Interleukin-6 Predicts Carotid Plaque Severity, Vulnerability, and Progression.

BACKGROUND: IL-6 (interleukin-6) has important roles in atherosclerosis pathophysiology. To determine if anti-IL-6 therapy warrants evaluation as an adjuvant stroke prevention strategy in patients with carotid atherosclerosis, we tested whether circulating IL-6 levels predict carotid plaque severity, vulnerability, and progression in the prospective population-based CHS (Cardiovascular Health Study). METHODS: Duplex carotid ultrasound was performed at baseline and 5 years. Baseline plaque severity was scored 0 to 5 based on North American Symptomatic Carotid Endarterectomy Trial grade of stenosis. Plaque vulnerability at baseline was the presence of markedly irregular, ulcerated, or echolucent plaques. Plaque progression at 5 years was a ≥1 point increase in stenosis severity. The relationship of baseline plasma IL-6 levels with plaque characteristics was modeled using multivariable linear (severity) or logistic (vulnerability and progression) regression. Risk factors of atherosclerosis were included as independent variables. Stepwise backward elimination was used with P>0.05 for variable removal. To assess model stability, we computed the E-value or minimum strength of association (odds ratio scale) that unmeasured confounders must have with log IL-6 and the outcome to suppress the association. We performed internal validation with 100 bootstrap samples. RESULTS: There were 4334 participants with complete data (58.9% women, mean age: 72.7±5.1 years), including 1267 (29.2%) with vulnerable plaque and 1474 (34.0%) with plaque progression. Log IL-6 predicted plaque severity (ß=0.09, P=1.3×10-3), vulnerability (OR, 1.21 [95% CI, 1.05-1.40]; P=7.4×10-3, E-value=1.71), and progression (OR, 1.44 [95% CI, 1.23-1.69], P=9.1×10-6, E-value 2.24). In participants with >50% predicted probability of progression, mean log IL-6 was 0.54 corresponding to 2.0 pg/mL. Dichotomizing IL-6 levels did not affect the performance of prediction models. CONCLUSIONS: Circulating IL-6 predicts carotid plaque severity, vulnerability, and progression. The 2.0 pg/mL cutoff could facilitate the selection of individuals that would benefit from anti-IL-6 drugs for stroke prevention.

High-risk carotid plaques and incident ischemic stroke in patients with atrial fibrillation in the Cardiovascular Health Study.

BACKGROUND AND PURPOSE: Whether carotid artery disease could improve stroke risk stratification tools in patients with atrial fibrillation (AF) remains uncertain. This study was undertaken to investigate the risk of ischemic stroke associated with occlusive and nonocclusive carotid atherosclerotic disease in patients with AF in the prospective population-based Cardiovascular Health Study. METHODS: We included participants aged ≥65 years with AF. We used multivariable Cox regression analysis to explore the risk of ischemic stroke associated with the percentage of carotid stenosis, plaque irregularity, echogenicity, and vulnerability (markedly irregular, ulcerated, or hypoechoic plaques). RESULTS: A total of 1398 participants were included (55.2% female, 61.7% aged 65-74 years). The maximum carotid stenosis was <50%, 50%-99%, and 100% in 94.5%, 5%, and 0.5% of participants, respectively. High-risk plaques based on echogenicity and plaque irregularity were found in 25.6% and 8.9% of participants, respectively. After a median follow-up of 10.9 years (interquartile range = 7.5-15.6), 298 ischemic strokes were recorded. There was no difference in the incidence of ischemic stroke according to the degree of carotid artery stenosis (p = 0.44), plaque echogenicity (low vs. high risk, p = 0.68), plaque irregularity (low vs. high risk, p = 0.55), and plaque vulnerability (p = 0.86). The CHA2DS2-VASc score was associated with an increased risk of ischemic stroke (adjusted hazard ratio = 1.28, 95% confidence interval = 1.18-1.40, p < 0.001). Both maximum grade of stenosis and plaque vulnerability were not associated with incident ischemic stroke (all p > 0.05). CONCLUSIONS: Neither the degree of carotid stenosis nor the presence of vulnerable plaques was associated with incident ischemic stroke in this cohort of individuals with AF. This suggests that carotid disease was probably not a significant contributor to ischemic stroke in this population.

Addition of direct oral anticoagulants to the World Health Organization model list of essential medicines for the treatment of atrial fibrillation: An African perspective.

Atrial fibrillation (AF) is a major cause of adverse cardiovascular outcomes, and its prevalence is fast rising in Africa. The advent of direct oral anticoagulants (DOACs) has been a major revolution for the prevention of AF-related stroke and systemic embolism given the significant advantage over vitamin K antagonists in terms of both efficacy, safety, and adherence. However, due to their high cost, equitable access to DOACs has been a challenge, especially in low- and middle-income countries. Therefore, the recent addition of DOACs to the 21st WHO list of essential medicines comes as good news. African governments should take this opportunity to scale up the accessibility to DOACs for African patients with AF. This could be achieved through advocacy, appropriate training of health professionals, task shifting, patient education, strategic partnership to increase availability and quality of low-cost generic drugs, and appropriate medico-economic studies.

Aging Immune System in Acute Ischemic Stroke: A Transcriptomic Analysis.

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Carotid Plaque With High-Risk Features in Embolic Stroke of Undetermined Source: Systematic Review and Meta-Analysis.

Background and Purpose- An ipsilateral mild carotid stenosis, defined as plaque with <50% luminal narrowing, is identified in nearly 40% of patients with embolic stroke of undetermined source and could represent an unrecognized source of atheroembolism. We aimed to summarize data about the frequency of mild carotid stenosis with high-risk features in embolic stroke of undetermined source. Methods- We searched Pubmed and Ovid-Embase for studies reporting carotid plaque imaging features in embolic stroke of undetermined source. The prevalence of ipsilateral and contralateral mild carotid stenosis with high-risk features was pooled using random-effect meta-analysis. Results- Eight studies enrolling 323 participants were included. The prevalence of mild carotid stenosis with high-risk features in the ipsilateral carotid was 32.5% (95% CI, 25.3-40.2) compared with 4.6% (95% CI, 0.1-13.1) in the contralateral carotid. The odds ratio of finding a plaque with high-risk features in the ipsilateral versus the contralateral carotid was 5.5 (95% CI, 2.5-12.0). Conclusions- Plaques with high-risk features are 5 times more prevalent in the ipsilateral compared with the contralateral carotid in embolic stroke of undetermined source, suggesting a relationship to stroke risk.

RNA expression studies in stroke: what can they tell us about stroke mechanism?

PURPOSE OF REVIEW: Diagnosis of stroke and understanding the mechanism of stroke is critical to implement optimal treatment. RNA expressed in peripheral blood cells is emerging as a precision biomarker to aid in stroke diagnosis and prediction of stroke cause. In this review, we summarize available data regarding the role of RNA to predict stroke, the rationale for these changes, and a discussion of novel mechanistic insight and clinical applications. RECENT FINDINGS: Differences in RNA gene expression in blood have been identified in patients with stroke, including differences to distinguish ischemic from hemorrhagic stroke, and differences between cardioembolic, large vessel atherosclerotic, and small vessel lacunar stroke cause. Gene expression differences show promise as novel stroke biomarkers to predict stroke of unclear cause (cryptogenic stroke). The differences in RNA expression provide novel insight to stroke mechanism, including the role of immune response and thrombosis in human stroke. Important insight to regulation of gene expression in stroke and its causes are being acquired, including alternative splicing, noncoding RNA, and microRNA. SUMMARY: Improved diagnosis of stroke and determination of stroke cause will improve stroke treatment and prevention. RNA biomarkers show promise to aid in the diagnosis of stroke and cause determination, as well as providing novel insight to mechanism of stroke in patients. While further study is required, an RNA profile may one day be part of the stroke armamentarium with utility to guide acute stroke therapy and prevention strategies and refine stroke phenotype.

Anti-Wolbachia therapy for onchocerciasis & lymphatic filariasis: Current perspectives.

Onchocerciasis and lymphatic filariasis (LF) are human filarial diseases belonging to the group of neglected tropical diseases, leading to permanent and long-term disability in infected individuals in the endemic countries such as Africa and India. Microfilaricidal drugs such as ivermectin and albendazole have been used as the standard therapy in filariasis, although their efficacy in eliminating the diseases is not fully established. Anti-Wolbachia therapy employs antibiotics and is a promising approach showing potent macrofilaricidal activity and also prevents embryogenesis. This has translated to clinical benefits resulting in successful eradication of microfilarial burden, thus averting the risk of adverse events from target species as well as those due to co-infection with loiasis. Doxycycline shows potential as an anti-Wolbachia treatment, leading to the death of adult parasitic worms. It is readily available, cheap and safe to use in adult non-pregnant patients. Besides doxycycline, several other potential antibiotics are also being investigated for the treatment of LF and onchocerciasis. This review aims to discuss and summarise recent developments in the use of anti-Wolbachia drugs to treat onchocerciasis and LF.

The potential role of Wolbachia in controlling the transmission of emerging human arboviral infections.

PURPOSE OF REVIEW: Wolbachia is a genus of Gram-negative intracellular bacteria that is naturally found in more than half of all arthropod species. These bacteria cannot only reduce the fitness and the reproductive capacities of arthropod vectors, but also increase their resistance to arthropod-borne viruses (arboviruses). This article reviews the evidence supporting a Wolbachia-based strategy for controlling the transmission of dengue and other arboviral infections. RECENT FINDINGS: Studies conducted 1 year after the field release of Wolbachia-infected mosquitoes in Australia have demonstrated the suppression of dengue virus (DENV) replication in and dissemination by mosquitoes. Recent mathematical models show that this strategy could reduce the transmission of DENV by 70%. Consequently, the WHO is encouraging countries to boost the development and implementation of Wolbachia-based prevention strategies against other arboviral infections. However, the evidence regarding the efficacy of Wolbachia to prevent the transmission of other arboviral infections is still limited to an experimental framework with conflicting results in some cases. There is a need to demonstrate the efficacy of such strategies in the field under various climatic conditions, to select the Wolbachia strain that has the best pathogen interference/spread trade-off, and to continue to build community acceptance. SUMMARY: Wolbachia represents a promising tool for controlling the transmission of arboviral infections that needs to be developed further. Long-term environmental monitoring will be necessary for timely detection of potential changes in Wolbachia/vector/virus interactions.

An exploratory cohort study of sensory extinction in acute stroke: prevalence, risk factors, and time course.

Most studies on sensory extinction have focused on selected patients with subacute and chronic right hemisphere lesions. In studies conducted on acute stroke patients, risk factors and time course were not evaluated. Our aim was to determine the prevalence, risk factors, and time course of sensory extinction in the acute stroke setting. Consecutive patients with acute stroke were tested for tactile, visual, auditory, and auditory-tactile cross-modal extinction, as well as for peripersonal visuospatial neglect (PVN). Tests were repeated at 2, 7, 15, 30, and 90 days after initial examination. A multivariable logistic regression analysis was performed to test the association between sensory extinction and demographic and clinical risk factors. Seventy-three patients (38.4% women) were recruited: 64 with ischemic stroke and nine with haemorrhagic stroke. Mean age was 62.3 years (95% CI 58.8-65.7), mean NIHSS score was 1.6 (95% CI 1.2-2.1), and mean time to first examination was 4.1 days (95% CI 3.5-4.8). The overall prevalence of all subtypes of sensory extinction was 13.7% (95% CI 6.8-23.8). Tactile extinction was the most frequent subtype with a prevalence of 8.2% (95% CI 3.1-17.0). No extinction was found beyond 15 days after the first examination. After adjustment for age, sex, lesion side, type of stroke, time to first examination and stroke severity, a lesion volume ≥2 mL (adjusted OR = 38.88, p = 0.04), and presence of PVN (adjusted OR = 24.27, p = 0.04) were independent predictors of sensory extinction. The insula, the putamen, and the pallidum were the brain regions most frequently involved in patients with sensory extinction. Extinction is a rare and transient phenomenon in patients with minor stroke. The presence of PVN and lesion volume ≥2 mL are independent predictors of sensory extinction in acute stroke.

Incidence, Risk Factors and Anatomy of Peripersonal Visuospatial Neglect in Acute Stroke.

AIM: The study aims to describe the epidemiology and the neural correlates of peripersonal visuospatial neglect (PVN) in patients admitted to the Geneva Stroke Unit for an acute stroke or a transient ischemic attack (TIA). METHODS: Eligible subjects were tested for PVN using both the Ota's discriminative cancellation task and a line bisection task. Brain lesions were identified on diffusion-weighted imaging. A multivariate analysis was performed to identify risk factors of PVN. RESULTS: Ninety-eight consecutive patients (40.8% females) were recruited: 64 cases of ischemic stroke, 9 cases of hemorrhagic stroke and 25 cases of TIAs. The mean age was 61.9 ± 2.86 years. The incidence of PVN was 23.5% (95% CI 15.5-33.1) and was not significantly different between patients with right and left hemisphere stroke. There were 5 cases of ipsilesional neglect. There was no association between PVN and age, sex, stroke severity, handedness, lesion type, lesion volume and time to first examination. Lesions of temporal and parietal lobes were the most frequent in patients with PVN. CONCLUSION: PVN has a low incidence in the acute stroke settings and there is no particular predictor of its presence. It is most often associated with temporo-parietal lesions.

Bridging the language gap - A call for the wider use of Human phenotype ontology by non-geneticist clinicians when requesting genomic tests.

Advances in genomic technology including the development of next-generation sequencing (NGS) have enabled the identification of thousands of variations at a time, allowing the discovery of novel genetic diseases. Given the volume of data generated by these investigations, attention is drawn towards reporting relevant clinical features by clinicians to guide the diagnosis and management of their patients. The Human Phenotype Ontology (HPO) developed in 2008, revolutionized the semantic vocabulary of phenotypic descriptions in genomic medicine allowing researchers, laboratories and clinical geneticists to better understand each other. In this era of personalized medicine where genetic tests are becoming more accessible, non-geneticist clinicians are expected to be more involved than ever in the process of ordering genetic tests and interpreting genetic reports. It is therefore essential that they understand and adequately apply HPO nomenclature to integrate the patient care chain and seize the opportunity offered by this tailored language. The current article highlights the importance of using HPO vocabularies in clinical practice and advocates for its wider use by non-geneticist clinicians. Correct use of HPO will reduce misunderstandings between healthcare professionals and ultimately improve the healthcare system.

Association of Thrombin Generation With Leukocyte Inflammatory Profile in Patients With Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Thrombosis is central to the pathogenesis of acute ischemic stroke, with higher thrombin generation being associated with increased stroke risk. The immune system may contribute to thrombin generation in stroke and thus may offer novel strategies for stroke prevention. This study addresses the research question regarding the relationship of thrombin generation to leukocyte gene expression in patients with acute ischemic stroke. METHODS: We isolated RNA from whole blood and examined the relationship to thrombin generation capacity in patients with acute ischemic stroke. Due to its effects on thrombin generation, patients on anticoagulants were excluded from the study. The relationship of gene expression with peak thrombin was evaluated by analysis of covariance across peak thrombin quartiles adjusted for sex and age. RESULTS: In 97 patients with acute ischemic stroke, peak thrombin was variable, ranging from 252.0 to 752.4 nM. Increased peak thrombin was associated with differences in thromboinflammatory leukocyte gene expression, including a decrease in ADAM metallopeptidase with thrombospondin type 1 motif 13 and an increase in nuclear factor κB (NF-κB)-activating protein, protein disulfide isomerase family A member 5, and tissue factor pathway inhibitor 2. Pathways associated with peak thrombin included interleukin 6 signaling, thrombin signaling, and NF-κB signaling. A linear discriminant analysis model summarizing the immune activation associated with peak thrombin in a first cohort of stroke could distinguish patients with low peak thrombin from high peak thrombin in a second cohort of 112 patients with acute ischemic stroke. DISCUSSION: The identified genes and pathways support a role of the immune system contributing to thrombus formation in patients with stroke. These may have relevance to antithrombotic strategies for stroke prevention.

Trends in Stroke Presentations before and during the COVID-19 Pandemic: A Meta-Analysis.

BACKGROUND AND PURPOSE: There are reports of decline in the rates of acute emergency presentations during coronavirus disease 2019 (COVID-19) pandemic including stroke. We performed a meta-analysis of the impact of COVID-19 pandemic on rates of stroke presentations and on rates of reperfusion therapy. METHODS: Following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines, we systematically searched the literature for studies reporting changes in stroke presentations and treatment rates before and during the COVID-19 pandemic. Aggregated data were pooled using meta-analysis with random-effect models. RESULTS: We identified 37 observational studies (n=375,657). Pooled analysis showed decline in rates of all strokes (26.0%; 95% confidence interval [CI], 22.4 to 29.7) and its subtypes; ischemic (25.3%; 95% CI, 21.0 to 30.0), hemorrhagic (27.6%; 95% CI, 20.4 to 35.5), transient ischemic attacks (41.9%; 95% CI, 34.8 to 49.3), and stroke mimics (45.6%; 95% CI, 33.5 to 58.0) during months of pandemic compared with the pre-pandemic period. The decline was most evident for mild symptoms (40% mild vs. 25%-29% moderate/severe). Although rates of intravenous thrombolytic (IVT) and endovascular thrombectomy (EVT) decreased during pandemic, the likelihood of being treated with IVT and EVT did not differ between the two periods, both in primary and in comprehensive stroke centers (odds ratio [OR], 1.08; 95% CI, 0.94 to 1.24 and OR, 0.95; 95% CI, 0.83 to 1.09, respectively). CONCLUSIONS: Rates of all strokes types decreased significantly during pandemic. It is of paramount importance that general population should be educated to seek medical care immediately for stroke-like symptoms during COVID-19 pandemic. Whether delay in initiation of secondary prevention would affect eventual stroke outcomes in the long run needs further study.