Patients with COVID-19 Infection and Stroke have Higher than Expected Mortality, Regardless of the Primary Presentation (preprint)

BackgroundCOVID-19 infection is associated with thrombotic events; however, this phenomenon is poorly understood. Few studies have reported the association between COVID-19 and stroke in the hospital setting. MethodsWe retrospectively reviewed and characterized all patients who presented to a single, quaternary medical center between March and December 2020 (N=603). COVID-19 positive patients who developed ischemic or hemorrhagic stroke were included in the analysis (N=66). This cohort was compared with patients who were COVID-19 negative at the time of stroke presentation in the same period (N=537). Statistical significance was evaluated using Pearsons Chi squared test with Yates continuity correction and linear model ANOVA. ResultsSixty-six patients had COVID-19 and Stroke. Of these patients, 22 (33.4%) patients initially presented with stroke and 44 (66.7%) initially presented with COVID-19. Patients who presented with COVID-19 and had a stroke during their hospitalization (COVID-first) had worse outcomes than patients presenting to the hospital with stroke whose COVID test became positive later in the hospitalization (stroke-first). Patients who presented with COVID-19 and had a stroke during their hospitalization had an increased rate of acute renal failure (48.9% vs 19.0%, p=0.021) and need for ventilation (60.0% vs 28.6%, p=0.017). Further, in the COVID-first cohort, the use of heparin prior to the stroke event was not associated with mortality or type of stroke (ischemic or hemorrhagic). ConclusionIn the early pandemic, patients with COVID-19 infection and stroke had a higher mortality rate compared to COVID-19 negative patients with stroke. Among patients with both COVID-19 and stroke, patients presenting with COVID-19 first had worse outcomes than patients presenting with stroke first. The use of heparin prior to the stroke event was not associated with mortality or type of stroke.

Navigating stroke care during the COVID-19 pandemic: A scoping review (preprint)

Background: Previous viral outbreaks have highlighted implications for the management of complex health conditions. This study delves into the repercussions of the COVID-19 pandemic on stroke care, by examining evidence of shifts in healthcare utilization, the enduring effects on post-stroke recovery, and the overall quality of life experienced by stroke survivors. Methods: A scoping review was conducted following the Joanna Briggs Institute Methodology for Scoping Reviews. The search strategy encompassed electronic databases (APA PsycInfo, Embase, Medline, and CINAHL). English language articles published between December 2019 and January 2022 were included, focusing on individuals who experienced a stroke during the COVID-19 pandemic. Data extraction involved identifying study characteristics and significant findings, facilitating a qualitative and narrative synthesis of the gathered evidence. Results: Seven domain summaries were identified. They all described the aspects of systemic transformations in stroke care during the COVID-19 pandemic: (1) patient behavior and awareness; (2) telemedicine and remote care; (3) delays in treatment; (4) impact on healthcare resources; (5) quality of care; (6) changes in stroke severity; and (7) reduction in stroke admissions. Conclusions: This study underscored the critical need to encourage swift patient response to acute stroke symptoms, by finding new avenues for treatment, mitigating hospital-related infection fears, and advocating for the establishment of centralized stroke centers. These measures are integral to optimizing stroke care delivery and ensuring timely interventions, particularly in the challenging context of a pandemic.

Combinatorial biomedicine: A novel discipline (preprint)

Based on the author’s previous work, this article proposed a novel discipline– combinatorial biomedicine. Currently, there are several classical examples. One is a magic “polypill” covering the “Health Essential (HE) 5”, that is, “environment-sleep-emotion-exercise-diet” intervention [E(e)SEEDi] lifestyle; Another is an innovative “traditional Chinese medicine (TCM) Hot Pot”. In addition, the iRT-ABCDEFG program is indeed suitable for better management of human diseases. In fact, combinatorial biomedicine is pivotal in the development of life science, biology and medicine, in particular the pandemic and post-COVID-19 era, and has obvious advantages in screening, diagnosis, treatments, prevention and rehabilitation of both major non-communicable diseases (such as cardiovascular disease, diabetes, cancer, stroke, and neurodegenerative diseases) and major infectious diseases (such as AIDS, Helicobacter pylori infection, and COVID-19). As a novel discipline, combinatorial biomedicine plays a crucial role in combating human diseases and improving population health. It is about time to propose and establish this novel discipline.

Impact of in-hospital COVID-19 quarantine policy changes on quality of acute stroke care: A single center experience (preprint)

Background and purpose The COVID-19 pandemic is known to impact in-hospital processes for acute stroke patients, potentially resulting in delays due to quarantine and screening measures. The purpose of this study was to determine effects of changes in in-hospital quarantine policies on quality of care for acute stroke patients.Methods Hyperacute ischemic stroke patients who were admitted to Korea University Guro Hospital between January 2019 and February 2021 via the emergency department were included in this study. All had neurological symptoms within six hours before arrival. As a mandatory COVID-19 real-time PCR screening test was implemented in March 2020, changes in quality indicators according to the progress of COVID-19 pandemic and changes in in-hospital quarantine policy, including door-to-image time (DIT), door-to-referral time, door-to-needle time (DNT), door-to-puncture time (DPT), and functional outcomes (discharge and 3-month modified Rankin's scale) were determined.Results A total of 268 hyperacute stroke patients were analyzed. The number of hyperacute stroke patients gradually decreased as the pandemic progressed. Time indicators, including door-to-referral time, DIT, and DPT during the pandemic were increased. When pre- and post-COVID-19 screening epochs were compared, DIT, door-to-neurologist referral time, and DPT showed numerical increases. However, after accounting for potential confounders, a significant delay in DIT was found to be associated with the in-hospital COVID-19 quarantine policy.Conclusions Our study showed that enhancing in-hospital COVID-19 quarantine measures might increase the response time for hyperacute stroke care, suggesting an impact on the quality of care.Trial registration: Not applicable.

Inadvertent Exposure to Pharmacologically Designed Lipid Nanoparticles Via Bodily Fluids: Biologic Plausibility and Potential Consequences (preprint)

Exposure to vaccine lipid nanoparticles, mRNA, adenoviral DNA, and or Spike protein from one of the approved Covid-19 vaccines, or through secondary exposure, as through blood transfusion, is a potential source of harm. Blood reactions are an acknowledged side-effect of Covid-19 vaccination, not limited to hemolysis, paroxysmal nocturnal hemoglobinuria, chronic cold agglutinin disease, immune thrombocytopenia, haemophagocytosis, hemophagocytic lymphohistiocytosis, and many other blood related conditions. The observation of adverse events has motivated investigation into the cardiovascular mechanisms of harm by Covid-19 vaccines, and the biodistribution of vaccine contents. Biodistribution may not be limited to the body of the vaccine recipient, as a growing body of evidence demonstrates the possibility of secondary exposure to vaccine particles. These can be via bodily fluids and include the following routes of exposure: blood transfusion, organ transplantation, breastfeeding, and possibly other means. As covid-19 vaccines are associated with an increased risk of stroke, the persistence of vaccine artifacts in the blood presents a possible threat to a recipient of a blood donation from a vaccinated donor who suffered from vaccine induced thrombosis or thrombocytopenia. (VITT) We assess the feasibility and significance of these risks through an overview of the case report literature of blood disorders in vaccinated individuals, pharmacovigilance reports from the US Vaccine Adverse Events Reporting System (VAERS) and a meta-analysis of the available literature on organ transplants from vaccinated organ donors. Our analysis establishes biological mechanistic plausibility, a coherent safety signal in pharmacovigilance databases for secondary vaccine contents exposure (for the cases of blood transfusion and breastfeeding) and also an elevated level of adverse events in organ transplants from VITT-deceased donors, echoing increases in organ transplantation related complications seen in national statistics for some countries. Secondary exposure to vaccine artifacts is a potential explanation for some of the cases put forth, and requires a deeper investigation.

Events of Immune Thrombocytopenic Purpura (ITP) Among COVID-19-positive Adults in the United States; an Analysis via the National Inpatient Sample for Cases Between April to November 2020 (preprint)

Various cases of immune thrombocytopenic purpura (ITP) were reported among COVID-19-positive patients in the literature. We used the National Inpatient Sample (NIS) to evaluate the odds of ITP among COVID-19 patients in the United States between April and November 2020. Females (vs. Males), Whites (vs. other races), and the presence of multiple comorbidities such as chronic kidney disease, cirrhosis, prior stroke, HIV, obesity, cachexia, neoplasms, and autoimmune conditions showed higher odds of ITP. Meanwhile, those with diabetes and peripheral vascular disease and covered by private insurance (vs. Medicare) were less likely to experience ITP while being positive for the virus. Events of ITP also led to a higher mortality risk in COVID-19-positive patients.

Capturing Dynamics in Online Public Discourse: A Case Study of Universal Basic Income Discussions on Reddit (preprint)

Societal change is often driven by shifts in public opinion. As citizens evolve in their norms, beliefs, and values, public policies change too. While traditional opinion polling and surveys can outline the broad strokes of whether public opinion on a particular topic is changing, they usually cannot capture the full multi-dimensional richness and diversity of opinion present in a large heterogeneous population. However, an increasing fraction of public discourse about public policy issues is now occurring on online platforms, which presents an opportunity to measure public opinion change at a qualitatively different scale of resolution and context. In this paper, we present a conceptual model of observed opinion change on online platforms and apply it to study public discourse on Universal Basic Income (UBI) on Reddit throughout its history. UBI is a periodic, no-strings-attached cash payment given to every citizen of a population. We study UBI as it is a clearly-defined policy proposal that has recently experienced a surge of interest through trends like automation and events like the COVID-19 pandemic. We find that overall stance towards UBI on Reddit significantly declined until mid-2019, when this historical trend suddenly reversed and Reddit became substantially more supportive. Using our model, we find the most significant drivers of this overall stance change were shifts within different user cohorts, within communities that represented similar affluence levels, and within communities that represented similar partisan leanings. Our method identifies nuanced social drivers of opinion change in the large-scale public discourse that now regularly occurs online, and could be applied to a broad set of other important issues and policies.

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome (preprint)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID Syndrome (PCS). A fraction of the PCS patients develops the full clinical picture of ME/CFS. New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure. Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing constriction of resistance vessels and of precapillary sphincters which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion. The detrimental coincidence of the microcirculatory with the precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in pre-disposed patients because the interaction causes a particular kind of perfusion disturbance - capillary ischemia-reperfusion - which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter in turns worsens the vascular situation by the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.

Ischemic Stroke after Bivalent COVID-19 Vaccination: A Self-Controlled Case Series Study (preprint)

Introduction The potential association between bivalent COVID-19 vaccination and ischemic stroke remains uncertain, despite several studies conducted thus far. The purpose is to evaluate the risk of ischemic stroke following bivalent COVID-19 vaccination. Methods A self-controlled case series study was conducted among members aged 12 years and older who experienced ischemic stroke between September 1, 2022 and March 31, 2023 in a large California health care system. Ischemic strokes were identified using ICD-10 codes in Emergency Department and inpatient settings. Exposures were Pfizer-BioNTech or Moderna bivalent COVID-19 vaccination. Risk intervals were pre-specified as 1-21 days and 1-42 days after bivalent COVID-19 vaccination; all non-risk-interval person-time served as control interval. We conducted overall and subgroup analyses by age, history of SARS-CoV-2 infection, and co-administration of influenza vaccine. When an elevated risk was detected, we performed chart review of ischemic strokes, and re-evaluated the risk. RESULTS With 4933 cases, we found no increased risk within 21-day risk interval across vaccines and by subgroups. However, an elevated risk emerged within 42-day risk interval among individuals <65 years who received co-administration of Pfizer-BioNTech bivalent vaccine and influenza vaccine on the same day; relative incidence (RI) was 2.14 (95% CI, 1.02-4.49). Among those who also had history of SARS-CoV-2 infection, RI was 3.94 (95% CI, 1.10-14.16). After chart review, RIs were 2.35 (95% CI, 0.98-5.65) and 4.33 (95% CI, 0.98-19.11), respectively. Among individuals <65 years who received Moderna bivalent vaccine and had history of SARS-CoV-2 infection, RI was 2.62 (95% CI, 1.13-6.03) before chart review and 2.24 (95% CI, 0.78-6.47) after chart review. CONCLUSIONS The potential association between bivalent COVID-19 vaccination and ischemic stroke in the 1-42-day analysis warrants further investigation among individuals <65 years with influenza vaccine co-administration and prior SARS-CoV-2 infection.

Evaluation of Stroke Risk Following COVID-19 mRNA Bivalent Vaccines Among U.S. Adults Aged >=65 Years (preprint)

In January 2023, the United States Food and Drug Administration and the Centers for Disease Control and Prevention noted a safety concern for ischemic stroke in adults 65 years of age or older receiving the BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine. This self-controlled case series analysis evaluated stroke risk among Medicare fee-for-service beneficiaries aged 65 years of age or older receiving: 1) a Pfizer-BioNTech (BNT162b2; WT OMI BA.4 and BA.5) or Moderna (mRNA 1273.222) COVID-19 bivalent vaccine, 2) high-dose/adjuvanted influenza vaccines, and 3) concomitant COVID-19 bivalent vaccines and influenza vaccines, from August 31 to November 6, 2022. The primary analysis did not find elevated stroke risk following COVID-19 bivalent vaccines. In the age subgroup analyses, only the 85+ year age group had a risk of NHS (Incident Rate Ratio (IRR)=1.36, 95% CI 1.09 to 1.69 [1 to 21 days]) and NHS/TIA (IRR=1.28, 95% CI 1.08 to 1.52 [1 to 21 days]) with BNT162b2 Bivalent WT OMI BA.4 and BA.5. Among beneficiaries receiving a concomitant COVID-19 bivalent vaccine and a high-dose/adjuvanted influenza vaccine, an increased risk was observed for NHS (IRR=1.20, 95% CI 1.01 to 1.42 [22 to 42 days]) with BNT162b2 Bivalent WT OMI BA.4 and BA.5 and for TIA (IRR=1.35, 95% CI 1.06 to 1.74 [1 to 21 days]) with mRNA 1273.222. Results of the secondary analyses showed a small increased risk of NHS following high-dose or adjuvanted influenza vaccines (IRR=1.09, 95% CI 1.02 to 1.17 [22 to 42 days]).

Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain (preprint)

Viral infection severity often varies with host factors such as age and sex. The pathogenesis of infections caused by a broad range of viruses, from neurotropic viruses like Rabies and Zika to respiratory viruses such as influenza and SARS-CoV-2, differ between the sexes and across the lifespan. Typically, older males are more susceptible to severe acute outcomes, while females are more vulnerable to the post-acute sequelae of infections. All of these complications can include neuroinflammation, stroke, cognitive dysfunction, and delirium. While these symptoms can be secondary to infection, recent studies suggest that even peripheral infections can lead to neuropathological changes in the brain. However, few studies have characterized the expression of viral receptors in the human brain or examined age- or sex-related differences in such expression. In this study, we used a publicly accessible transcriptomic database to assess the impact of age and sex on the expression of 67 viral host factor genes, associated with ten virus families. Analyzing data from 15 brain areas (n=33, F=14, M=19, age:4 mo-80 yrs), we determined the lifespan trajectory for each gene in each area via LOESS regressions. We used unsupervised hierarchical clustering to determine if a brain-wide pattern or virus family pattern can be detected. Using Dense-tSNE, a dimension-reduction and visualization technique, we discovered four distinct developmental trajectories, clustering the areas into two mixed-sex subcortical clusters and one each of male and female cortical clusters. Applying Differential Expression Sliding Window Analysis (DeSWAN), we identified the genes driving these age- and sex-related differences. Many sex differences were noted in childhood, potentially impacting the brain\'s susceptibility to viral infections and underscoring a broader dimorphic organization of male and female brains. These insights contribute to our understanding of sex-specific responses to viral infections, offering the potential for more personalized treatment strategies.

In-person and online mixed method non-randomised studies exploring feasibility and acceptability of HEADS: UP, an adapted Mindfulness Based Stress Reduction programme for stroke survivors experiencing symptoms of anxiety and depression (preprint)

Background Depression and anxiety are prevalent after stroke and associated with poor outcomes. We previously co-developed a stroke-specific self-management intervention, HEADS: UP (Helping Ease Anxiety and Depression after Stroke). The two studies reported here aimed to test the feasibility and acceptability of the HEADS: UP course and supporting materials, and research processes ahead of a definitive trial. Methods We recruited community-dwelling stroke survivors (SS) ≥3 months post-stroke, with symptoms of mood disorder (Hospital Anxiety and Depression Scale ≥8). Participants could ‘enrol’ a family member/‘other’ to take part with them, if desired. Study 1 tested HEADS: UP delivered in-person, and informed optimisation of research processes and intervention delivery and materials. In response to Covid-related socialising restrictions HEADS: UP was then adapted for online delivery; tested in Study 2. The primary outcome (both studies) was feasibility (acceptability, fidelity) of the intervention and of research processes. Quantitative data (including patient reported outcomes measures (PROMs) assessing mood and quality of life), and qualitative data were collected pre-/post-intervention. Descriptive statistics were used to analyse quantitative data; a thematic framework approach was used to analyse qualitative data. Both studies received ethical approval prior to commencement. Results Study 1: Feasibility: 13 (59.1%) of 22 potentially eligible stroke survivors consented; aged 66 (median, IQR 14); male (n=9; 69%); 28 (IQR 34; 13.5-48) months poststroke. Of these n=10 (76.9%) completed PROMS pre-intervention; n=6 (46.2%) post-intervention. Acceptability: Six (85.7%) stroke survivors attended ≥4 core intervention sessions. Aspects of screening and data collection were found to be burdensome. Study 2: Feasibility: SS n=9 (41%) of 22 potentially eligible stroke survivors consented; aged 58 years (median; IR 12); male (n=4; 44.4%); 23 (IQR 34; 10-38) months poststroke. Of these n=5 (55.6%) completed PROMS pre-intervention; n=5 (55.6%) post-intervention. Acceptability: Five (55.6%) stroke survivors attended ≥ 4 core sessions. They found online screening and data collection processes straightforward. Conclusions Stroke survivors found in-person and online HEADS: UP intervention and research processes feasible and acceptable. A pilot RCT is warranted, after making the adaptations to intervention delivery and research processes identified in this feasibility and acceptability research. Trial registration Study 1 (in-person delivery): ClinicalTrials.gov: NCT03956693, registered 20 May 2019, https://www.clinicaltrials.gov/study/NCT03956693 Study 2 (online delivery): ClinicalTrials.gov: NCT04567472, registered 23, September 2020, https://clinicaltrials.gov/study/NCT04567472?tab=results

Risk of Ischemic Stroke after COVID-19 Bivalent Booster Vaccination in an Integrated Health System (preprint)

Abstract: Purpose: What is the absolute occurrence of ischemic stroke and transient ischemic attack after a COVID-19 bivalent vaccination? Methods: We conducted a retrospective cohort study of Kaiser Permanente Northwest (KPNW) patients 18 years and older who were vaccinated with either the Pfizer or Moderna formulation of the COVID19 bivalent vaccine between September 1, 2022 and March 1st 2023. Patients were included in the study if they had KP membership at the time of vaccination and through the 21-day follow up period. We replicated the Vaccine Safety Datalink (VSD) rapid cycle analysis methodology and searched for possible cases of ischemic stroke or TIA in the 21 days following vaccination using ICD10CM diagnosis codes in both the primary position and any position. We waited 90 days from the end of the follow up (March 21, 2023) for complete non KP data accrual before analyzing the data to account for the lag in processing outside hospital insurance claims. Two physicians adjudicated possible cases by reviewing the clinical notes in the electronic health record. The analyses were stratified by age 65 years and older to allow for comparisons with VSDs reporting at the Advisory Committee on Immunization Practices (ACIP) meeting of incidence of ischemic stroke or TIA (VSD reported incidence; 24.6 cases of ischemic stroke or TIA per 100,000 patients vaccinated). Results: The incidence of ischemic stroke or TIA was 34.3 per 100,000 (95% CI, 17.7 to 59.9) in patients 65 years or older who received the bivalent Pfizer vaccine, based on a diagnosis code in the primary position of the emergency department or hospital discharge. The incidence increased to 45.7 per 100,000 (95% CI 26.1 to 74.2) when we expanded the search to a diagnosis in any position and did not adjudicate to confirm. However, most of those additional apparent stroke or TIA diagnoses were false-positive diagnoses based on physicians adjudications. Estimating the incidence based on the primary position agreed closely with estimating the incidence based on any position and physician adjudication: 37.1 per 100,000 (95% CI 19.8 to 63.5). Seventy-nine percent of the ischemic stroke cases were admitted to hospitals that are not owned by the integrated delivery system. Conclusion: We identified a 50% increase in the incidence of ischemic stroke per 100,000 patients ages 65 and older vaccinated with the Pfizer bivalent vaccine, compared to the data presented by the VSD. Seventy-nine percent of the ischemic stroke cases were admitted to hospitals that are not owned by the integrated delivery system and a delay in processing outside hospital insurance claims was likely responsible for the discrepancy in case ascertainment of ischemic stroke. Physician adjudication of all cases in this study allowed accurate absolute incidence estimates of stroke per 100,000 vaccine recipients and is helpful in calculation of net benefit for policy recommendations and shared decision-making.

Navigating the Neurological Aftermath of COVID-19: An In-Depth Exploration (preprint)

Background: The COVID-19 pandemic caused by SARS-CoV-2 has affected millions of people and can result in both immediate and prolonged neurological effects, including severe complications. While numerous studies have explored the occurrence and consequences of neurological issues in COVID-19, they have often involved limited sample sizes. Purpose: This paper aims to determine the overall occurrence of neurological complications in COVID-19, examine their links with patient demographics, and assess their impact on patient outcomes. Additionally, it seeks to provide an overview of the current understanding of the underlying mechanisms. Methodology: Two systematic reviews were conducted to investigate acute and chronic neurological complications associated with COVID-19. A comprehensive search of medical databases was performed, and relevant studies were evaluated following PRISMA guidelines. Meta-analysis was carried out using the Mantel-Haenszel method, with subgroup analysis and meta-regression used to assess heterogeneity. Results: The analysis of acute complications included 20,011 patients with an average age of 58.1 years and a slight male predominance (55.2%). Common neurological symptoms included loss of taste and smell, headaches, acute encephalopathy, and stroke. For the analysis of long-term complications, 2,094 patients were included. Survivors of COVID-19 experienced ongoing neurological issues ranging from sensory impairments to fatigue, headaches, strokes, and even cognitive and psychiatric problems. Conclusion: By examining various neurological symptoms, this study found a significant association between these manifestations and worse overall outcomes, especially in patients over 60 years old. Identifying high-risk individuals and maintaining a high level of suspicion are crucial for enhancing our understanding of the underlying mechanisms, validating biomarkers, and improving the management of these neurological issues.

Emerging Links Between COVID-19 and Cardiovascular & Cerebrovascular Thromboembolic Events: A Systematic Review (preprint)

COVID-19, caused by the SARS-CoV-2 virus, initially identified as a respiratory illness, has increasingly been linked to a broader range of organ complications. This systematic review explores the impact of COVID-19 on cardiovascular and cerebrovascular health, focusing on thromboembolic events in post-COVID patients. A comprehensive literature search was conducted in PubMed and Google Scholar databases up to July 2023, utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies meeting eligibility criteria were analyzed for outcomes and associations between COVID-19 and cardiovascular and cerebrovascular events. The review includes 6 studies involving over 12 million patients, demonstrating a strong connection between COVID-19 and elevated risks of cardiovascular and cerebrovascular thromboembolic events. The risk of these events is evident in conditions such as ischemic heart disease, stroke, and cardiac arrhythmias. The burden of these events beyond the acute phase of the disease is concerning, warranting further exploration of long-term implications. Variability in event rates among different cohorts and healthcare settings underscores the need for understanding underlying factors influencing these differences. Potential mechanisms behind these events include endothelial dysfunction, systemic inflammation, and viral invasion. Implications for public health policies, clinical guidelines, and future research directions are discussed. This review serves as a valuable resource for healthcare providers, policymakers, and researchers to enhance patient care, outcomes, and preparedness for future waves of COVID-19 infections. However, there remain unexplored aspects of the COVID-19 and thromboembolic events relationship, urging further investigations into mechanistic insights and potential therapeutic interventions.

SARS-CoV-2 infection triggers pro-atherogenic inflammatory 1 responses in human coronary vessels (preprint)

COVID-19 patients present higher risk for myocardial infarction (MI), acute coronary syndrome, and stroke for up to 1 year after SARS-CoV-2 infection. While the systemic inflammatory response to SARS-CoV-2 infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques to locally promote inflammation remains unknown. Here, we report that SARS-CoV-2 viral RNA (vRNA) is detectable and replicates in coronary atherosclerotic lesions taken at autopsy from patients with severe COVID-19. SARS-CoV-2 localizes to plaque macrophages and shows a stronger tropism for arterial lesions compared to corresponding perivascular fat, correlating with the degree of macrophage infiltration. In vitro infection of human primary macrophages highlights that SARS-CoV-2 entry is increased in cholesterol-loaded macrophages (foam cells) and is dependent, in part, on neuropilin-1 (NRP-1). Furthermore, although viral replication is abortive, SARS-CoV-2 induces a robust inflammatory response that includes interleukins IL-6 and IL-1{beta}, key cytokines known to trigger ischemic cardiovascular events. SARS-CoV-2 infection of human atherosclerotic vascular explants recapitulates the immune response seen in cultured macrophages, including proatherogenic cytokine secretion. Collectively, our data establish that SARS-CoV-2 infects macrophages in coronary atherosclerotic lesions, resulting in plaque inflammation that may promote acute CV complications and long-term risk for CV events

SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection (preprint)

Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20% of hospitalized patients are at risk for thromboembolic events. This prothrombotic state is considered a key factor in the increased risk of stroke, which has been observed clinically during both acute infection and long after symptoms have cleared. Here we developed a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells, pericytes, and smooth muscle cells to recapitulate the vascular pathology associated with SARS-CoV-2 exposure. Our results demonstrate that perivascular cells, particularly smooth muscle cells (SMCs), are a specifically susceptible vascular target for SARS-CoV-2 infection. Utilizing RNA sequencing, we characterized the transcriptomic changes accompanying SARS-CoV-2 infection of SMCs, and endothelial cells (ECs). We observed that infected human SMCs shift to a pro-inflammatory state and increase the expression of key mediators of the coagulation cascade. Further, we showed human ECs exposed to the secretome of infected SMCs produce hemostatic factors that can contribute to vascular dysfunction, despite not being susceptible to direct infection. The findings here recapitulate observations from patient sera in human COVID-19 patients and provide mechanistic insight into the unique vascular implications of SARS-CoV-2 infection at a cellular level.

The impact of COVID-19 on community-dwelling people post-stroke and informal caregivers: a qualitative study (preprint)

Background/ aims: Little is known about the experience of people post-stroke and their informal caregivers during the COVID-19 pandemic. The aim of this study was to understand the challenges faced by people post-stroke and informal caregivers during the pandemic, as well as the impact on their healthcare support, lifestyle, and self-care behaviors. Methods: A multi-perspective qualitative study was undertaken, with semi-structured interviews being carried out to sixteen participants: eight stroke patients and eight informal caregivers, mostly performed online. Reflexive thematic analysis was used, with data being independently coded and categorized before consolidated into themes and subthemes. Findings: Three themes were derived from the data analysis: i) Perceived impact of COVID-19 pandemic, ii) What helped? - strategies to manage the distress provoked by COVID-19, and iii) The value of rehabilitation and physical activity, with findings highlighting the negative psychological impact of the pandemic. In response to the perceived lack of support and access to health and social services, participants highlighted the use of digital approaches and professional support. Conclusions: Findings suggest the importance of self-management support and/or digital content in order to mitigate the impact of COVID-19. The involvement of peers, family members, friends or others seems to be an important strategy to increase motivation in remote rehabilitation and physical activity.