Stroke genetics and how it Informs novel drug discovery.

INTRODUCTION: Stroke is one of the main causes of death and disability worldwide. Nevertheless, despite the global burden of this disease, our understanding is limited and there is still a lack of highly efficient etiopathology-based treatment. It is partly due to the complexity and heterogenicity of the disease. It is estimated that around one-third of ischemic stroke is heritable, emphasizing the importance of genetic factors identification and targeting for therapeutic purposes. AREAS COVERED: In this review, the authors provide an overview of the current knowledge of stroke genetics and its value in diagnostics, personalized treatment, and prognostication. EXPERT OPINION: As the scale of genetic testing increases and the cost decreases, integration of genetic data into clinical practice is inevitable, enabling assessing individual risk, providing personalized prognostic models and identifying new therapeutic targets and biomarkers. Although expanding stroke genetics data provides different diagnostics and treatment perspectives, there are some limitations and challenges to face. One of them is the threat of health disparities as non-European populations are underrepresented in genetic datasets. Finally, a deeper understanding of underlying mechanisms of potential targets is still lacking, delaying the application of novel therapies into routine clinical practice.

Hypotensive Effect of Electric Stimulation of Caudal Ventrolateral Medulla in Freely Moving Rats.

Background and Objectives: An altered sympathetic function is established in primary arterial hypertension (PAH) development. Therefore, PAH could be targeted by applying an electric current to the medulla where reflex centers for blood pressure control reside. This study aims to evaluate the electric caudal ventrolateral medulla (CVLM) stimulation effect on blood pressure and animal survivability in a freely moving rat model. Materials and Methods: A total of 20 Wistar rats aged 12-16 weeks were randomly assigned to either: the experimental group (n = 10; electrode tip implanted in CVLM region) or the control group (n = 10; tip implanted 4 mm above the CVLM in the cerebellum). After a period of recovery (4 days), an experimental phase ensued, divided into an "OFF stimulation" period (5-7 days post-surgery) and an "ON stimulation" period (8-14 days post-surgery). Results: Three animals (15%, one in the control, two in the experimental group) dropped out due to postoperative complications. Arterial pressure in the experimental group rats during the "OFF stimulation" period decreased by 8.23 mm Hg (p = 0.001) and heart rate by 26.93 beats/min (p = 0.008). Conclusions: From a physiological perspective, CVLM could be an effective deep brain stimulation (DBS) target for drug-resistant hypertension: able to influence the baroreflex arc directly, having no known direct integrative or neuroendocrine function. Targeting the baroreflex regulatory center, but not its sensory or effector parts, could lead to a more predictable effect and stability of the control system. Although targeting neural centers in the medullary region is considered dangerous and prone to complications, it could open a new vista for deep brain stimulation therapy. A possible change in electrode design would be required to apply CVLM DBS in clinical trials in the future.

Remotely Programmable Deep Brain Stimulator Combined with an Invasive Blood Pressure Monitoring System for a Non-Tethered Rat Model in Hypertension Research.

The control circuits of blood pressure have a strong neural regulatory element important in the pathogenesis of essential drug-resistant hypertension. Targeting lower medullary neural control mechanisms of blood pressure by electrical stimulation could be beneficial, and therefore, a novel device is needed. This paper presents a remotely programmable deep brain stimulator with an invasive continuous blood pressure monitoring system in a non-tethered rat model. The device is designed for lower medullary deep brain stimulation research with minimal interference to a daily animal routine. Electrodes were implanted in the caudal ventrolateral medulla. Animal survivability, catheter patency rates, and device data drift were evaluated. Eight out of ten rats survived the surgery and testing period with no or mild temporary neurological compromise. The study revealed that carotid catheters filled with heparinized glycerol ensure better catheter patency rates and blood pressure transduction. There was no significant drift in the device's pressure sensitivity during the experiment. To our knowledge, this is the first experimental study to show considerable animal survival after lower medullary implantation. Combining the ability to measure and monitor invasive blood pressure with a closed-loop brain pulse generator in a single device could be of potential value in future hemodynamic animal research.

Prehospital Stroke Care, Paramedic Training Needs, and Hospital-Directed Feedback in Lithuania.

Background: Emergency medical services (EMS) are the first health care contact for the majority of stroke patients. However, there is a lack of data on the current paramedics' hospital-directed feedback and training needs across different health care settings. We aimed to evaluate paramedics' prehospital stroke care knowledge, training needs, and current status of feedback on suspected stroke patients. Methods: We surveyed paramedics from the Vilnius region from September to November 2019 and compared the answers between the city and the district agencies. The questionnaire content included questions on paramedics' demographic characteristics, prehospital stroke care self-assessment, knowledge on stroke mimics, stroke training needs, and the importance of hospital-directed feedback on suspected stroke patients. Results: A total number of 161 paramedics (or 49.4% of all paramedics from our stroke care network) were surveyed, with more district paramedics rating their prehospital stroke care knowledge as inadequate (44.8% (95% confidence interval (CI) 32.8−57.6) vs. 28.1% (95% CI 20.1−27.8), p = 0.028). In addition, more district paramedics indicated a need for additional stroke training (83.1% (95% CI 71.5−90.5) vs. 69.8% (60.0−78.1), p = 0.043). However, respondents reported being the most confident while dealing with stroke (71.3%, 95% CI 63.8−77.7) compared to other time-critical conditions (p < 0.001). Vertigo (60.8%, 95% CI 53.0−68.0), brain tumors (56.3%, 95% CI 48.5−63.8), and seizures (54.4%, 95% CI 46.7−62.0) were indicated as the most common stroke mimics. Only 6.2% (95% CI 3.4−11.1) of respondents received formal feedback on the outcome of suspected stroke patients brought to the emergency department. Conclusions: A high proportion of paramedics self-perceive having inadequate stroke knowledge and an urgent need for further stroke training. The EMS staff indicate receiving insufficient feedback on suspected stroke patients, even though its usefulness is perceived as paramount.

Interactive Training of the Emergency Medical Services Improved Prehospital Stroke Recognition and Transport Time.

Background and Purpose: Acute stroke treatment outcomes are predicated on reperfusion timeliness which can be improved by better prehospital stroke identification. We aimed to assess the effect of interactive emergency medical services (EMS) training on stroke recognition and prehospital care performance in a very high-risk cardiovascular risk population in Lithuania. Methods: We conducted a single-center interrupted time-series study between March 1, 2019 and March 15, 2020. Two-hour small-group interactive stroke training sessions were organized for 166 paramedics serving our stroke network. We evaluated positive predictive value (PPV) and sensitivity for stroke including transient ischemic attack identification, onset-to-door time, and hospital-based outcomes during 6-months prior and 3.5 months after the training. The study outcomes were compared between EMS providers in urban and suburban areas. Results: In total, 677 suspected stroke cases and 239 stroke chameleons (median age 75 years, 54.8% women) were transported by EMS. After the training, we observed improved PPV for stroke recognition (79.8% vs. 71.8%, p = 0.017) and a trend of decreased in-hospital mortality (7.8% vs. 12.3, p = 0.070). Multivariable logistic regression models adjusted for age, gender, EMS location, and stroke subtype showed an association between EMS stroke training and improved odds of stroke identification (adjusted odds ratio [aOR] 1.6 [1.1-2.3]) and onset-to-door ≤ 90 min (aOR 1.6 [1.1-2.5]). The improvement of PPV was observed in urban EMS (84.9% vs. 71.2%, p = 0.003), but not in the suburban group (75.0% vs. 72.6%, p = 0.621). Conclusions: The interactive EMS training was associated with a robust improvement of stroke recognition, onset to hospital transport time, and a trend of decreased in-hospital mortality. Adapted training strategies may be needed for EMS providers in suburban areas. Future studies should evaluate the long-term effects of the EMS training and identify optimal retraining intervals.

Changes in Prehospital Stroke Care and Stroke Mimic Patterns during the COVID-19 Lockdown.

The impact of COVID-19 lockdown on prehospital stroke care is largely unknown. We aimed to compare stroke care patterns before and during a state-wide lockdown. Thus, we analysed prospective data of stroke alerts referred to our stroke centre between 1 December 2019 and 16 June 2020, and compared them between two periods-15 weeks before and 13 weeks during the state-wide lockdown declared in Lithuania on 16 March 2020. Among 719 referrals for suspected stroke, there was a decrease in stroke alerts (rate ratio 0.61, 95% CI (0.52-0.71)), stroke admissions (0.63, 95% CI (0.52-0.76)), and decrease in prehospital stroke triage quality (positive predictive value 72.1% vs. 79.9%, p = 0.042) during the lockdown. The onset-to-door time was longer (153.0 vs. 120.5 min, p = 0.049) and seizures and intracranial tumours were more common among stroke mimics (16.9% vs. 6.7%, p = 0.012 and 9.6% vs. 3.0%, p = 0.037, respectively). We conclude that there was a decline in prehospital stroke triage quality during the lockdown despite low COVID-19 incidence in the country. Moreover, we observed an increase in hospital arrival delays and severe conditions presenting as stroke mimics. Our findings suggest that improved strategies are required to maintain optimal neurological care during public health emergencies.