collected from farmed (n = 358) and wild (n = 236) populations, we aimed to determine the distribution and prevalence of P. olseni in green-lipped mussels around New Zealand, and assess the performance of diagnostic tests, including real-time PCR, conventional PCR, and culture using Ray's fluid thioglycolate medium (RFTM). Prevalence and diagnostic test performance was evaluated using Bayesian latent class analysis with informative priors. The prevalence of P. olseni was 0-3%, except for 1 wild population from a harbour where prevalence was 22%. Real-time PCR had the highest diagnostic sensitivity (87%) compared to 62 and 21% for conventional PCR and RFTM, respectively. Diagnostic specificity was similar among all methods (96-98%). No mortality was observed during the study. Our results suggest that real-time PCR is the diagnostic test best suited for surveillance of P. olseni in subclinically infected green-lipped mussels under New Zealand conditions.

Oral Anticoagulation Use and Left Atrial Appendage Occlusion in LAAOS III.

BACKGROUND: LAAOS III (Left Atrial Appendage Occlusion Study III) showed that left atrial appendage (LAA) occlusion reduces the risk of ischemic stroke or systemic embolism in patients with atrial fibrillation undergoing cardiac surgery. This article examines the effect of LAA occlusion on stroke reduction according to variation in the use of oral anticoagulant (OAC) therapy. METHODS: Information regarding OAC use was collected at every follow-up visit. Adjusted proportional hazards modeling, including using landmarks of hospital discharge, 1 and 2 years after randomization, evaluated the effect of LAA occlusion on the risk of ischemic stroke or systemic embolism, according to OAC use. Adjusted proportional hazard modeling, with OAC use as a time-dependent covariate, was also performed to assess the effect of LAA occlusion, according to OAC use throughout the study. RESULTS: At hospital discharge, 3027 patients (63.5%) were receiving a vitamin K antagonist, and 879 (18.5%) were receiving a non-vitamin K antagonist oral anticoagulant (direct OAC), with no difference in OAC use between treatment arms. There were 2887 (60.5%) patients who received OACs at all follow-up visits, 1401 (29.4%) who received OAC at some visits, and 472 (9.9%) who never received OACs. The effect of LAA occlusion on the risk of ischemic stroke or systemic embolism was consistent after discharge across all 3 groups: hazard ratios of 0.70 (95% CI, 0.51-0.96), 0.63 (95% CI, 0.43-0.94), and 0.76 (95% CI, 0.32-1.79), respectively. An adjusted proportional hazards model with OAC use as a time-dependent covariate showed that the reduction in stroke or systemic embolism with LAA occlusion was similar whether patients were receiving OACs or not. CONCLUSIONS: The benefit of LAA occlusion was consistent whether patients were receiving OACs or not. LAA occlusion provides thromboembolism reduction in patients independent of OAC use.