List of Peer-Reviewed Publications
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92. Bhaskar SMM. An Equity and Justice-Informed Ethical Framework to Guide Incidental Findings in Brain Imaging Research. Clin Pract. 2023 Jan 16;13(1):116-124. doi: 10.3390/clinpract13010011. PMID: 36648851; PMCID: PMC9890311.
The handling of incidental findings (IFs) in brain imaging studies has been a source of contention among scientists and bioethicists. A conceptual framework informed by diversity, equity, and inclusion (DEI) and distributive justice approaches, namely EUSTICE, is proposed for the ethical handling and reporting of IFs in brain imaging research. I argue that EUSTICE provides a systematic and inclusive approach to addressing the ethical conundrum around IF disclosure and managing IFs proportionately and sensitively in brain imaging research. The EUSTICE framework may have implications for the field of neurosciences or human studies broadly in guiding ethics of IFs in research.
Keywords: brain imaging; ethics; framework; neuroscience; radiology.
91. Global Burden of Disease 2021 Health Financing Collaborator Network. Global investments in pandemic preparedness and COVID-19: development assistance and domestic spending on health between 1990 and 2026. Lancet Glob Health. 2023 Mar;11(3):e385-e413. doi: 10.1016/S2214-109X(23)00007-4. Epub 2023 Jan 24. PMID: 36706770; PMCID: PMC9998276.
Background: The COVID-19 pandemic highlighted gaps in health surveillance systems, disease prevention, and treatment globally. Among the many factors that might have led to these gaps is the issue of the financing of national health systems, especially in low-income and middle-income countries (LMICs), as well as a robust global system for pandemic preparedness. We aimed to provide a comparative assessment of global health spending at the onset of the pandemic; characterise the amount of development assistance for pandemic preparedness and response disbursed in the first 2 years of the COVID-19 pandemic; and examine expectations for future health spending and put into context the expected need for investment in pandemic preparedness.
Methods: In this analysis of global health spending between 1990 and 2021, and prediction from 2021 to 2026, we estimated four sources of health spending: development assistance for health (DAH), government spending, out-of-pocket spending, and prepaid private spending across 204 countries and territories. We used the Organisation for Economic Co-operation and Development (OECD)’s Creditor Reporting System (CRS) and the WHO Global Health Expenditure Database (GHED) to estimate spending. We estimated development assistance for general health, COVID-19 response, and pandemic preparedness and response using a keyword search. Health spending estimates were combined with estimates of resources needed for pandemic prevention and preparedness to analyse future health spending patterns, relative to need.
Findings: In 2019, at the onset of the COVID-19 pandemic, US$9·2 trillion (95% uncertainty interval [UI] 9·1-9·3) was spent on health worldwide. We found great disparities in the amount of resources devoted to health, with high-income countries spending $7·3 trillion (95% UI 7·2-7·4) in 2019; 293·7 times the $24·8 billion (95% UI 24·3-25·3) spent by low-income countries in 2019. That same year, $43·1 billion in development assistance was provided to maintain or improve health. The pandemic led to an unprecedented increase in development assistance targeted towards health; in 2020 and 2021, $1·8 billion in DAH contributions was provided towards pandemic preparedness in LMICs, and $37·8 billion was provided for the health-related COVID-19 response. Although the support for pandemic preparedness is 12·2% of the recommended target by the High-Level Independent Panel (HLIP), the support provided for the health-related COVID-19 response is 252·2% of the recommended target. Additionally, projected spending estimates suggest that between 2022 and 2026, governments in 17 (95% UI 11-21) of the 137 LMICs will observe an increase in national government health spending equivalent to an addition of 1% of GDP, as recommended by the HLIP.
Interpretation: There was an unprecedented scale-up in DAH in 2020 and 2021. We have a unique opportunity at this time to sustain funding for crucial global health functions, including pandemic preparedness. However, historical patterns of underfunding of pandemic preparedness suggest that deliberate effort must be made to ensure funding is maintained.
Funding: Bill & Melinda Gates Foundation.
90. International Lipid Expert Panel (ILEP). Nutraceutical approaches to non-alcoholic fatty liver disease (NAFLD): A position paper from the International Lipid Expert Panel (ILEP). Pharmacol Res. 2023 Mar;189:106679. doi: 10.1016/j.phrs.2023.106679. Epub 2023 Feb 8. PMID: 36764041.
Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.
Keywords: Dietary supplements; Liver steatosis; NAFLD; Nutraceuticals; Position paper.
89. Bhaskar SMM. The Impact of the COVID-19 Pandemic on e-Services and Digital Tools Development in Medicine. In: Banach, M. (eds) Cardiovascular Complications of COVID-19. Contemporary Cardiology. Humana, Cham. 2022. https://doi.org/10.1007/978-3-031-15478-2_25 [Book Chapter]
COVID-19 has impacted health systems and communities. The restrictions imposed during the COVID-19 outbreak to mitigate community transmission of the virus led to the rapid incorporation of e-services and digital tools to support patient continuity and limit infection exposure to health systems. COVID-19 has led to increased efforts to deliver healthcare digitally, offering rapid and easy healthcare access to individuals. In this article, a comprehensive overview and summary update on tools available for digital care and services, as well as their potential benefits and limitations have been provided. Perspectives on mitigating barriers and improving access and use of these tools to deliver digital care have been discussed. Lastly, specific indications for integrating digital tools, such as telemedicine, into a conceptual pandemic preparedness and response framework along with conventional public health measures are also provided. The shift to digital care will improve universal health coverage as well as complement other socioeconomic interventions in supporting post-pandemic recovery.
88. Sun M-Y; Bhaskar SMM**. Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy: A Systematic Review and Meta-Analysis. Diagnostics 2022, 12, 2954. https://doi.org/10.3390/diagnostics12122954
Objective: Venous thromboembolism (VTE) is a life-threatening complication that may exacerbate cancer prognosis. Whilst some studies indicate an increased risk of VTE in cancer patients undergoing chemotherapy, the prevalence estimates on the pooled prevalence of VTE in cancer patients undergoing chemotherapy are not known. This study aims to calculate the pooled prevalence of VTE in chemotherapy-treated cancer patients.
Methods: Studies on VTE occurrence in cancer patients undergoing chemotherapy were retrieved after database search. The terms used included “cancer”, “chemotherapy”, and “venous thromboembolism”. A random-effects meta-analysis was conducted to obtain a pooled estimate of VTE prevalence in cancer patients undergoing chemotherapy.
Results: A total of 102 eligible studies involving 30, 671 patients (1773 with VTE, 28, 898 without) were included in the meta-analysis. The pooled estimate of VTE prevalence was found to be 6%, ranging from 6 to 7% (ES 6%; 95% CI 6–7%; z = 18.53; p < 0.001).
Conclusions: The estimated pooled prevalence rate of VTEs was 6% in cancer patients undergoing CRT, which was higher than the overall crude prevalence rate (5.78%). Comprehensive cancer care should consider stratified VTE risk assessment based on cancer phenotype, given that certain phenotypes of cancer such as bladder, gastric and ovarian posing particularly high risks of VTE.
87. GBD 2019 Antimicrobial Resistance Collaborators. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2022 Nov 18:S0140-6736(22)02185-7. doi: 10.1016/S0140-6736(22)02185-7. Epub ahead of print. PMID: 36423648.
Background: Reducing the burden of death due to infection is an urgent global public health priority. Previous studies have estimated the number of deaths associated with drug-resistant infections and sepsis and found that infections remain a leading cause of death globally. Understanding the global burden of common bacterial pathogens (both susceptible and resistant to antimicrobials) is essential to identify the greatest threats to public health. To our knowledge, this is the first study to present global comprehensive estimates of deaths associated with 33 bacterial pathogens across 11 major infectious syndromes.
Methods: We estimated deaths associated with 33 bacterial genera or species across 11 infectious syndromes in 2019 using methods from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, in addition to a subset of the input data described in the Global Burden of Antimicrobial Resistance 2019 study. This study included 343 million individual records or isolates covering 11 361 study-location-years. We used three modelling steps to estimate the number of deaths associated with each pathogen: deaths in which infection had a role, the fraction of deaths due to infection that are attributable to a given infectious syndrome, and the fraction of deaths due to an infectious syndrome that are attributable to a given pathogen. Estimates were produced for all ages and for males and females across 204 countries and territories in 2019. 95% uncertainty intervals (UIs) were calculated for final estimates of deaths and infections associated with the 33 bacterial pathogens following standard GBD methods by taking the 2·5th and 97·5th percentiles across 1000 posterior draws for each quantity of interest.
Findings: From an estimated 13·7 million (95% UI 10·9-17·1) infection-related deaths in 2019, there were 7·7 million deaths (5·7-10·2) associated with the 33 bacterial pathogens (both resistant and susceptible to antimicrobials) across the 11 infectious syndromes estimated in this study. We estimated deaths associated with the 33 bacterial pathogens to comprise 13·6% (10·2-18·1) of all global deaths and 56·2% (52·1-60·1) of all sepsis-related deaths in 2019. Five leading pathogens-Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa-were responsible for 54·9% (52·9-56·9) of deaths among the investigated bacteria. The deadliest infectious syndromes and pathogens varied by location and age. The age-standardised mortality rate associated with these bacterial pathogens was highest in the sub-Saharan Africa super-region, with 230 deaths (185-285) per 100 000 population, and lowest in the high-income super-region, with 52·2 deaths (37·4-71·5) per 100 000 population. S aureus was the leading bacterial cause of death in 135 countries and was also associated with the most deaths in individuals older than 15 years, globally. Among children younger than 5 years, S pneumoniae was the pathogen associated with the most deaths. In 2019, more than 6 million deaths occurred as a result of three bacterial infectious syndromes, with lower respiratory infections and bloodstream infections each causing more than 2 million deaths and peritoneal and intra-abdominal infections causing more than 1 million deaths.
Interpretation: The 33 bacterial pathogens that we investigated in this study are a substantial source of health loss globally, with considerable variation in their distribution across infectious syndromes and locations. Compared with GBD Level 3 underlying causes of death, deaths associated with these bacteria would rank as the second leading cause of death globally in 2019; hence, they should be considered an urgent priority for intervention within the global health community. Strategies to address the burden of bacterial infections include infection prevention, optimised use of antibiotics, improved capacity for microbiological analysis, vaccine development, and improved and more pervasive use of available vaccines. These estimates can be used to help set priorities for vaccine need, demand, and development.
Funding: Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care, using UK aid funding managed by the Fleming Fund.
86. Chen S, Spring KJ, Killingsworth MC, Calic Z, Beran RG, Bhaskar SMM**. Association of Lesion Topography with Functional Outcomes in Acute Ischemic Stroke Patients Considered for, or Receiving, Reperfusion Therapy: A Meta-Analysis. Neurology International. 2022; 14(4):903-922. https://doi.org/10.3390/neurolint14040073
Background: The impact of lesion topography (LT), characterised by the Alberta Stroke Programme Early CT Score (ASPECTS), on outcomes after reperfusion therapy in acute ischemic stroke (AIS) is poorly elucidated. We investigated the prognostic accuracy of ASPECTS-based LT assessment and its association with clinical outcomes in AIS patients considered for reperfusion therapy or receiving intravenous thrombolysis (IVT), endovascular thrombectomy (EVT), or none or both.
Methods: Studies were identified from PubMed with additional studies added from Google Scholar. The prevalence of individual ASPECTS regions will also be determined. The association of individual ASPECTS regions with the functional outcome at 90 days will be assessed using random-effects modelling for various cut-offs, such as 6, 7 and 8. The association of continuous ASPECTS with the functional outcome at 90 days will also be undertaken. Forest plots of odds ratios (ORs) will be generated.
Results: A total of 25 studies have been included in the final analysis, encompassing 11,404 patients. Pooled estimates indicate that the highest prevalence rates were in cases involving the insula and lentiform nucleus. Subgroup analysis for ASPECTS < 6 (OR 6.10; 95% CI 2.50–14.90; p < 0.0001), ASPECTS < 7 (OR 4.58; 95% CI 1.18–17.86; p < 0.0001) and ASPECTS < 8 (OR 2.26; 95% CI 1.32–3.89; p < 0.0001) revealed a significant association with poor functional outcome at 90 days. Decreasing ASPECTS significantly increased the odds of poor functional outcomes at 90 days (SMD −1.15; 95% CI −1.77–−0.52; p < 0.0001).
Conclusions: Our meta-analysis demonstrates that decreasing ASPECTS is significantly associated with poor functional outcomes. Individual ASPECTS regions associated with the highest odds of poor functional outcomes were identified. Future studies on the association of LT and clinical outcomes specific to EVT are required.
85. Bhaskar SMM**, Nurtazina A, Mittoo S, Banach M and Weissert R (2022) Editorial: Telemedicine during and beyond COVID-19, volume II. Front. Public Health 10:1057879. doi: 10.3389/fpubh.2022.1057879
84. Huang JC, Bhaskar SMM**. Clot Morphology in Acute Ischemic Stroke Decision Making. International Journal of Molecular Sciences. 2022; 23(20):12373. https://doi.org/10.3390/ijms232012373
Stroke is a leading cause of death and disability in the world, and the provision of reperfusion therapy and endovascular therapy, in particular, have revolutionized the treatment of patients with stroke and opened opportunities to look at brain clots retrieved after the procedure. The use of histopathology and molecular profiling of clots is of growing research and clinical interest. However, its clinical implications and incorporation within stroke workflows remain suboptimal. Recent studies have indicated that the study of brain clots may inform the mechanism of stroke and hence guide treatment decision-making in select groups of patients, especially patients without a defined cause or known mechanism. This article provides a comprehensive overview of various clot histopathological examinations in acute stroke-care settings, their clinical utility, and existing gaps and opportunities for further research. We also provide targeted recommendations to improve clot analysis workflow, hence standardizing its incorporation into clinical practice.
83. Huang J, Killingsworth MC, Bhaskar SMM**. Is Composition of Brain Clot Retrieved by Mechanical Thrombectomy Associated with Stroke Aetiology and Clinical Outcomes in Acute Ischemic Stroke?—A Systematic Review and Meta-Analysis. Neurology International. 2022; 14(4):748-770. https://doi.org/10.3390/neurolint14040063
Background: Brain clots retrieved following endovascular thrombectomy in acute ischemic stroke patients may offer unique opportunities to characterise stroke aetiology and aid stroke decision-making in select groups of patients. However, the evidence around the putative association of clot morphology with stroke aetiology is limited and remains inconclusive. This study aims to perform a systematic review and meta-analysis to delineate the association of brain clot composition with stroke aetiology and post-reperfusion outcomes in patients receiving endovascular thrombectomy.
Methods: The authors conducted a systematic literature review and meta-analysis by extracting data from several research databases (MEDLINE/PubMed, Cochrane, and Google Scholar) published since 2010. We used appropriate key search terms to identify clinical studies concerning stroke thrombus composition, aetiology, and clinical outcomes, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Results: The authors identified 30 articles reporting on the relationship between stroke thrombus composition or morphology and aetiology, imaging, or clinical outcomes, of which 21 were included in the meta-analysis. The study found that strokes of cardioembolic origin (SMD = 0.388; 95% CI, 0.032–0.745) and cryptogenic origin (SMD = 0.468; 95% CI, 0.172–0.765) had significantly higher fibrin content than strokes of non-cardioembolic origin. Large artery atherosclerosis strokes had significantly lower fibrin content than cardioembolic (SMD = 0.552; 95% CI, 0.099–1.004) or cryptogenic (SMD = 0.455; 95% CI, 0.137–0.774) strokes. Greater red blood cell content was also significantly associated with a thrombolysis in cerebral infarction score of 2b–3 (SMD = 0.450; 95% CI, 0.177–0.722), and a positive hyperdense middle cerebral artery sign (SMD = 0.827; 95% CI, 0.472–1.183). No significant associations were found between red blood cell, platelet, or white blood cell content and aetiology, or between clot composition and bridging thrombolysis.
Conclusions: This meta-analysis found that fibrin composition is significantly higher in strokes of cardioembolic and cryptogenic origin, and that red blood cell content is positively associated with the hyperdense middle cerebral artery sign and better reperfusion outcomes. Important advances to stroke clinical workup can be derived from these findings, in which many aspects of stroke workflow remain to be optimised. As data are still limited in terms of the association of various thrombus components with stroke aetiology as well as a standardised method of analysis, further studies are required to validate these findings to guide their use in clinical decision-making.
82. GBD 2019 Healthcare Access and Quality Collaborators. Assessing performance of the Healthcare Access and Quality Index, overall and by select age groups, for 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet Glob Health. 2022 Oct 6:S2214-109X(22)00429-6. doi: 10.1016/S2214-109X(22)00429-6. Epub ahead of print. PMID: 36209761.
Background: Health-care needs change throughout the life course. It is thus crucial to assess whether health systems provide access to quality health care for all ages. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019), we measured the Healthcare Access and Quality (HAQ) Index overall and for select age groups in 204 locations from 1990 to 2019.
Methods: We distinguished the overall HAQ Index (ages 0-74 years) from scores for select age groups: the young (ages 0-14 years), working (ages 15-64 years), and post-working (ages 65-74 years) groups. For GBD 2019, HAQ Index construction methods were updated to use the arithmetic mean of scaled mortality-to-incidence ratios (MIRs) and risk-standardised death rates (RSDRs) for 32 causes of death that should not occur in the presence of timely, quality health care. Across locations and years, MIRs and RSDRs were scaled from 0 (worst) to 100 (best) separately, putting the HAQ Index on a different relative scale for each age group. We estimated absolute convergence for each group on the basis of whether the HAQ Index grew faster in absolute terms between 1990 and 2019 in countries with lower 1990 HAQ Index scores than countries with higher 1990 HAQ Index scores and by Socio-demographic Index (SDI) quintile. SDI is a summary metric of overall development.
Findings: Between 1990 and 2019, the HAQ Index increased overall (by 19·6 points, 95% uncertainty interval 17·9-21·3), as well as among the young (22·5, 19·9-24·7), working (17·2, 15·2-19·1), and post-working (15·1, 13·2-17·0) age groups. Large differences in HAQ Index scores were present across SDI levels in 2019, with the overall index ranging from 30·7 (28·6-33·0) on average in low-SDI countries to 83·4 (82·4-84·3) on average in high-SDI countries. Similarly large ranges between low-SDI and high-SDI countries, respectively, were estimated in the HAQ Index for the young (40·4-89·0), working (33·8-82·8), and post-working (30·4-79·1) groups. Absolute convergence in HAQ Index was estimated in the young group only. In contrast, divergence was estimated among the working and post-working groups, driven by slow progress in low-SDI countries.
Interpretation: Although major gaps remain across levels of social and economic development, convergence in the young group is an encouraging sign of reduced disparities in health-care access and quality. However, divergence in the working and post-working groups indicates that health-care access and quality is lagging at lower levels of social and economic development. To meet the needs of ageing populations, health systems need to improve health-care access and quality for working-age adults and older populations while continuing to realise gains among the young.
Funding: Bill & Melinda Gates Foundation.
81. European Antimicrobial Resistance Collaborators. The burden of bacterial antimicrobial resistance in the WHO European region in 2019: a cross-country systematic analysis. The Lancet Public Health. 2022 Oct 13. doi: 10.1016/S2468-2667(22)00225-0.
Antimicrobial resistance (AMR) represents one of the most crucial threats to public health and modern health care. Previous studies have identified challenges with estimating the magnitude of the problem and its downstream effect on human health and mortality. To our knowledge, this study presents the most comprehensive set of regional and country-level estimates of AMR burden in the WHO European region to date.
We estimated deaths and disability-adjusted life-years attributable to and associated with AMR for 23 bacterial pathogens and 88 pathogen–drug combinations for the WHO European region and its countries in 2019. Our methodological approach consisted of five broad components: the number of deaths in which infection had a role, the proportion of infectious deaths attributable to a given infectious syndrome, the proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antimicrobial drug of interest, and the excess risk of mortality (or duration of an infection) associated with this resistance. These components were then used to estimate the disease burden by using two counterfactual scenarios: deaths attributable to AMR (considering an alternative scenario where infections with resistant pathogens are replaced with susceptible ones) and deaths associated with AMR (considering an alternative scenario where drug-resistant infections would not occur at all). Data were solicited from a wide array of international stakeholders; these included research hospitals, surveillance networks, and infection databases maintained by private laboratories and medical technology companies. We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity.
We estimated 541 000 deaths (95% UI 370 000–763 000) associated with bacterial AMR and 133 000 deaths (90 100–188 000) attributable to bacterial AMR in the whole WHO European region in 2019. The largest fatal burden of AMR in the region came from bloodstream infections, with 195 000 deaths (104 000–333 000) associated with resistance, followed by intra-abdominal infections (127 000 deaths [81 900–185 000]) and respiratory infections (120 000 deaths [94 500–154 000]). Seven leading pathogens were responsible for about 457 000 deaths associated with resistance in 53 countries of this region; these pathogens were, in descending order of mortality, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, Streptococcus pneumoniae, and Acinetobacter baumannii. Methicillin-resistant S aureus was shown to be the leading pathogen–drug combination in 27 countries for deaths attributable to AMR, while aminopenicillin-resistant E coli predominated in 47 countries for deaths associated with AMR.
The high levels of resistance for several important bacterial pathogens and pathogen–drug combinations, together with the high mortality rates associated with these pathogens, show that AMR is a serious threat to public health in the WHO European region. Our regional and cross-country analyses open the door for strategies that can be tailored to leading pathogen–drug combinations and the available resources in a specific location. These results underscore that the most effective way to tackle AMR in this region will require targeted efforts and investments in conjunction with continuous outcome-based research endeavours.
Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.
80. Chatzis DG, Magounaki K, Pantazopoulos I, Bhaskar SMM. COVID-19 and the cardiovascular system-current knowledge and future perspectives. World J Clin Cases. 2022 Sep 26;10(27):9602-9610. doi: 10.12998/wjcc.v10.i27.9602. PMID: 36186205; PMCID: PMC9516937.
The current coronavirus disease 2019 (COVID-19) pandemic has had devastating impact on populations around the world. The high mortality rates in patients with COVID-19 has been attributed to the influence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), its causative viral agent, on several physiological systems in human body, including the respiratory, cardiovascular, and neurological systems. There is emerging evidence on propensity of this virus to attack cardiovascular system. However, various pathophysiological mechanisms by which SARS-CoV-2 interacts with cardiovascular system and leads to high morbidity and mortality, including cardiovascular complications, are poorly understood. This mini review aims to provide an update on the current knowledge and perspectives on areas of future research.
Keywords: Angiotensin-converting enzyme 2 receptors; COVID-19; Cardiovascular manifestations; Therapies.
79. Bhaskar SMM**. Incidental findings in brain imaging research: spotlight on ethical considerations. Eur Radiol. 2022 Jun 22. doi: 10.1007/s00330-022-08944-8. Epub ahead of print. PMID: 35731289
Brain imaging has revolutionized our ability to characterize brain structure and function. Since the first use of magnetic resonance imaging in a live human subject in 1977, the use of brain imaging in research and clinical medicine has seen exponential growth. Incidental findings (IFs) in brain imaging research have been a subject of contentious debate regarding the disclosure of IFs to human participants of research. In this paper, ethical considerations, as they apply, to IFs in brain imaging research have been discussed.
KEY POINTS: • Ethical considerations merit discussion vis a vis disclosure of incidental findings in brain imaging research.
Keywords: Ethics; Health equity; Incidental findings; Neuroimaging; Neuroscience.
78. GBD 2020 Alcohol Collaborators. Population-level risks of alcohol consumption by amount, geography, age, sex, and year: a systematic analysis for the Global Burden of Disease Study 2020. Lancet. 2022 Jul 16;400(10347):185-235. doi: 10.1016/S0140-6736(22)00847-9. PMID: 35843246; PMCID: PMC9289789.
Background: The health risks associated with moderate alcohol consumption continue to be debated. Small amounts of alcohol might lower the risk of some health outcomes but increase the risk of others, suggesting that the overall risk depends, in part, on background disease rates, which vary by region, age, sex, and year.
Methods: For this analysis, we constructed burden-weighted dose-response relative risk curves across 22 health outcomes to estimate the theoretical minimum risk exposure level (TMREL) and non-drinker equivalence (NDE), the consumption level at which the health risk is equivalent to that of a non-drinker, using disease rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 for 21 regions, including 204 countries and territories, by 5-year age group, sex, and year for individuals aged 15-95 years and older from 1990 to 2020. Based on the NDE, we quantified the population consuming harmful amounts of alcohol.
Findings: The burden-weighted relative risk curves for alcohol use varied by region and age. Among individuals aged 15-39 years in 2020, the TMREL varied between 0 (95% uncertainty interval 0-0) and 0·603 (0·400-1·00) standard drinks per day, and the NDE varied between 0·002 (0-0) and 1·75 (0·698-4·30) standard drinks per day. Among individuals aged 40 years and older, the burden-weighted relative risk curve was J-shaped for all regions, with a 2020 TMREL that ranged from 0·114 (0-0·403) to 1·87 (0·500-3·30) standard drinks per day and an NDE that ranged between 0·193 (0-0·900) and 6·94 (3·40-8·30) standard drinks per day. Among individuals consuming harmful amounts of alcohol in 2020, 59·1% (54·3-65·4) were aged 15-39 years and 76·9% (73·0-81·3) were male.
Interpretation: There is strong evidence to support recommendations on alcohol consumption varying by age and location. Stronger interventions, particularly those tailored towards younger individuals, are needed to reduce the substantial global health loss attributable to alcohol.
Funding: Bill & Melinda Gates Foundation.
77. GBD 2019 Adolescent Transport and Unintentional Injuries Collaborators. Adolescent transport and unintentional injuries: a systematic analysis using the Global Burden of Disease Study 2019. Lancet Public Health. 2022 Jun 29:S2468-2667(22)00134-7. doi: 10.1016/S2468-2667(22)00134-7. Epub ahead of print. PMID: 35779567.
Background: Globally, transport and unintentional injuries persist as leading preventable causes of mortality and morbidity for adolescents. We sought to report comprehensive trends in injury-related mortality and morbidity for adolescents aged 10-24 years during the past three decades.
Methods: Using the Global Burden of Disease, Injuries, and Risk Factors 2019 Study, we analysed mortality and disability-adjusted life-years (DALYs) attributed to transport and unintentional injuries for adolescents in 204 countries. Burden is reported in absolute numbers and age-standardised rates per 100 000 population by sex, age group (10-14, 15-19, and 20-24 years), and sociodemographic index (SDI) with 95% uncertainty intervals (UIs). We report percentage changes in deaths and DALYs between 1990 and 2019.
Findings: In 2019, 369 061 deaths (of which 214 337 [58%] were transport related) and 31·1 million DALYs (of which 16·2 million [52%] were transport related) among adolescents aged 10-24 years were caused by transport and unintentional injuries combined. If compared with other causes, transport and unintentional injuries combined accounted for 25% of deaths and 14% of DALYs in 2019, and showed little improvement from 1990 when such injuries accounted for 26% of adolescent deaths and 17% of adolescent DALYs. Throughout adolescence, transport and unintentional injury fatality rates increased by age group. The unintentional injury burden was higher among males than females for all injury types, except for injuries related to fire, heat, and hot substances, or to adverse effects of medical treatment. From 1990 to 2019, global mortality rates declined by 34·4% (from 17·5 to 11·5 per 100 000) for transport injuries, and by 47·7% (from 15·9 to 8·3 per 100 000) for unintentional injuries. However, in low-SDI nations the absolute number of deaths increased (by 80·5% to 42 774 for transport injuries and by 39·4% to 31 961 for unintentional injuries). In the high-SDI quintile in 2010-19, the rate per 100 000 of transport injury DALYs was reduced by 16·7%, from 838 in 2010 to 699 in 2019. This was a substantially slower pace of reduction compared with the 48·5% reduction between 1990 and 2010, from 1626 per 100 000 in 1990 to 838 per 100 000 in 2010. Between 2010 and 2019, the rate of unintentional injury DALYs per 100 000 also remained largely unchanged in high-SDI countries (555 in 2010 vs 554 in 2019; 0·2% reduction). The number and rate of adolescent deaths and DALYs owing to environmental heat and cold exposure increased for the high-SDI quintile during 2010-19.
Interpretation: As other causes of mortality are addressed, inadequate progress in reducing transport and unintentional injury mortality as a proportion of adolescent deaths becomes apparent. The relative shift in the burden of injury from high-SDI countries to low and low-middle-SDI countries necessitates focused action, including global donor, government, and industry investment in injury prevention. The persisting burden of DALYs related to transport and unintentional injuries indicates a need to prioritise innovative measures for the primary prevention of adolescent injury.
Funding: Bill & Melinda Gates Foundation.
76. Sharma D, Bhaskar SMM**. Prognostic role of the platelet-lymphocyte ratio in acute ischemic stroke patients undergoing reperfusion therapy: a meta-analysis. Journal of Central Nervous System Disease. 2022 Jul 15;14:11795735221110373. doi: 10.1177/11795735221110373. PMID: 35860715; PMCID: PMC9290168.
Background: Both inflammation and thrombotic/hemostatic mechanisms may play a role in acute ischemic stroke (AIS) pathogenesis, and a biomarker, such as the platelet-to-lymphocyte ratio (PLR), considering both mechanisms may be of clinical utility.
Objectives: This meta-analysis sought to examine the effect of PLR on functional outcomes, early neurological changes, bleeding complications, mortality, and adverse outcomes in AIS patients treated with reperfusion therapy (RT).
Design: Systematic Review and Meta-Analysis.
Data sources and methods: Individual studies were retrieved from the PubMed/Medline, EMBASE and Cochrane databases. References thereof were also consulted. Data were extracted using a standardised data sheet, and systematic reviews and meta-analyses on the association of admission (pre-RT) or delayed (post-RT) PLR with defined clinical and safety outcomes were conducted. In the case of multiple delayed PLR timepoints, the timepoint closest to 24 hours was selected.
Results: Eighteen studies (n=4878) were identified for the systematic review, of which 14 (n=4413) were included in the meta-analyses. PLR collected at admission was significantly negatively associated with 90-day good functional outcomes (SMD=-.32; 95% CI = -.58 to -.05; P=.020; z=-2.328), as was PLR collected at delayed timepoints (SMD=-.43; 95% CI = -.54 to -.32; P<.0001; z=-7.454). PLR at delayed timepoints was also significantly negatively associated with ENI (SMD=-.18; 95% CI = -.29 to -.08; P=.001. Conversely, the study suggested that a higher PLR at delayed timepoints may be associated with radiological bleeding and mortality. The results varied based on the type of RT administered.
Conclusions: A higher PLR is associated with worse outcomes after stroke in terms of morbidity, mortality, and safety outcomes after stroke.
Keywords: endovascular therapy; meta-analysis; platelet-lymphocyte ratio; reperfusion therapy; stroke.
75. Penson PE, Bruckert E, Marais D, Reiner Ž, Pirro M, Sahebkar A, Bajraktari G, Mirrakhimov E, Rizzo M, Mikhailidis DP, Sachinidis A, Gaita D, Latkovskis G, Mazidi M, Toth PP, Pella D, Alnouri F, Postadzhiyan A, Yeh HI, Mancini GBJ, von Haehling S, Banach M, Bhaskar S; International Lipid Expert Panel (ILEP). Step-by-step diagnosis and management of the nocebo/drucebo effect in statin-associated muscle symptoms patients: a position paper from the International Lipid Expert Panel (ILEP). J Cachexia Sarcopenia Muscle. 2022 Jun;13(3):1596-1622. doi: 10.1002/jcsm.12960. Epub 2022 Mar 10. PMID: 35969116; PMCID: PMC9178378.
Statin intolerance is a clinical syndrome whereby adverse effects (AEs) associated with statin therapy [most commonly statin-associated muscle symptoms (SAMS)] result in the discontinuation of therapy and consequently increase the risk of adverse cardiovascular outcomes. However, complete statin intolerance occurs in only a small minority of treated patients (estimated prevalence of only 3-5%). Many perceived AEs are misattributed (e.g. physical musculoskeletal injury and inflammatory myopathies), and subjective symptoms occur as a result of the fact that patients expect them to do so when taking medicines (the nocebo/drucebo effect)-what might be truth even for over 50% of all patients with muscle weakness/pain. Clear guidance is necessary to enable the optimal management of plasma in real-world clinical practice in patients who experience subjective AEs. In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step-by-step patient-centred approach to the identification and management of SAMS with a particular focus on strategies to prevent and manage the nocebo/drucebo effect and to improve long-term compliance with lipid-lowering therapy.
Keywords: Drucebo effect; Nocebo effect; SAMS; Statin intolerance.
74. Zeleňák K, Meyer L, Kurča E, Bhaskar SMM, Fiehler J. Successful mechanical thrombectomy of the left superior cerebellar artery. Cesk Slov Neurol N 2022; 85(2): 176-178 DOI: 10.48095/cccsnn2022176
73. Rastogi A, Bhaskar SMM**. Incidence of white matter lesions in hospitalised COVID-19 patients: a meta-analysis. Microcirculation. 2022 Feb 6:e12749. DOI: 10.1111/micc.12749. Epub ahead of print. PMID: 35124866.
Objective: Novel coronavirus disease 2019 (COVID-19) has been found to be associated with encephalopathy and brain imaging abnormalities. The identification of incident white matter lesions, known to be associated with cerebral microcirculatory failure and cerebrovascular disease, in COVID-19 patients is of clinical and scientific interest. We performed a meta-analysis to investigate the incidence of white matter lesions (WMLs) in hospitalised COVID-19 patients.
Methods: PubMed, EMBASE and the Cochrane Library were searched for studies on brain imaging abnormalities in hospitalised COVID-19 patients. The terms used included “white matter lesions”, “white matter hyperintensity”, “COVID-19”, “coronavirus” and “SARS-CoV-2”. A random-effects meta-analysis was conducted to obtain a pooled estimate of WML prevalence in hospitalised COVID-19 patients.
Results: A total of 4 eligible studies involving 362 patients (144 with WMLs and 218 without) were included in the meta-analysis. We found the pooled estimate of WML prevalence to be 20% (ES 0.20; 95% CI 0.00-0.54; p=0.03).
Conclusions: The estimated pooled prevalence rate of WMLs was approximately 20% in hospitalised COVID-19 patients, albeit lower than the crude prevalence rate (39.8%).
Keywords: COVID-19; SARS-CoV-2; White matter lesions; cerebrovascular disease; leukoaraiosis; microcirculation; stroke.
This article is protected by copyright. All rights reserved.
72. Shaban S, Rastogi A, Phuyal S, Huasen B, Haridas A, Zelenak K, Iacobucci M, Martínez-Galdámez M, Jabbour P, Bhaskar SMM**. The association of transradial access and transfemoral access with procedural outcomes in acute ischemic stroke patients receiving endovascular thrombectomy: A meta-analysis. Clinical Neurology & Neurosurgery. 2022 Mar 11. DOI: 10.1016/j.clineuro.2022.107209. Epub ahead of print. PMID: 35290788.
Objective: There is an ongoing debate regarding the benefits of using transradial access (TRA) over trans-femoral access (TFA) in endovascular therapies including endovascular thrombectomy (EVT) for acute ischemic stroke (AIS) patients. This study sought to investigate the association of TRA and TFA with procedural success, access-site complications, first-pass reperfusion (FPR), puncture-to-recanalisation (PTR) time and hemorrhagic transformation (HT) by performing a meta-analysis.
Materials and methods: PubMed, EMBASE and Scopus were searched. Studies with patients aged ≥ 18 years and head-to-head TRA vs TFA comparisons were included. Random-effects modeling was performed to obtain summary effects and forest plots were plotted to study the association of TFA with access site complications, FPR, HT, PTR time and procedural success.
Results: Six studies encompassing 945 patients (347 TRA and 598 TFA) were included in the meta-analysis. Meta- analysis revealed that in AIS patients receiving EVT, TRA was significantly associated with a decreased risk of ac- cess-site complications (RR 0.17, 95% CI 0.05 0.54; p = 0.003, z = −2.957) and HT (RR 0.07, 95% CI 0.02 0.27; p < 0.0001, z = −3.8841). However, TRA was not significantly associated with procedural success (RR 0.96, 95% CI 0.90 1.01; p = 0.141, z = −1.473), FPR (RR 0.91, 95% CI 0.79 1.05; p = 0.194, z = −1.299) and PTR time (SMD −0.14, 95% CI −0.42 −0.14; p = 0.323, z = −0.989).
Conclusion: Our meta-analysis demonstrated that TRA is a safe alternative to TFA, in AIS patients receiving EVT, with significantly decreased access-site complications and HT with TRA, albeit with comparable procedural success, FPR and PTR time to TFA.
71. Sinha A, Stanwell P, Killingsworth MC, Bhaskar SMM*. Prognostic accuracy and impact of cerebral collateral status on clinical and safety outcomes in acute ischemic stroke patients receiving reperfusion therapy: a systematic meta-analysis. Acta Radiol. 2022 Mar 20:2841851221080517. doi: 10.1177/02841851221080517. Epub ahead of print. PMID: 35311387.
Background: Cerebral collateral status has a potential role in mediating postreperfusion clinical and safety outcomes in acute ischemic stroke (AIS).
Purpose: To investigate the prognostic accuracy and impact of collateral status on clinical and safety outcomes in patients with AIS receiving reperfusion therapy.
Material and methods: Studies with AIS patients treated with reperfusion therapy, collateral status assessed using Tan, ASITN/SIR, or similar collateral grading methods and data stratified according to collateral status were included. Relevant data on clinical outcomes, such as functional outcome at 90 days, mortality at 90 days, angiographic reperfusion, symptomatic intracerebral hemorrhage (sICH) and hemorrhagic transformation (HT), were collated and analyzed.
Results: A meta-analysis of 18 studies involving 4132 patients with AIS was conducted. Good collateral status was significantly associated with angiographic reperfusion (odds ratio [OR]=1.97, 95% confidence interval [CI]=1.38-2.80; P < 0.0001), sICH (OR=0.67, 95% CI=0.46-0.99; P = 0.042), and 90-day functional outcome (OR=3.05, 95% CI=1.78-5.24; P < 0.0001). However, its association with HT (OR=0.76, 95% CI=0.38-1.51; P = 0.425) and three-month mortality (OR=0.53, 95% CI=0.17-1.69; P = 0.280) did not reach statistical significance. The prognostic accuracy of collaterals for predicting angiographic reperfusion, HT, functional outcome (at 90 days), and mortality (at 90 days) were 63%, 49%, 66%, and 48%, respectively.
Conclusion: Cerebral collaterals are significantly associated with clinical and safety outcomes, albeit with a prognostic accuracy range of 48%-66%; thus, evaluation of their patency is a useful prognostic tool in patients with AIS receiving reperfusion therapy.
Keywords: Collaterals; cerebrovascular; clinical decision making; reperfusion therapy; stroke.
70. El Naamani K, Abbas R, Mukhtar S, El Fadel O, Sathe A, Kazan AS, El Hajjar R, Sioutas GS, Tjoumakaris SI, Menachem Maimonides Bhaskar S, Herial NA, Gooch MR, Rosenwasser RH, Jabbour P (2022) Telemedicine During and Post-COVID 19: The Insights of Neurosurgery Patients and Physicians. Journal of Clinical Neuroscience. 2022 Mar 3. DOI:10.1016/j.jocn.2022.03.006. Epub ahead of print. PMID: 35286972; PMCID: PMC8894734.
COVID-19 has caused massive surge in telemedicine utilization as patients and physicians tried to minimize in-person contact to avoid the spread and impact of the pandemic.This study aims to expand on the knowledge of telemedicine during and beyond the COVID-19 era as it pertains to its use, efficacy, and patient and provider satisfaction through surveys.
This is a retrospective study involving 93 patients and 33 Neurosurgery physicians who anonymously participated in the survey about their experience with telemedicine visits.
Most respondents indicated extreme satisfaction with their telemedicine encounters during the pandemic (77%). As for how comfortable physicians are in providing a diagnosis via telemedicine compared to clinic visits, 7 (21.9%) physicians felt extremely comfortable, 13 (40.6%) felt somewhat comfortable, 2 (6.4%) were neutral, 9 (28.1%) felt somewhat uncomfortable and 1 (3.1%) felt extremely uncomfortable. Physical examination was the main thing that telemedicine didn’t provide (n=21, 100%).
Telemedicine has become a major force in the health care system under the circumstances the world is witnessing. Physicians and patients have displayed high levels of satisfaction with telemedicine which could be pivotal to improving healthcare access to underprivileged areas beyond the pandemic.
Neurosurgery, Telemedicine, COVID-19, Patient Experience, Physicians, Health Systems
69. Sharma D, Spring KJ, Bhaskar SMM**. Role of neutrophil-lymphocyte ratio in the prognosis of acute ischemic stroke after reperfusion therapy: A systematic review and meta-analysis. Journal of Central Nervous System Disease. 2022. 14: 1-21. DOI: 10.1177/11795735221092518
Inflammation may mediate response to acute reperfusion therapy (RT) in acute cerebral ischaemia. Neutrophil-lymphocyte ratio (NLR), an inflammatory biomarker, may play an important role in acute ischaemic stroke (AIS) prognostication.
This meta-analysis sought to examine the effect of NLR on functional outcomes, mortality and adverse outcomes in AIS patients receiving RT.
Individual studies were retrieved from PubMed/Medline, EMBASE and Cochrane databases. Data were extracted using a standardised data sheet and meta-analysis on association of admission (pre-RT) or delayed (post-RT) NLR with clinical/safety outcomes after RT was conducted.
Thirty-five studies (n = 10 308) were identified for the systematic review with 27 (n = 8537) included in the meta-analyses. Lower admission NLR was associated with good functional outcomes (GFOs), defined as 3-month modified Rankin scale (mRS) 0–2 (SMD = −.46; 95% CI = −.62 to −.29; P < .0001), mRS 0–1 (SMD = −.44; 95% CI = −.66 to −.22; P < .0001) and early neurological improvement (ENI) (SMD = −.55; 95 %CI = −.84 to −.25; P < .0001). Lower delayed admission NLR was also associated with GFOs (SMD = −.80; 95%CI = −.91 to −.68; P < .0001). Higher admission NLR was significantly associated with mortality (SMD = .49; 95%CI = .12 to .85; P = .009), intracerebral haemorrhage (ICH) (SMD = .34; 95% CI = .09 to .59; P = .007), symptomatic ICH (sICH) (SMD = .48; 95% CI = .07 to .90; P = .022) and stroke-associated infection or pneumonia (SMD = .85; 95% CI = .50, 1.19; P < .0001). Higher delayed NLR was significantly associated with sICH (SMD = 1.40; 95% CI = .60 to 2.19; P = .001), ICH (SMD = .94; 95% CI = .41 to 1.46; P < .0001) and mortality (SMD = 1.12; 95% CI = .57 to 1.67; P < .0001). There were variations in outcomes across RT groups.
Higher admission or delayed NLR is significantly associated with worse morbidity, mortality and safety outcomes in AIS patients receiving RT.
Keywords: Stroke; Endovascular Therapy; Meta-analysis; Neutrophil-to-lymphocyte ratio; Overall survival; Prognosis; Systematic review; Reperfusion Therapy; Intravenous Thrombolysis
68. GBD 2019 Diabetes Mortality Collaborators. Diabetes mortality and trends before 25 years of age: an analysis of the Global Burden of Disease Study 2019. Lancet Diabetes Endocrinol. 2022 Feb 7:S2213-8587(21)00349-1. DOI: 10.1016/S2213-8587(21)00349-1. Epub ahead of print. PMID: 35143780.
Background: Diabetes, particularly type 1 diabetes, at younger ages can be a largely preventable cause of death with the correct health care and services. We aimed to evaluate diabetes mortality and trends at ages younger than 25 years globally using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.
Methods: We used estimates of GBD 2019 to calculate international diabetes mortality at ages younger than 25 years in 1990 and 2019. Data sources for causes of death were obtained from vital registration systems, verbal autopsies, and other surveillance systems for 1990-2019. We estimated death rates for each location using the GBD Cause of Death Ensemble model. We analysed the association of age-standardised death rates per 100 000 population with the Socio-demographic Index (SDI) and a measure of universal health coverage (UHC) and described the variability within SDI quintiles. We present estimates with their 95% uncertainty intervals.
Findings: In 2019, 16 300 (95% uncertainty interval 14 200 to 18 900) global deaths due to diabetes (type 1 and 2 combined) occurred in people younger than 25 years and 73·7% (68·3 to 77·4) were classified as due to type 1 diabetes. The age-standardised death rate was 0·50 (0·44 to 0·58) per 100 000 population, and 15 900 (97·5%) of these deaths occurred in low to high-middle SDI countries. The rate was 0·13 (0·12 to 0·14) per 100 000 population in the high SDI quintile, 0·60 (0·51 to 0·70) per 100 000 population in the low-middle SDI quintile, and 0·71 (0·60 to 0·86) per 100 000 population in the low SDI quintile. Within SDI quintiles, we observed large variability in rates across countries, in part explained by the extent of UHC (r2=0·62). From 1990 to 2019, age-standardised death rates decreased globally by 17·0% (-28·4 to -2·9) for all diabetes, and by 21·0% (-33·0 to -5·9) when considering only type 1 diabetes. However, the low SDI quintile had the lowest decline for both all diabetes (-13·6% [-28·4 to 3·4]) and for type 1 diabetes (-13·6% [-29·3 to 8·9]).
Interpretation: Decreasing diabetes mortality at ages younger than 25 years remains an important challenge, especially in low and low-middle SDI countries. Inadequate diagnosis and treatment of diabetes is likely to be major contributor to these early deaths, highlighting the urgent need to provide better access to insulin and basic diabetes education and care. This mortality metric, derived from readily available and frequently updated GBD data, can help to monitor preventable diabetes-related deaths over time globally, aligned with the UN’s Sustainable Development Targets, and serve as an indicator of the adequacy of basic diabetes care for type 1 and type 2 diabetes across nations.
Funding: Bill & Melinda Gates Foundation.
Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
67. Sinha A, Priglinger-Coorey M, Stanwell P, Alvarado N, Killingsworth M, Bhaskar SMM**. Diagnostic and prognostic utility of brain collaterals in acute ischaemic stroke: Current knowledge and insights on treatment decision-making. Ro J Neurol. 2021;20(4): 424-433. DOI: 10.37897/RJN.2021.4.3
Stroke is a leading cause of death and disability worldwide. The advent of acute reperfusion therapy, intravenous thrombolysis and endovascular thrombectomy, has revolutionised the field of stroke medicine, and neurology in general. Recent studies have implicated a major role of cerebral collaterals in the trajectory of acute ischemic stroke patients receiving reperfusion therapy. Collaterals sustain blood supply to the tissue in the setting of acute ischaemia which prevents further expansion of the hypoperfused tissue, playing an important role in determining outcomes after acute ischaemic stroke. The use of collateral assessment in routine practice in acute ischaemic stroke, let alone in reperfusion therapy, is far from universal and limited. Future work in embedding collateral assessment in standards of care in acute stroke and management is warranted. This article provides a comprehensive update on the diagnostic and prognostic utility of col-laterals in acute ischaemic stroke and recommendations on collateral-based decision making in acute stroke and steps that can be taken for its rapid uptake in clinical practice.
66. Sinha A, Stanwell P, Killingsworth M, Bhaskar SMM**. Prognostic accuracy and impact of cerebral collateral status on clinical and safety outcomes in acute ischemic stroke patients receiving reperfusion therapy: a systematic meta-analysis. Acta Radiologica. 2022 Mar 20:2841851221080517. DOI: 10.1177/02841851221080517. Epub ahead of print. PMID: 35311387.
Cerebral collateral status has a potential role in mediating postreperfusion clinical and safety outcomes in acute ischemic stroke (AIS).
To investigate the prognostic accuracy and impact of collateral status on clinical and safety outcomes in patients with AIS receiving reperfusion therapy.
Material and Methods
Studies with AIS patients treated with reperfusion therapy, collateral status assessed using Tan, ASITN/SIR, or similar collateral grading methods and data stratified according to collateral status were included. Relevant data on clinical outcomes, such as functional outcome at 90 days, mortality at 90 days, angiographic reperfusion, symptomatic intracerebral hemorrhage (sICH) and hemorrhagic transformation (HT), were collated and analyzed.
A meta-analysis of 18 studies involving 4132 patients with AIS was conducted. Good collateral status was significantly associated with angiographic reperfusion (odds ratio [OR]=1.97, 95% confidence interval [CI]=1.38–2.80; P < 0.0001), sICH (OR=0.67, 95% CI=0.46–0.99; P = 0.042), and 90-day functional outcome (OR=3.05, 95% CI=1.78–5.24; P < 0.0001). However, its association with HT (OR=0.76, 95% CI=0.38–1.51; P = 0.425) and three-month mortality (OR=0.53, 95% CI=0.17–1.69; P = 0.280) did not reach statistical significance. The prognostic accuracy of collaterals for predicting angiographic reperfusion, HT, functional outcome (at 90 days), and mortality (at 90 days) were 63%, 49%, 66%, and 48%, respectively.
Cerebral collaterals are significantly associated with clinical and safety outcomes, albeit with a prognostic accuracy range of 48%–66%; thus, evaluation of their patency is a useful prognostic tool in patients with AIS receiving reperfusion therapy.
65. Maheshwari R, Cordato DJ, Wardman D, Thomas P, Bhaskar SMM**. Clinical outcomes following reperfusion therapy in acute ischemic stroke patients with Infective endocarditis: A systematic review. Journal of Central Nervous System Disease. 2022;14:11795735221081597. DOI: 10.1177/11795735221081597. PMID: 35282315; PMCID: PMC8905057.
Acute ischemic stroke (AIS) is a common and fatal complication of infective endocarditis (IE); however, there is a lack of understanding regarding treatment efficacy. This systematic review aimed to evaluate the safety and efficacy of intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) in IE patients experiencing AIS.
The aim of this study was to perform a systematic review investigating the outcomes of AIS in IE patients receiving IVT and/or EVT as a treatment method and to evaluate the safety and efficacy of these methods of reperfusion therapy.
A systematic review in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines was conducted.
Data Sources and Methods
The EMBASE, Cochrane, and PubMed databases were searched for literature published between 2005 and 2021 investigating outcomes of reperfusion therapy post-AIS in IE and non-IE patients. Descriptive statistics were used to describe the overall frequency of clinical outcomes, and groupwise comparisons were performed using Fisher’s exact test to assess the significance of groupwise differences.
Three studies were finally included in the systematic review. A total of 13.5% of IE patients compared to 37% of non-IE patients achieved a good functional outcome (modified Rankin Scale score≤ 2) (P < .001). Furthermore, a larger percentage of the IE cohort achieved good functional outcomes after EVT (22.0%) compared to IVT (10.4%) (P = .013). The IE cohort also had a higher 3-month postreperfusion mortality rate (48.8%) compared to the non-IE cohort (24.9%) (P < .001). The rate of intracranial hemorrhage (ICH) postreperfusion was also significantly higher in the IE cohort (23.5%) than in the non-IE cohort (6.5%) (P < .001).
AIS patients with IE, treated with IVT, EVT, or a combination of the two, experience worse clinical and safety outcomes than non-IE patients. EVT yielded better functional outcomes, albeit with higher postreperfusion ICH rates, than IVT.
Keywords: stroke, cerebrovascular, infective endocarditis, reperfusion, prognosis, pathology
64. Bradley SA, Smokovski I, Bhaskar SMM**. Impact of diabetes on clinical and safety outcomes in acute ischemic stroke patients receiving reperfusion therapy: a meta-analysis. [published online as ahead of print on February 25, 2022]. Adv Clin Exp Med. 2022. doi:10.17219/acem/146273
Background. Patients with diabetes are known to have worse outcomes after an acute ischemic stroke (AIS) relative to those without diabetes. However, the impact of diabetes on the outcomes after the reperfusion therapy is poorly understood.
Objectives. This study investigated prognostic accuracy of diabetes and its association with clinical and safety outcomes in AIS patients receiving intravenous thrombolysis (IVT), endovascular thrombectomy (EVT), or both.
Materials and methods. Studies were identified from PubMed, Embase and Cochrane databases, using the following inclusion criteria: (a) AIS patients receiving reperfusion therapy, (b) age ≥ 18 years, (c) hemispheric stroke, and (d) the availability of comparative data between diabetic and nondiabetic groups and relevant poststroke outcomes. Random effects modelling was used to study the association of diabetes with functional outcome at discharge and at 90 days, mortality at 90 days, recanalization status, and postreperfusion safety outcomes, including rates of symptomatic intracerebral hemorrhage (sICH) and hemorrhagic transformation (HT). Forest plots of odds ratios (ORs) were generated.
Results. Of a total cohort of 82,764 patients who received reperfusion therapy, 16,877 had diabetes. Diabetes significantly increased the odds of poor functional outcome at discharge (OR 1.310; 95% confidence interval (95% CI): [1.091; 1.574]; p = 0.0037) and at 90 days (OR 1.487; 95% CI: [1.335; 1.656]; p < 0.00010), mortality at 90 days (OR 1.709; 95% CI: [1.633; 1.788]; p < 0.0001), sICH (OR 1.595; 95% CI: [1.301; 1.956]; p < 0.0001), and HT (OR 1.276; 95% CI: [1.055; 1.543]; p = 0.0118).
Conclusions. Our meta-analysis demonstrates that diabetes is significantly associated with poor functional outcome, increased mortality and poor postprocedural safety outcomes, including sICH and HT.
Key words: diabetes, stroke, meta-analysis, cerebrovascular disease, reperfusion therapy
63. Rastogi A, Weissert R, Bhaskar SMM**. Leukoaraiosis severity and post-reperfusion outcomes in acute ischaemic stroke: A meta-analysis. Acta Neurol Scand. 2022 Feb;145(2):171-184. doi: 10.1111/ane.13519. Epub 2021 Aug 21. PMID: 34418060.
Objectives: Severity of leukoaraiosis may mediate outcomes after reperfusion therapy in acute ischaemic stroke (AIS) patients. However, the level of the association remains poorly understood. We performed a meta-analysis to investigate the impact of leukoaraiosis severity on functional outcome, survival, haemorrhagic complications, and procedural success in AIS patients treated with intravenous thrombolysis and/or endovascular thrombectomy.
Materials and methods: PubMed, EMBASE and the Cochrane library were searched for studies on leukoaraiosis in AIS receiving reperfusion therapy. A random-effects meta-analysis was conducted for post-reperfusion outcomes in AIS patients with absent-to-mild leukoaraiosis and moderate-to-severe leukoaraiosis. The strength of association between moderate-to-severe leukoaraiosis and poor outcomes was quantified using odds ratios (OR).
Results: A total of 15 eligible studies involving 6460 patients (1451 with moderate-to-severe leukoaraiosis and 5009 with absent-to-mild leukoaraiosis) were included in the meta-analysis. Moderate-to-severe leukoaraiosis was significantly associated with poor 90-day functional outcome (OR 3.16; 95% confidence interval (CI) 2.69-3.72; p < .0001), 90-day mortality (OR 3.11; 95% CI 2.27-4.26; p < .0001) and increased risk of symptomatic intracerebral haemorrhage (OR 1.69; 95% CI 1.24-2.32; p = .001) after reperfusion therapy. Overall, no significant association of leukoaraiosis severity with haemorrhagic transformation (HT) and angiographic recanalization status were observed. However, subgroup analysis revealed a significant association of WML severity with HT in patients receiving EVT.
Conclusion: Leukoaraiosis is a useful prognostic biomarker in AIS. Patients with moderate-to-severe leukoaraiosis on baseline imaging are likely to have worse clinical and safety outcomes after reperfusion therapy.
Keywords: Leukoaraiosis; acute ischaemic stroke; cerebrovascular disease; meta-analysis; safety outcomes; thrombectomy; thrombolysis; white matter lesions.
62. GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022 Jan 6:S2468-2667(21)00249-8. doi: 10.1016/S2468-2667(21)00249-8. Epub ahead of print. PMID: 34998485.
Given the projected trends in population ageing and population growth, the number of people with dementia is expected to increase. In addition, strong evidence has emerged supporting the importance of potentially modifiable risk factors for dementia. Characterising the distribution and magnitude of anticipated growth is crucial for public health planning and resource prioritisation. This study aimed to improve on previous forecasts of dementia prevalence by producing country-level estimates and incorporating information on selected risk factors.
We forecasted the prevalence of dementia attributable to the three dementia risk factors included in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 (high body-mass index, high fasting plasma glucose, and smoking) from 2019 to 2050, using relative risks and forecasted risk factor prevalence to predict GBD risk-attributable prevalence in 2050 globally and by world region and country. Using linear regression models with education included as an additional predictor, we then forecasted the prevalence of dementia not attributable to GBD risks. To assess the relative contribution of future trends in GBD risk factors, education, population growth, and population ageing, we did a decomposition analysis.
We estimated that the number of people with dementia would increase from 57·4 (95% uncertainty interval 50·4–65·1) million cases globally in 2019 to 152·8 (130·8–175·9) million cases in 2050. Despite large increases in the projected number of people living with dementia, age-standardised both-sex prevalence remained stable between 2019 and 2050 (global percentage change of 0·1% [–7·5 to 10·8]). We estimated that there were more women with dementia than men with dementia globally in 2019 (female-to-male ratio of 1·69 [1·64–1·73]), and we expect this pattern to continue to 2050 (female-to-male ratio of 1·67 [1·52–1·85]). There was geographical heterogeneity in the projected increases across countries and regions, with the smallest percentage changes in the number of projected dementia cases in high-income Asia Pacific (53% [41–67]) and western Europe (74% [58–90]), and the largest in north Africa and the Middle East (367% [329–403]) and eastern sub-Saharan Africa (357% [323–395]). Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia.
Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia.
Bill & Melinda Gates Foundation and Gates Ventures.
61. GBD 2019 Adolescent Young Adult Cancer Collaborators. The global burden of adolescent and young adult cancer in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Oncol. 2022 Jan;23(1):27-52. doi: 10.1016/S1470-2045(21)00581-7. Epub 2021 Dec 3. PMID: 34871551; PMCID: PMC8716339.
Background: In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults.
Methods: Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults.
Findings: There were 1·19 million (95% UI 1·11-1·28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59·6 [54·5-65·7] per 100 000 person-years) and high-middle SDI countries (53·2 [48·8-57·9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14·2 [12·9-15·6] per 100 000 person-years) and middle SDI (13·6 [12·6-14·8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23·5 million (21·9-25·2) DALYs to the global burden of disease, of which 2·7% (1·9-3·6) came from YLDs and 97·3% (96·4-98·1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally.
Interpretation: Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts.
Funding: Bill & Melinda Gates Foundation, American Lebanese Syrian Associated Charities, St Baldrick’s Foundation, and the National Cancer Institute.
60. Bradley SA, Banach M, Alvarado N, Smokovski I, Bhaskar SMM**. Prevalence and impact of diabetes in hospitalized COVID-19 patients: A systematic review and meta-analysis. J Diabetes. 2021 Dec 23; DOI: 10.1111/1753-0407.13243. [Epub ahead of print] PubMed PMID: 34939735.
Background: Diabetes is a cardiometabolic comorbidity that may predispose COVID-19 patients to worse clinical outcomes. This study sought to determine the prevalence of diabetes in hospitalized COVID-19 patients and investigate the association of diabetes severe COVID-19, rate of acute respiratory distress syndrome (ARDS), mortality, and need for mechanical ventilation by performing a systematic review and meta-analysis.
Methods: Individual studies were selected using a defined search strategy, including results up until July 2021 from PubMed, Embase, and Cochrane Central Register of Controlled Trials. A random-effects meta-analysis was performed to estimate the proportions and level of association of diabetes with clinical outcomes in hospitalized COVID-19 patients. Forest plots were generated to retrieve the odds ratios (OR), and the quality and risk assessment was performed for all studies included in the meta-analysis.
Results: The total number of patients included in this study was 10 648, of whom 3112 had diabetes (29.23%). The overall pooled estimate of prevalence of diabetes in the meta-analysis cohort was 31% (95% CI, 0.25-0.38; z = 16.09, P < .0001). Diabetes significantly increased the odds of severe COVID-19 (OR 3.39; 95% CI, 2.14-5.37; P < .0001), ARDS (OR 2.55; 95% CI, 1.74-3.75; P = <.0001), in-hospital mortality (OR 2.44; 95% CI, 1.93-3.09; P < .0001), and mechanical ventilation (OR 3.03; 95% CI, 2.17-4.22; P < .0001).
Conclusions: Our meta-analysis demonstrates that diabetes is significantly associated with increased odds of severe COVID-19, increased ARDS rate, mortality, and need for mechanical ventilation in hospitalized patients. We also estimated an overall pooled prevalence of diabetes of 31% in hospitalized COVID-19 patients.
Keywords: COVID-19; SARS-CoV-2; diabetes; meta-analysis; mortality; prevalence; ventilation.
59. Sharma D, Bhaskar SMM**. Prevalence of paediatric hyperinflammatory conditions in paediatric and adolescent hospitalized COVID-19 patients: a systematic review and meta-analysis. APMIS. 2021 Dec 11; DOI: 10.1111/apm.13199. [Epub ahead of print] PubMed PMID: 34894016.
In the milieu of coronavirus disease 2019 (COVID-19), there are increasing reports of paediatric hyperinflammatory conditions (PHICs), including multisystem inflammatory syndrome in children (MIS-C), paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and Kawasaki disease (KD). Few analyses of PHIC prevalence in paediatric and adolescent hospitalized COVID-19 patients exist. The purpose of this study was to perform a meta-analysis to determine a pooled prevalence estimate of PHICs in paediatric and adolescent hospitalized patients admitted for treatment due to COVID-19. Individual studies were retrieved from PubMed/Medline, EMBASE and Cochrane databases. Relevant prevalence, baseline, treatment and outcome data were extracted using a standardized datasheet. The systematic review and meta-analysis were conducted as per the PRISMA and MOOSE guidelines. Overall, 14 studies with 2202 patients admitted for treatment due to COVID-19, among whom 780 were diagnosed with PHICs, were included. The crude estimate of prevalence was 35.42%, and the pooled estimate of prevalence was 29% (random pooled ES = 0.29; 95% CIs = 0.18-0.42; p < 0.0001; z = 7.45). A sizeable proportion of paediatric and adolescent hospitalized patients admitted for treatment due to COVID-19 are diagnosed with a PHIC warranting a high index of clinical suspicion for PHICs. Further studies are required to validate these findings.
Keywords: COVID-19; Kawasaki disease; MIS-C; immunology; prevalence.
© 2021 Scandinavian Societies for Medical Microbiology and Pathology.
58. Global Burden of Disease 2019 Cancer Collaboration, Kocarnik JM, et al. Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019. JAMA Oncol. 2021 Dec 30. DOI: 10.1001/jamaoncol.2021.6987. [Epub ahead of print] PMID: 34967848.
Importance: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden.
Objective: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019.
Evidence review: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs).
Findings: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles.
Conclusions and relevance: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.
57. Blair C, Firtko A, Thomas P, Lin L, Miller M, Tran L, Edwards L, Bhaskar S, Parsons M, Cordato DJ. A Multicentre Study Comparing Cerebrovascular Disease Profiles in Pacific Islander and Caucasian Populations Presenting with Stroke and Transient Ischaemic Attack. Neuroepidemiology. 2021 Dec 1; 1-7. DOI: 10.1159/000520058. [Epub ahead of print] PubMed PMID: 34852344.
Introduction: In a multicentre study, we contrasted cerebrovascular disease profiles in Pacific Island (PI)-born patients (Indigenous Polynesian [IP] or Indo-Fijian [IF]) presenting with transient ischaemic attack (TIA), ischaemic stroke (IS) or intracerebral haemorrhage (ICH) with those of Caucasians (CSs).
Methods: Using a retrospective case-control design, we compared PI-born patients with age- and gender-matched CS controls. Consecutive patients were admitted to 3 centres in South Western Sydney (July 2013-June 2020). Demographic and clinical data studied included vascular risk factors, stroke subtypes, and imaging characteristics.
Results: There were 340 CS, 183 (27%) IP, and 157 (23%) IF patients; mean age 65 years; and 302 (44.4%) female. Of these, 587 and patients presented with TIA/IS and 93 (13.6%) had ICH. Both IP and IF patients were significantly more likely to present >24 h from symptom onset (odds ratios [ORs] vs. CS 1.87 and 2.23). IP patients more commonly had body mass indexes >30 (OR 1.94). Current smoking and excess alcohol intake were higher in CS. Hypertension, diabetes, and chronic kidney disease were significantly higher in both IP and IF groups in comparison to CS. IP patients had higher rates of AF and those with known AF were more commonly undertreated than both IF and CS patients (OR 2.24, p = 0.007). ICH was more common in IP patients (OR 2.32, p = 0.005), while more IF patients had intracranial arterial disease (OR 5.10, p < 0.001).
Discussion/conclusion: Distinct cerebrovascular disease profiles are identifiable in PI-born patients who present with TIA or stroke symptoms in Australia. These may be used in the future to direct targeted approaches to stroke prevention and care in culturally and linguistically diverse populations.
Keywords: Cerebrovascular risk; Culturally and linguistically diverse; Indo-Fijian; Polynesian; Stroke prevention.
56. Rastogi A, Weissert R, Bhaskar SMM**. Brain atrophy in acute ischaemic stroke patients treated with reperfusion therapy: a systematic review. Acta Radiol. 2021 Dec 1; 2841851211060427. DOI: 10.1177/02841851211060427. [Epub ahead of print] PubMed PMID: 34851161.
Background: Brain atrophy (BA) may have a role in acute ischemic stroke (AIS) in mediating outcomes after reperfusion therapy. The extent of this association is not well understood.
Purpose: : To examine the impact of pre-existing BA on functional outcome, survival, symptomatic intracerebral hemorrhage (sICH), and early neurological change in patients with AIS treated with intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT).
Material and methods: PubMed, EMBASE, and the Cochrane library were searched for studies on BA in AIS receiving reperfusion therapy. Studies were included if: (i) patients were aged ≥18 years; (ii) patients had been diagnosed with AIS; (iii) patients received IVT and/or EVT; (iv) studies reported on BA; (v) studies reported on post-reperfusion outcomes; and (vi) studies had a sample size of >25 patients.
Results: A total of 4444 patients from eight studies were included. Four out of seven studies reporting on 90-day functional outcome found pre-existing BA to be significantly associated with poor functional outcome. Moreover, two out of four studies found BA to be a significant predictor of 90-day mortality. None of the included studies reported a significant association of BA with sICH or early neurological deterioration.
Conclusion: This systematic review indicates a potential prognostic role of BA in AIS. Quantitative analysis of association of BA with outcomes in AIS is not possible given the heterogeneity in BA assessment and reporting across studies. Future studies using standardized BA assessment are warranted to clarify its association with clinical and safety outcomes in AIS.
Keywords: Brain atrophy; acute ischemic stroke; cerebral atrophy; cerebrovascular disease; reperfusion.
55. Sinha A, Stanwell P, Beran RG, Calic Z, Killingsworth MC, Bhaskar SMM**. Stroke Aetiology and Collateral Status in Acute Ischemic Stroke Patients Receiving Reperfusion Therapy-A Meta-Analysis. Neurol Int. 2021 Nov 16;13(4):608-621. DOI: 10.3390/neurolint13040060. PubMed PMID: 34842774; PubMed Central PMCID: PMC8628951.
Background: The interplay between collateral status and stroke aetiology may be crucial in the evaluation and management of acute ischemic stroke (AIS). Our understanding of this relationship and its level of association remains sub-optimal. This study sought to examine the association of pre-intervention collateral status with stroke aetiology, specifically large artery atherosclerosis (LAA) and cardio-embolism (CE), in AIS patients receiving reperfusion therapy, by performing a meta-analysis.
Methods: Relevant search terms were explored on Medline/PubMed, Embase and Cochrane databases. Studies were included using the following inclusion criteria: (a) patients aged 18 or above; (b) AIS patients; (c) patients receiving reperfusion therapy; (d) total cohort size of >20, and (e) qualitative or quantitative assessment of pre-intervention collateral status on imaging using a grading scale. Random-effects meta-analysis was performed to investigate the association of aetiology with pre-intervention collateral status, and forest plots of risk ratio (RR) were generated.
Results: A meta-analysis was conducted on seven studies, with a cumulative cohort of 1235 patients, to assess the association of pre-intervention collateral status with stroke aetiology. Patients with LAA were associated significantly with an increased rate of good collaterals (RR 1.24; 95% CI 1.04-1.50; p = 0.020, z = 2.33). Contrarily, CE aetiology was associated significantly with a decreased rate of good collaterals (RR 0.83; 95% CI 0.71-0.98; p = 0.027, z = -2.213).
Conclusions: This study demonstrates that, in AIS patients receiving reperfusion therapy, LAA and CE aetiologies are associated significantly with collateral status.
Keywords: aetiology; cardiovascular disease; cerebrovascular disease; collaterals; neuroimaging; reperfusion therapy; stroke.
54. Goire N, Edwards L, Thomas P, Bhaskar SMM, Cordato D, Buckland ME, Beran RG. Creutzfeldt – Jakob Disease in South West Sydney 2014-2020: An Unusually High Incidence of a Rare Disease. Neuroepidemiology. 2021 Nov 11;. DOI: 10.1159/000520736. [Epub ahead of print] PubMed PMID: 34763340.
Introduction Creutzfeldt – Jakob Disease (CJD), a spongiform encephalopathy, caused by a transmissible misfolded cellular prion protein is a rapidly progressive, debilitating neuro-degenerative disorder with no effective treatment. The estimated global incidence is at 1/ million inhabitants. This retrospective study examined the incidence of CJD in South Western Sydney Local Health District (SWSLHD) from 2014 to 2020. Background SWSLHD had an estimated population of 1,038,534 in 2020, with CJD data being limited. Methods New South Wealth (NSW) Health-Information-Exchange (HIE) database, for all admissions with CJD diagnoses in SWSLHD, between 2014-2020, was reviewed according to World Health Organization (WHO) diagnostic criteria, consistent with the Australian national CJD registry. Only probable CJD cases were included. Incidence was calculated based on the projected SWSLHD population. Results 35 patients, diagnosed with CJD, were identified. Each was evaluated by two independent investigators, including clinical presentation; MRI; EEGs; 14-3-3; and RT-QUIC results, before assigning CJD-probable status. Four failed the CJD criteria and were excluded. Of the 31 CJD-probable cases, most (59%) were male and older (37% range 61-70 years). The incidence rate peaked at 9/million in 2017 and was above 2/million, throughout the seven years, with an average of 4.859/million/year. Conclusions The incidence of CJD, in SWSLHD, exceeds the national average of 1/million. Cost-effective, adequate diagnostic and screening tools, implementable over a large population, will become increasingly essential.
53. Bradley SA, Varghese FM, Menon B, Mehndiratta MM, Bhaskar SMM**. Stroke in patients with diabetes: is it time to expand public health priority to encompass high-risk patients with increased insulin resistance?. EMJ Diabetes. 2021 November; 9(1):84-91. DOI: 10.33590/emjdiabet/21-00171.
Diabetes and stroke, with an interlinking aetiology, contribute to a growing cardiovascular disease burden and mortality around the world. Given the disproportionate prevalence and the burden of these conditions in the developing world, as well as the high risk of both Type 2 diabetes and cardiovascular disease carried by patients with metabolic syndrome, public health strategies are vital to mitigate the impact. Systematic approaches towards identifying undiagnosed patients in the community and building health systems around those targeted interventions have been implemented. However, growing evidence indicates potential for approaches to capture high-risk patients, such as those who suffer from pre-diabetes or increased insulin resistance, to provide early and optimal treatments, which could translate to population-level benefits, including reduced prevalence, disability, and disease burden.
52. Chowdhury S, Wardman D, Cordato D, Thomas P, Zagami A, Middleton P, McDougall A, Cheung A, Manning N, Wenderoth J, Beran R, Spring K, Calic Z, Killingsworth M, Bhaskar SMM**. Optimising Prehospital Pathways to Improve Acute Stroke Reperfusion Therapy Delivery: Systems-Based Approaches. SN Comprehensive Clinical Medicine. 2021/11. DOI: 10.1007/s42399-021-01069-x.
Intravenous thrombolysis and endovascular thrombectomy are the only approved reperfusion treatments available for patients with acute ischemic stroke. Despite the advances in reperfusion therapy, time continues to be a critical factor in the delivery of reperfusion treatment in acute stroke settings. In recent years, some systems-based approaches have been pursued with considerable success. However, approaches aimed at optimising and reducing treatment delays specifically in the prehospital settings are limited. A systems-based approach aimed at improving the process of care in the prehospital setting may result in the reduction of treatment delays and potentially improve clinical outcomes. In this article, we present an overview of the current prehospital acute stroke pathway. Areas to reduce treatment delays are identified and optimisations to the prehospital workflow addressing the identified gaps in acute stroke settings are proposed. Improving process and system gaps would translate to improved post-stroke outcomes following reperfusion therapy.
51. Katyal A, Bhaskar SMM**. Value of pre-intervention CT perfusion imaging in acute ischemic stroke prognosis. Diagn Interv Radiol. 2021 Nov;27(6):774-785. doi: 10.5152/dir.2021.20805. PubMed PMID: 34792033; PubMed Central PMCID: PMC8621643.
Noninvasive imaging plays an important role in acute stroke towards diagnosis and ongoing management of patients. Systemic thrombolysis and endovascular thrombectomy (EVT) are proven treatments currently used in standards of care in acute stroke settings. The role of computed tomography angiography (CTA) in selecting patients with large vessel occlusion for EVT is well established. However, the value of CT perfusion (CTP) imaging in predicting outcomes after stroke remains ambiguous. This article critically evaluates the value of multimodal CT imaging in early diagnosis and prognosis of acute ischemic stroke with a focus on the role of CTP in delineating tissue characteristics, patient selection, and outcomes after reperfusion therapy. Insights on various technical and clinical considerations relevant to CTP applications in acute ischemic stroke, recommendations for existing workflow, and future areas of research are discussed.
50. Sharma D, Spring KJ, Bhaskar SMM**. Neutrophil-lymphocyte ratio in acute ischemic stroke: Immunopathology, management, and prognosis. Acta Neurol Scand. 2021 Nov;144(5):486-499. DOI: 10.1111/ane.13493. Epub 2021 Jun 30. Review. PubMed PMID: 34190348.
There is an ongoing need for accurate prognostic biomarkers in the milieu of acute ischemic stroke (AIS) receiving reperfusion therapy. Neutrophil-lymphocyte ratio (NLR) has been implicated in emergency medicine and acute stroke setting as an important biomarker in the prognosis of patients. However, there are ongoing questions around its accuracy and translation into clinical practice given suboptimal sensitivity and specificity results, as well as varying thresholds and lack of clarity around which NLR time points are most clinically indicative. This article provides a comprehensive overview of the role of NLR in AIS patients receiving reperfusion therapy and perspectives on areas of future research. NLR may be an important biomarker in risk stratifying patients in AIS to identify and select those who are more likely to benefit from reperfusion therapy. Appropriate clinical decision-making tools and models are required to harness the predictive value of NLR, which could be useful in identifying and monitoring high-risk patients to guide early treatment and achieve improved outcomes. Our understanding of the role of NLR in the immunopathogenesis of AIS is also suboptimal, which hinders the ability to translate this into clinical practice.
Keywords: acute ischemic stroke; clinical decision making; immunopathogenesis; neutrophil-lymphocyte ratio; pathophysiology; prognosis; reperfusion therapy.
49. Sinha A, Bhaskar SMM**. In-hospital prevalence of mucormycosis among coronavirus disease 2019 (COVID-19) patients and COVID-19 in mucormycosis: a systematic review and meta-analysis. Int Forum Allergy Rhinol. 2021 Oct 11; DOI: 10.1002/alr.22906. [Epub ahead of print] PubMed PMID: 34633150; PubMed Central PMCID: PMC8652882.
Keywords: COVID-19; SARS-CoV2; cerebrovascular disease; global health; infectious disease; meta-analysis; mucormycosis; public health.
48. Tracking development assistance for health and for COVID-19: a review of development assistance, government, out-of-pocket, and other private spending on health for 204 countries and territories, 1990-2050. Lancet. 2021 Oct 9;398(10308):1317-1343. DOI: 10.1016/S0140-6736(21)01258-7. Epub 2021 Sep 22. Review. PubMed PMID: 34562388; PubMed Central PMCID: PMC8457757.
Background: The rapid spread of COVID-19 renewed the focus on how health systems across the globe are financed, especially during public health emergencies. Development assistance is an important source of health financing in many low-income countries, yet little is known about how much of this funding was disbursed for COVID-19. We aimed to put development assistance for health for COVID-19 in the context of broader trends in global health financing, and to estimate total health spending from 1995 to 2050 and development assistance for COVID-19 in 2020.
Methods: We estimated domestic health spending and development assistance for health to generate total health-sector spending estimates for 204 countries and territories. We leveraged data from the WHO Global Health Expenditure Database to produce estimates of domestic health spending. To generate estimates for development assistance for health, we relied on project-level disbursement data from the major international development agencies’ online databases and annual financial statements and reports for information on income sources. To adjust our estimates for 2020 to include disbursements related to COVID-19, we extracted project data on commitments and disbursements from a broader set of databases (because not all of the data sources used to estimate the historical series extend to 2020), including the UN Office of Humanitarian Assistance Financial Tracking Service and the International Aid Transparency Initiative. We reported all the historic and future spending estimates in inflation-adjusted 2020 US$, 2020 US$ per capita, purchasing-power parity-adjusted US$ per capita, and as a proportion of gross domestic product. We used various models to generate future health spending to 2050.
Findings: In 2019, health spending globally reached $8·8 trillion (95% uncertainty interval [UI] 8·7-8·8) or $1132 (1119-1143) per person. Spending on health varied within and across income groups and geographical regions. Of this total, $40·4 billion (0·5%, 95% UI 0·5-0·5) was development assistance for health provided to low-income and middle-income countries, which made up 24·6% (UI 24·0-25·1) of total spending in low-income countries. We estimate that $54·8 billion in development assistance for health was disbursed in 2020. Of this, $13·7 billion was targeted toward the COVID-19 health response. $12·3 billion was newly committed and $1·4 billion was repurposed from existing health projects. $3·1 billion (22·4%) of the funds focused on country-level coordination and $2·4 billion (17·9%) was for supply chain and logistics. Only $714·4 million (7·7%) of COVID-19 development assistance for health went to Latin America, despite this region reporting 34·3% of total recorded COVID-19 deaths in low-income or middle-income countries in 2020. Spending on health is expected to rise to $1519 (1448-1591) per person in 2050, although spending across countries is expected to remain varied.
Interpretation: Global health spending is expected to continue to grow, but remain unequally distributed between countries. We estimate that development organisations substantially increased the amount of development assistance for health provided in 2020. Continued efforts are needed to raise sufficient resources to mitigate the pandemic for the most vulnerable, and to help curtail the pandemic for all.
Funding: Bill & Melinda Gates Foundation.
47. Baskar PS, Chowdhury SZ, Bhaskar SMM**. In-hospital systems interventions in acute stroke reperfusion therapy: a meta-analysis. Acta Neurol Scand. 2021 Oct;144(4):418-432. DOI: 10.1111/ane.13476. Epub 2021 Jun 8. PubMed PMID: 34101170.
Objectives: The value of in-hospital systems-based interventions in streamlining treatment delays associated with reperfusion therapy delivery in acute ischaemic stroke (AIS), in the emergency department (ED), is poorly understood. This systematic review and meta-analysis aimed to assess and quantify the value of in-hospital systems-based interventions in streamlining reperfusion therapy delivery following AIS.
Material & methods: Articles from the following databases were retrieved: Medline, Embase and Cochrane Central Register of Controlled Trials. The primary endpoint was in-hospital time metrics between the intervention and control group. The secondary endpoint included the rate of good functional outcome at 90 days.
Results: 393 Systems intervention studies published after 2015 were screened, and 231 full articles were then read. In total, 35 studies with 35,815 patients were included in the final systematic review and 26 studies with 7,089 patients were used in the meta-analysis. The greatest time reductions from in-hospital system interventions were achieved in door-to-needle (DTN) time (SMD: -2.696, 95% CI: -2.976, -2.416, z = 3.03, p = 0.002). Systems interventions were also associated with a statistically significant improvement in mortality (RR: 0.25, 95% CI: 0.18, 0.38), rate of symptomatic intracerebral haemorrhage (RR: 0.07, 95% CI: 0.04, 0.1) and ≤60-minute reperfusion rates (RR: 0.63, 95% CI: 0.51, 0.79).
Conclusions: The use of in-hospital workflow optimization is imperative to expedite reperfusion therapy delivery and improving patient outcomes. To reduce the morbidity and mortality of stroke globally, in-hospital workflow guidelines should be adhered to and incorporated including the optimal elements identified in this study.
Keywords: Meta-analysis; Reperfusion Therapy; Stroke; Stroke Workflow; Systems Interventions.
46. Maheshwari R, Wardman D, Cordato DJ, Bhaskar SM**. Acute Ischaemic Stroke in Infective Endocarditis: Pathophysiology and Clinical Outcomes in Patients Treated with Reperfusion Therapy. Immuno. 2021 September; 1(4):347-359. DOI: 10.3390/immuno1040023.
Infective endocarditis in the setting of acute stroke poses a clinical challenge given the high mortality and morbidity associated with the condition. The pathophysiological mechanisms including clinical and imaging biomarkers that can provide insights into clinical trajectories of such patients are of immense interest. The current paper aims to provide a comprehensive overview of acute stroke with infective endocarditis and provide insights into various clinical factors mediating outcomes and therapeutic strategies, specifically in the setting of reperfusion therapy. Prognostic and therapeutic pathways to potentially improve functional outcomes in these patients are also discussed.
Keywords: stroke; infective endocarditis; reperfusion therapy; clinical outcomes; prognosis; cerebrovascular disease; thrombolysis; thrombectomy
45. Leontsinis I, Katsiki N, Papademetriou V, Chrysοhoou C, Kariori M, Dalakouras I, Tolis P, Fragoulis C, Kalos T, Tatakis F, Dimitriadis K, Doumas M, Sambatakou H, Pirounaki M, Mihas C, Bhaskar S, Tsivgoulis G, Tousoulis D, Banach M, Tsioufis K. Hypertensive urgencies during the first wave of COVID-19 pandemic in a tertiary hospital setting: A “U” shaped alarming curve. Archives of Medical Science. 2021 September. DOI: 10.5114/aoms/141243.
Corona virus disease (COVID)-19 pandemic provoked unprecedented disturbance in hypertension care, while alarming concerns arose about its long-term consequences. We assessed the impact of COVID-19 spread on population behavior regarding hypertension urgencies during its first wave.
Material and methods:
Data from daily unscheduled visits and admission counts in the Cardiology sector were collected from the Emergency Department database of a tertiary General Hospital in Athens, Greece from January 15th-July 15th 2020. This data was compared with the ones from the previous year. Cases presented with hypertensive urgency or admitted due to uncontrolled hypertension were separately analyzed.
A total of 7,373 patients records were analyzed. Hypertension urgency cases demonstrated a “U” shaped distribution in 2020, showing declining trend during the rapid virus spread, an image that was reversed after the transmission rate’s fade. COVID-19 incidence in Greece was inversely associated with uncontrolled hypertension admissions during its declining phase (r=-0.64 p=0.009), whereas total attendance exhibited a similar correlation during the first and the following months of the pandemic (r=0.677, p=0.031, r=-0.789, p=0.001). Uncontrolled hypertension rate on admission was positively related to the national incidence of COVID-19 cases during the first months of 2020 (r= 0.82, p=0.045).
Hypertensive urgency-related visits followed a “U” shape distribution during the pandemic’s first wave with attendance nadir coincidence to the virus spread peak. The initial relative increase in uncontrolled hypertension-related admissions rate, combined with the later increment of hypertensive urgencies may indicate blood pressure deregulation among the studied population which is multifactorial and potentially detrimental.
44. Shaban S, Huasen B, Haridas A, Killingsworth M, Worthington J, Jabbour P, Bhaskar SMM**. Digital subtraction angiography in cerebrovascular disease: current practice and perspectives on diagnosis, acute treatment and prognosis. Acta Neurol Belg. 2021 Sep 22; DOI: 10.1007/s13760-021-01805-z. [Epub ahead of print] PubMed PMID: 34553337.
Digital Subtraction Angiography (DSA) is the gold-standard imaging modality in acute cerebrovascular diagnosis. The role of DSA has become increasingly prominent since the incorporation of endovascular therapy in standards of care for acute ischemic stroke. It is used in the assessment of cerebral vessel patency; however, the therapeutic role of DSA from a prognostic standpoint merits further investigation. The current paper provides an update on current practice on diagnostic, therapeutic and prognostic use of DSA in acute cerebrovascular diseases and various indications and perspectives that may apply, or limit its use, in ongoing surveillance or prognosis. Pre-clinical and clinical studies on the aspects, including but not limited to the morphology of cerebrovasculature in acute ischaemic stroke, are required to delineate and inform its prognostic role.
Keywords: Acute ischaemic stroke; Cerebrovascular angiography; Cerebrovascular disease; Digital subtraction angiography (DSA); Interventional neurology; Prognosis; Reperfusion.
43. Bradley SA, Spring KJ, Beran RG, Chatzis D, Killingsworth MC, Bhaskar SMM**. Role of diabetes in stroke: Recent advances in pathophysiology and clinical management. Diabetes Metab Res Rev. 2021 Sep 16;:e3495. DOI: 10.1002/dmrr.3495. [Epub ahead of print] Review. PubMed PMID: 34530485.
The increasing prevalence of diabetes and stroke is a major global public health concern. Specifically, acute stroke patients, with pre-existing diabetes, pose a clinical challenge. It is established that diabetes is associated with a worse prognosis after acute stroke and the various biological factors that mediate poor recovery profiles in diabetic patients is unknown. The level of association and impact of diabetes, in the setting of reperfusion therapy, is yet to be determined. This article presents a comprehensive overview of the current knowledge of the role of diabetes in stroke, therapeutic strategies for primary and secondary prevention of cardiovascular disease and/or stroke in diabetes, and various therapeutic considerations that may apply during pre-stroke, acute, sub-acute and post-stroke stages. The early diagnosis of diabetes as a comorbidity for stroke, as well as tailored post-stroke management of diabetes, is pivotal to our efforts to limit the burden. Increasing awareness and involvement of neurologists in the management of diabetes and other cardiovascular risk factors is desirable towards improving stroke prevention and efficacy of reperfusion therapy in acute stroke patients with diabetes.
Keywords: cerebrovascular disease; diabetes; pathophysiology; prognosis; reperfusion therapy; stroke.
42. Measuring routine childhood vaccination coverage in 204 countries and territories, 1980-2019: a systematic analysis for the Global Burden of Disease Study 2020, Release 1. Lancet. 2021 Aug 7;398(10299):503-521. DOI: 10.1016/S0140-6736(21)00984-3. Epub 2021 Jul 21. PubMed PMID: 34273291; PubMed Central PMCID: PMC8358924.
Background: Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time.
Methods: For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dose-specific observations of routine childhood vaccination coverage between 1980 and 2019. Using spatiotemporal Gaussian process regression, we produced location-specific and year-specific estimates of 11 routine childhood vaccine coverage indicators for 204 countries and territories from 1980 to 2019, adjusting for biases in country-reported data and reflecting reported stockouts and supply disruptions. We analysed global and regional trends in coverage and numbers of zero-dose children (defined as those who never received a diphtheria-tetanus-pertussis [DTP] vaccine dose), progress towards GVAP targets, and the relationship between vaccine coverage and sociodemographic development.
Findings: By 2019, global coverage of third-dose DTP (DTP3; 81·6% [95% uncertainty interval 80·4-82·7]) more than doubled from levels estimated in 1980 (39·9% [37·5-42·1]), as did global coverage of the first-dose measles-containing vaccine (MCV1; from 38·5% [35·4-41·3] in 1980 to 83·6% [82·3-84·8] in 2019). Third-dose polio vaccine (Pol3) coverage also increased, from 42·6% (41·4-44·1) in 1980 to 79·8% (78·4-81·1) in 2019, and global coverage of newer vaccines increased rapidly between 2000 and 2019. The global number of zero-dose children fell by nearly 75% between 1980 and 2019, from 56·8 million (52·6-60·9) to 14·5 million (13·4-15·9). However, over the past decade, global vaccine coverage broadly plateaued; 94 countries and territories recorded decreasing DTP3 coverage since 2010. Only 11 countries and territories were estimated to have reached the national GVAP target of at least 90% coverage for all assessed vaccines in 2019.
Interpretation: After achieving large gains in childhood vaccine coverage worldwide, in much of the world this progress was stalled or reversed from 2010 to 2019. These findings underscore the importance of revisiting routine immunisation strategies and programmatic approaches, recentring service delivery around equity and underserved populations. Strengthening vaccine data and monitoring systems is crucial to these pursuits, now and through to 2030, to ensure that all children have access to, and can benefit from, lifesaving vaccines.
Funding: Bill & Melinda Gates Foundation.
41. Katyal A, Bhaskar SMM**. Value of pre-intervention computed tomography perfusion imaging in the assessment of tissue outcome and long-term clinical prognosis in patients with anterior circulation acute ischemic stroke receiving reperfusion therapy: a systematic review. Acta Radiol. 2021 Aug 3; 2841851211035892. DOI: 10.1177/02841851211035892. [Epub ahead of print] PubMed PMID: 34342497.
Background: Computed tomography perfusion (CTP) imaging has emerged as an important adjunct to the current armamentarium of acute ischemic stroke (AIS) workflow. However, its adoption in routine clinical practice is far from optimal.
Purpose: To investigate the putative association of CTP imaging biomarkers in the assessment of prognosis in acute ischemic stroke.
Material and methods: We performed a systematic review of the literature using MEDLINE, EMBASE, and Cochrane Central Register of Clinical Trials focusing on CTP biomarkers, tissue-based and clinical-based patient outcomes. We included randomized controlled trials, prospective cohort studies, and case-controlled studies published from January 2005 to 28 August 2020. Two independent reviewers conducted the study appraisal, data extraction, and quality assessment of the studies.
Results: A total of 60 full-text studies were included in the final systematic review analysis. Increasing infarct core volume is associated with reduced odds of achieving functional independence (modified Rankin score 0-2) at 90 days and is correlated with the final infarct volume when reperfusion is achieved.
Conclusion: CTP has value in assessing tissue perfusion status in the hyperacute stroke setting and the long-term clinical prognosis of patients with AIS receiving reperfusion therapy. However, the prognostic use of CTP requires optimization and further validation.
Keywords: Acute ischemic stroke; biomarkers; computed tomography perfusion; functional outcomes; reperfusion therapy.
40. Katyal A, Calic Z, Killingsworth M, Bhaskar SMM**. Diagnostic and prognostic utility of computed tomography perfusion imaging in posterior circulation acute ischemic stroke: A systematic review and meta-analysis. Eur J Neurol. 2021 Aug;28(8):2657-2668. DOI: 10.1111/ene.14934. Epub 2021 Jun 12. PubMed PMID: 34021664.
Background: Computed tomography perfusion (CTP) imaging could be useful in the diagnosis of posterior circulation stroke (PCS) and in identifying patients who are likely to experience favorable outcomes following reperfusion therapy. The current study sought to investigate the diagnostic and prognostic capability of CTP in acute ischemic PCS by performing a systematic review and meta-analysis.
Methods: Medline/PubMed and the Cochrane Library were searched using the terms: “posterior circulation”, “CT perfusion”, “acute stroke”, and “reperfusion therapy”. The following studies were included: (1) patients aged 18 years or above; (2) patients diagnosed with PCS; and (3) studies with good methodological design. Pooled sensitivity (SENS), specificity (SPEC), and area under the curve (AUC), computed using the summary receiver operating characteristic (SROC) curves, were used to determine diagnostic/prognostic capability.
Results: Out of 14 studies included, a meta-analysis investigating diagnostic accuracy of CTP was performed on nine studies. Meta-analysis demonstrated comparable diagnostic accuracy of CTP to non-contrast computed tomography (NCCT) (AUCCTP : 0.90 [95% CI 0.87-0.92] vs. AUCNCCT : 0.96 [95% CI 0.94-0.97]); however, with higher pooled sensitivity (SENSCTP : 72% [95% CI 57%-83%] vs. SENSNCCT : 25% [95% CI 17%-35%]) and lower specificity (SPECCTP : 90% [95% CI 83%-94%] vs. SPECNCCT : 96% [95% CI 95%-98%]) than NCCT. Meta-analysis to determine prognostic capability of CTP could not be performed.
Conclusions: CTP has limited diagnostic utility in acute ischemic PCS, albeit with superior diagnostic sensitivity and inferior diagnostic specificity to NCCT. Further prospective trials are required to validate the prognostic capability of CTP-derived parameters in PCS.
Keywords: CT perfusion; diagnosis; ischemic stroke; posterior circulation; prognosis.
© 2021 European Academy of Neurology.
39. Rastogi A, Weissert R, Bhaskar SMM**. Emerging role of white matter lesions in cerebrovascular disease. Eur J Neurosci. 2021 Aug;54(4):5531-5559. DOI: 10.1111/ejn.15379. Epub 2021 Jul 26. Review. PubMed PMID: 34233379.
White matter lesions have been implicated in the setting of stroke, dementia, intracerebral haemorrhage, several other cerebrovascular conditions, migraine, various neuroimmunological diseases like multiple sclerosis, disorders of metabolism, mitochondrial diseases and others. While much is understood vis a vis neuroimmunological conditions, our knowledge of the pathophysiology of these lesions, and their role in, and implications to, management of cerebrovascular diseases or stroke, especially in the elderly, are limited. Several clinical assessment tools are available for delineating white matter lesions in clinical practice. However, their incorporation into clinical decision-making and specifically prognosis and management of patients is suboptimal for use in standards of care. This article sought to provide an overview of the current knowledge and recent advances on pathophysiology, as well as clinical and radiological assessment, of white matter lesions with a focus on its development, progression and clinical implications in cerebrovascular diseases. Key indications for clinical practice and recommendations on future areas of research are also discussed. Finally, a conceptual proposal on putative mechanisms underlying pathogenesis of white matter lesions in cerebrovascular disease has been presented. Understanding of pathophysiology of white matter lesions and how they mediate outcomes is important to develop therapeutic strategies.
Keywords: cerebrovascular disease; clinical decision-making; leukoaraiosis; prognosis; reperfusion therapy; stroke; white matter lesion.
38. Chowdhury SZ, Baskar PS, Bhaskar S**. Effect of prehospital workflow optimization on treatment delays and clinical outcomes in acute ischemic stroke: A systematic review and meta-analysis. Acad Emerg Med. 2021 Jul;28(7):781-801. DOI: 10.1111/acem.14204. Epub 2021 Apr 3. Review. PubMed PMID: 33387368.
Background: The prehospital phase is critical in ensuring that stroke treatment is delivered quickly and is a major source of time delay. This study sought to identify and examine prehospital stroke workflow optimizations (PSWOs) and their impact on improving health systems, reperfusion rates, treatment delays, and clinical outcomes.
Methods: The authors conducted a systematic literature review and meta-analysis by extracting data from several research databases (PubMed, Cochrane, Medline, and Embase) published since 2005. We used appropriate key search terms to identify clinical studies concerning prehospital workflow optimization, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Results: The authors identified 27 articles that looked at the impact of prehospital workflow optimizations on time and treatment parameters; 26 were included in the meta-analysis. The PSWO were subgrouped into three categories: improved intravenous thrombolysis (IVT) triage, large-vessel occlusion (LVO) bypass, and mobile stroke unit (MSU). The salient findings are as follows: improved IVT triage led to significantly improved rates of IVT (relative risk [RR] = 1.80, 95% confidence interval [CI] = 1.18 to 2.75); however, MSU did not (RR = 1.22, 95% CI = 0.98 to 1.52). Improved IVT triage (standard mean difference [SMD] = -0.82, 95% CI = -1.32 to -0.32), LVO bypass (SMD = -0.80, 95% CI = -1.13 to -0.47), and MSU (SMD = -0.87, 95% CI = -1.57 to -0.17) were found to significantly reduce door-to-needle time for IVT. MSU was found to significantly reduce call-to-needle (SMD = -1.41, 95% CI = -1.94 to -0.88) and onset-to-needle (SMD = -1.15, 95% CI = -1.74 to -0.56) times for IVT. MSU additionally demonstrated significant reduction in door-to-perfusion (SMD = -0.72, 95% CI = -1.32 to -0.12) as well as call-to-perfusion (SMD = -0.73, 95% CI = -1.08 to -0.38) times for EVT. Finally, PSWO did not demonstrate significant improvements in rates of good functional outcome (RR = 1.04, 95% CI = 0.97 to 1.12) or mortality at 90 days (RR = 1.00, 95% CI = 0.76 to 1.31).
Conclusions: This systematic review and meta-analysis found that PSWO significantly improves several time metrics related to stroke treatment leading to improvement in IVT reperfusion rates. Thus, the implementation of these measures in stroke networks is a promising avenue to improve an often-neglected aspect of the stroke response. However, the limited available data suggest functional outcomes and mortality are not significantly improved by PSWO; hence, further studies and improvement strategies vis-à-vis PSWOs are warranted.
Keywords: acute stroke; ambulatory; clinical outcomes; health systems; implementation; prehospital screening; prehospital workflow; reperfusion therapy; system optimization; thrombectomy; thrombolysis; treatment delay; workflows.
37. Ruscica M, Penson PE, Ferri N, Sirtori CR, Pirro M, Mancini GBJ, Sattar N, Toth PP, Sahebkar A, Lavie CJ, Wong ND, Banach M. Impact of nutraceuticals on markers of systemic inflammation: Potential relevance to cardiovascular diseases – A position paper from the International Lipid Expert Panel (ILEP). Prog Cardiovasc Dis. 2021 Jul-Aug;67:40-52. DOI: 10.1016/j.pcad.2021.06.010. Epub 2021 Jun 27. Review. PubMed PMID: 34186099.
Inflammation is a marker of arterial disease stemming from cholesterol-dependent to -independent molecular mechanisms. In recent years, the role of inflammation in atherogenesis has been underpinned by pharmacological approaches targeting systemic inflammation that have led to a significant reduction in cardiovascular disease (CVD) risk. Although the use of nutraceuticals to prevent CVD has largely focused on lipid-lowering (e.g, red-yeast rice and omega-3 fatty acids), there is growing interest and need, especially now in the time of coronavirus pandemic, in the use of nutraceuticals to reduce inflammatory markers, and potentially the inflammatory CVD burden, however, there is still not enough evidence to confirm this. Indeed, diet is an important lifestyle determinant of health and can influence both systemic and vascular inflammation, to varying extents, according to the individual nutraceutical constituents. Thus, the aim of this Position Paper is to provide the first attempt at recommendations on the use of nutraceuticals with effective anti-inflammatory properties.
Keywords: C-reactive protein; Cardiovascular disease; Inflammation; Nutraceuticals; Omega-3; Position paper; Red-yeast rice.
36. Shi C, Killingsworth MC, Bhaskar SMM**. Prognostic capacity of hyperdense middle cerebral artery sign in anterior circulation acute ischaemic stroke patients receiving reperfusion therapy: a systematic review and meta-analysis. Acta Neurol Belg. 2021 Jun 6; DOI: 10.1007/s13760-021-01720-3. [Epub ahead of print] PubMed PMID: 34095978; PubMed Central PMCID: PMC8180356.
Pre-intervention CT imaging-based biomarkers, such as hyperdense middle cerebral artery sign (HMCAS) may have a role in acute ischaemic stroke prognostication. However, the clinical utility of HMCAS in settings of reperfusion therapy and the level of prognostic association is still unclear. This systematic review and meta-analysis investigated the association of HMCAS sign with clinical outcomes and its prognostic capacity in acute ischaemic stroke patients treated with reperfusion therapy. Prospective and retrospective studies from the following databases were retrieved from EMBASE, MEDLINE and Cochrane. Association of HMCAS with functional outcome, symptomatic intracerebral haemorrhage (sICH) and mortality were investigated. The random effect model was used to calculate the risk ratio (RR). Subgroup analyses were performed for subgroups of patients receiving thrombolysis (tPA), mechanical thrombectomy (EVT) and/or combined therapy (tPA + EVT). HMCAS significantly increased the rate of poor functional outcome by 1.43-fold in patients (RR 1.43; 95% CI 1.30-1.57; p < 0.0001) without any significant differences in sICH rates (RR 0.91; 95% CI 0.68-1.23; p = 0.546) and mortality (RR 1.34; 95% CI 0.72-2.51; p = 354) in patients with positive HMCAS as compared to negative HMCAS. In subgroup analyses, significant association between HMCAS and 90 days functional outcome was observed in patients receiving tPA (RR 1.53; 95% CI 1.40-1.67; p < 0.0001) or both therapies (RR 1.40; 95% CI 1.08-1.80; p = 0.010). This meta-analysis demonstrated that pre-treatment HMCAS increases risk of poor functional outcomes. However, its prognostic sensitivity and specificity in predicting long-term functional outcome, mortality and sICH after reperfusion therapy is poor.
Keywords: Endovascular therapy; Functional outcome; HMCAS; Meta-analysis; Mortality; Stroke; Symptomatic intracerebral haemorrhage.
35. Bhaskar S**, Jovanovic S, Katyal A, Namboodiri NK, Chatzis D, Banach M. Is COVID-19 Another Case of Obesity Paradox? – Results from An International Ecological Study on behalf of the REPROGRAM Consortium Obesity Study Group. Archives of Medical Science. 2021. doi:10.5114/aoms/136447.
Obesity has emerged as one of the major risk factors of severe morbidity and cause-specific mortality among severe acute respiratory syndromes coronavirus-2 (SARS-CoV-2) infected individuals. Patients with obesity also have overlapping cardiovascular diseases and diabetes, which make them increasingly vulnerable. This novel ecological study examines the impact of obesity and/or body mass index (BMI) on rates of population-adjusted cases and deaths due to coronavirus diseases 2019 (COVID-19).
Material and methods:
Publicly available datasets were used to obtain relevant data on COVID-19, obesity and ecological variables. Group-wise comparisons and multivariate logistic regression analyses were performed. The receiver operating characteristic curve (ROC) was plotted to compute the area under the curve.
We demonstrate that male BMI is an independent predictor of cause-specific (COVID-19) mortality, and not of the caseload per million population. Countries with obesity rates of 20-30% had a significantly higher (approximately double) number of deaths per million population to both those in <20% and >30% slabs. We postulate that there may be a U-shaped paradoxical relationship between obesity and COVID-19 with cause-specific mortality burden more pronounced in the countries with 20-30% obesity rates. These findings are novel along with the methodological approach of doing ecological analyses on country-wide data from publicly available sources.
We anticipate, in light of our findings, that appropriate targeted public health approaches or campaigns could be developed to minimize risk and cause-specific morbidity burden due to COVID-19 in countries with nationwide obesity rates of 20-30%.
34. Dugarte N, Alvarez A, Dugarte E, Alvarado N, Bhaskar S. Practical Design of Flow Meter for Mechanical Ventilation Equipment. Journal of Computer Science and Technology. 2021 April; 21(1):42-48. DOI: 10.24215/16666038.21.e5.
This paper introduces a practical technique for the design of an instrument used in air flow measurement or flowmeter. This instrument is an essential component in the hospital medical ventilation equipment functioning, therefore, the parameters design presented in this article focus on this purpose. However, this instrument can be employed to any measurement scale. The technique is based on indirect flow measurement, using a sensor that converts the flow parameter into a differential pressure measurement. An electronic transducer allows the differential pressure values to be obtained as an electrical signal, which is then digitized and analyzed to obtain the original parameter. The experimental procedure presented in this paper utilizes a computational algorithm to perform the signal analysis; however, given the simplicity of the procedure, this could be adapted to any digital processing card or platform, to show the measurement obtained immediately. Preliminary analyses demonstrated instrument efficiency with sensitivity of 0.0681 L/s. Accuracy evaluation showed an average measurement error lesser than 1.4%, with a standard deviation of 0.0612 and normal distribution over the set of test measurements.
33. Katyal A, Bhaskar S**. CTP-guided reperfusion therapy in acute ischemic stroke: a meta-analysis. Acta Neurol Scand. 2021 Apr;143(4):355-366. DOI: 10.1111/ane.13374. Epub 2020 Nov 27. PubMed PMID: 33188539.
Background: Computed tomography perfusion (CTP) imaging could be useful in guiding reperfusion therapy or patient selection in acute ischemic stroke (AIS) patients. The aim of the current study was to determine the efficacy of the CTP-guided reperfusion therapy in AIS by performing a systematic review and meta-analysis.
Methods: Medline/PubMed, Embase, and the Cochrane library were searched using the terms: “CT perfusion”, “acute stroke” and “reperfusion therapy”. The following studies were included: (a) studies reporting original data; (b) patients aged 18 years or above; (c) patients diagnosed with anterior circulation AIS; and (d) studies with good methodological design.
Results: Twenty-two studies were finally included in the metanalysis with a total of 5, 687 patients. CTP-guided reperfusion therapy was associated with increased odds of good functional outcome without significant difference in safety profile.
Conclusions: CTP-guided reperfusion therapy improved functional outcomes in AIS, with increased benefits to patients treated with endovascular thrombectomy.
Keywords: CT perfusion; decision-making; ischemic stroke; patient selection; treatment.
32. Bhaskar S**, Nurtazina A, Mittoo S, Banach M, Weissert R. Editorial: Telemedicine During and Beyond COVID-19. Front Public Health. 2021;9:662617. DOI: 10.3389/fpubh.2021.662617. eCollection 2021. PubMed PMID: 33796502; PubMed Central PMCID: PMC8007781.
Keywords: COVID-19; digital health; policy; public health; telemedicine.
31. Ravindran AV, Killingsworth MC, Bhaskar S**. Cerebral collaterals in acute ischaemia: Implications for acute ischaemic stroke patients receiving reperfusion therapy. Eur J Neurosci. 2021 Feb;53(4):1238-1261. DOI: 10.1111/ejn.14955. Epub 2020 Sep 18. Review. PubMed PMID: 32871623.
The cerebral collaterals play an important role in penumbral tissue sustenance after an acute ischaemic stroke. Recent studies have demonstrated the potential role of collaterals in the selection of acute ischaemic stroke patients eligible for reperfusion therapy. However, the understanding of the significance and evidence around the role of collateral status in predicting outcomes in acute ischaemic stroke patients treated with reperfusion therapy is still unclear. Moreover, the use of pre-treatment collaterals in patient selection and prognosis is relatively underappreciated in clinical settings. A focused review of the literature was performed on the various methods of collateral evaluation and the role of collateral status in acute ischaemic stroke patients receiving reperfusion therapy. We discuss the methods of evaluating pre-treatment collaterals in clinical settings. The patient selection based on collateral status as well as the prognostic and therapeutic value of collaterals in acute ischaemic stroke, in settings of intravenous thrombolysis or endovascular therapy alone, and bridge therapy, are summarized. Recommendations for future research and possible pharmacological intervention strategies aimed at collateral enhancement are also discussed. Collaterals may play an important role in identifying acute ischaemic stroke patients who are likely to benefit from endovascular treatment in an extended time window. Future neuroscientific efforts to better improve our understanding of the role of collaterals in acute ischaemia as well as clinical studies to delineate its role in patient selection and acute stroke prognosis are warranted.
Keywords: acute stroke; collaterals; neuroimaging; neurovasculature; prognosis; reperfusion therapy.
© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
30. Santana Baskar P, Cordato D, Wardman D, Bhaskar S**. In-hospital acute stroke workflow in acute stroke – Systems-based approaches. Acta Neurol Scand. 2021 Feb;143(2):111-120. DOI: 10.1111/ane.13343. Epub 2020 Oct 12. Review. PubMed PMID: 32882056.
Clinical outcomes of acute ischaemic stroke patients have significantly improved with the advent of reperfusion therapy. However, time continues to be a critical factor. Reducing treatment delays by improving workflows can improve the efficacy of acute reperfusion therapy. Systems-based approaches have improved in-hospital temporal parameters, maximizing the utility of reperfusion therapies and improving clinical benefit to patients. However, studies aimed at optimizing and hence reducing treatment delays in emergency department (ED) settings are limited. The aim of this article is to discuss existing systems-based approaches to optimize ED acute stroke workflows and its value in reducing treatment delays and identify gaps in existing workflows that need optimization. Identifying gaps in acute stroke workflow, variations in processes and challenges in implementation, in the in-hospital settings, is essential for systems-based interventions to be effective in delivering improved outcomes for patients with acute ischaemic stroke.
Keywords: acute stroke; collaboration; emergency; implementation science; in-hospital workflows; reperfusion therapy; systems intervention; systems optimization.
29. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J Am Coll Cardiol. 2020 Dec 22;76(25):2982-3021. DOI: 10.1016/j.jacc.2020.11.010. Review. PubMed PMID: 33309175; PubMed Central PMCID: PMC7755038.
Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.
Keywords: cardiovascular diseases; global health; health policy; population health.
28. Bhaskar S**, Rastogi A, Menon KV, Kunheri B, Balakrishnan S, Howick J. Call for Action to Address Equity and Justice Divide During COVID-19. Front Psychiatry. 2020;11:559905. DOI: 10.3389/fpsyt.2020.559905. eCollection 2020. PubMed PMID: 33343410; PubMed Central PMCID: PMC7744756.
The coronavirus 2019 disease (COVID-19) is deepening the inequity and injustice among the vulnerable communities. The current study aims to present an overview of the impact of COVID-19 on equity and social justice with a focus on vulnerable communities. Vulnerable communities include, but not limited to, healthcare workers, those from lower socioeconomic backgrounds, ethnic or minority groups, immigrants or refugees, justice-involved populations, and people suffering from chronic diseases or mental illness. The implications of COVID-19 on these communities and systemic disparities beyond the current pandemic are also discussed. People from vulnerable communities’ experience disproportionately adverse impacts of COVID-19. COVID-19 has exacerbated systemic disparities and its long-term negative impact on these populations foretell an impending crisis that could prevail beyond the COVID-19 era. It is onerous that systemic issues be addressed and efforts to build inclusive and sustainable societies be pursued to ensure the provision of universal healthcare and justice for all. Without these reinforcements, we would not only compromise the vulnerable communities but also severely limit our preparedness and response to a future pandemic.
Keywords: COVID-19; health equity; health policy; mental health; social determinants of health; social justice; social medicine; vulnerable communities.
27. Sharma D, Bhaskar S**. Addressing the Covid-19 Burden on Medical Education and Training: The Role of Telemedicine and Tele-Education During and Beyond the Pandemic. Front Public Health. 2020;8:589669. DOI: 10.3389/fpubh.2020.589669. eCollection 2020. PubMed PMID: 33330333; PubMed Central PMCID: PMC7728659.
Medical students are the future of sustainable health systems that are severely under pressure during COVID-19. The disruption in medical education and training has adversely impacted traditional medical education and medical students and is likely to have long-term implications beyond COVID-19. In this article, we present a comprehensive analysis of the existing structural and systemic challenges applicable to medical students and teaching/training programs and the impact of COVID-19 on medical students and education. Use of technologies such as telemedicine or remote education platforms can minimize increased mental health risks to this population. An overview of challenges during and beyond the COVID-19 pandemic are also discussed, and targeted recommendations to address acute and systemic issues in medical education and training are presented. During the transition from conventional in-person or classroom teaching to tele-delivery of educational programs, medical students have to navigate various social, economic and cultural factors which interfere with their personal and academic lives. This is especially relevant for those from vulnerable, underprivileged or minority backgrounds. Students from vulnerable backgrounds are influenced by environmental factors such as unemployment of themselves and family members, lack of or inequity in provision and access to educational technologies and remote delivery-platforms, and increased levels of mental health stressors due to prolonged isolation and self-quarantine measures. Technologies for remote education and training delivery as well as sustenance and increased delivery of general well-being and mental health services to medical students, especially to those at high-risk, are pivotal to our response to COVID-19 and beyond.
Keywords: Coronavirus Disease 2019 (COVID-19); digital humanities; medical education; remote delivery; technologies; tele-education; telemedicine; training.
26. Bhaskar S**, Tan J, Bogers MLAM, Minssen T, Badaruddin H, Israeli-Korn S, Chesbrough H. At the Epicenter of COVID-19-the Tragic Failure of the Global Supply Chain for Medical Supplies. Front Public Health. 2020;8:562882. DOI: 10.3389/fpubh.2020.562882. eCollection 2020. PubMed PMID: 33335876; PubMed Central PMCID: PMC7737425.
The tragic failure of the global supply chain in the face of the current coronavirus outbreak has caused acute shortages of essential frontline medical devices and personal protective equipment, crushing fear among frontline health workers and causing fundamental concerns about the sustainability of the health system. Much more coordination, integration, and management of global supply chains will be needed to mitigate the impact of the pandemics. This article describes the pressing need to revisit the governance and resilience of the supply chains that amplified the crisis at pandemic scale. We propose a model that profiles critical stockpiles and improves production efficiency through new technologies such as advanced analytics and blockchain. A new governance system that supports intervention by public-health authorities during critical emergencies is central to our recommendation, both in the face of the current crisis and to be better prepared for potential future crises. These reinforcements offer the potential to minimize the compromise of our healthcare workers and health systems due to infection exposure and build capacity toward preparedness and action for a future outbreak.
Keywords: blockchain; coronavirus disease 2019 (COVID-19); global supply chain; governance; grand challenge; health policy; open innovation; personal protective equipments (PPEs).
25. Bhaskar S**, Bradley S, Sakhamuri S, Moguilner S, Chattu VK, Pandya S, Schroeder S, Ray D, Banach M. Designing Futuristic Telemedicine Using Artificial Intelligence and Robotics in the COVID-19 Era. Front Public Health. 2020;8:556789. DOI: 10.3389/fpubh.2020.556789. eCollection 2020. PubMed PMID: 33224912; PubMed Central PMCID: PMC7667043.
Technological innovations such as artificial intelligence and robotics may be of potential use in telemedicine and in building capacity to respond to future pandemics beyond the current COVID-19 era. Our international consortium of interdisciplinary experts in clinical medicine, health policy, and telemedicine have identified gaps in uptake and implementation of telemedicine or telehealth across geographics and medical specialties. This paper discusses various artificial intelligence and robotics-assisted telemedicine or telehealth applications during COVID-19 and presents an alternative artificial intelligence assisted telemedicine framework to accelerate the rapid deployment of telemedicine and improve access to quality and cost-effective healthcare. We postulate that the artificial intelligence assisted telemedicine framework would be indispensable in creating futuristic and resilient health systems that can support communities amidst pandemics.
Keywords: artificial intelligence; coronavirus disease 2019 (COVID-19); digital medicine; pandemic (COVID-19); robotics; telehealth; telemedicine.
24. Bhaskar S**, Bradley S, Chattu VK, Adisesh A, Nurtazina A, Kyrykbayeva S, Sakhamuri S, Yaya S, Sunil T, Thomas P, Mucci V, Moguilner S, Israel-Korn S, Alacapa J, Mishra A, Pandya S, Schroeder S, Atreja A, Banach M, Ray D. Telemedicine Across the Globe-Position Paper From the COVID-19 Pandemic Health System Resilience PROGRAM (REPROGRAM) International Consortium (Part 1). Front Public Health. 2020;8:556720. DOI: 10.3389/fpubh.2020.556720. eCollection 2020. PubMed PMID: 33178656; PubMed Central PMCID: PMC7596287.
Coronavirus disease 2019 (COVID-19) has accelerated the adoption of telemedicine globally. The current consortium critically examines the telemedicine frameworks, identifies gaps in its implementation and investigates the changes in telemedicine framework/s during COVID-19 across the globe. Streamlining of global public health preparedness framework that is interoperable and allow for collaboration and sharing of resources, in which telemedicine is an integral part of the public health response during outbreaks such as COVID-19, should be pursued. With adequate reinforcement, telemedicine has the potential to act as the “safety-net” of our public health response to an outbreak. Our focus on telemedicine must shift to the developing and under-developing nations, which carry a disproportionate burden of vulnerable communities who are at risk due to COVID-19.
Keywords: COVID-19; digital technologies; framework; geographics; health policy; recommendations (guidelines); telehealth; telemedicine.
23. Bhaskar S**, Bradley S, Chattu VK, Adisesh A, Nurtazina A, Kyrykbayeva S, Sakhamuri S, Moguilner S, Pandya S, Schroeder S, Banach M, Ray D. Telemedicine as the New Outpatient Clinic Gone Digital: Position Paper From the Pandemic Health System REsilience PROGRAM (REPROGRAM) International Consortium (Part 2). Front Public Health. 2020;8:410. DOI: 10.3389/fpubh.2020.00410. eCollection 2020. PubMed PMID: 33014958; PubMed Central PMCID: PMC7505101.
Technology has acted as a great enabler of patient continuity through remote consultation, ongoing monitoring, and patient education using telephone and videoconferencing in the coronavirus disease 2019 (COVID-19) era. The devastating impact of COVID-19 is bound to prevail beyond its current reign. The vulnerable sections of our community, including the elderly, those from lower socioeconomic backgrounds, those with multiple comorbidities, and immunocompromised patients, endure a relatively higher burden of a pandemic such as COVID-19. The rapid adoption of different technologies across countries, driven by the need to provide continued medical care in the era of social distancing, has catalyzed the penetration of telemedicine. Limiting the exposure of patients, healthcare workers, and systems is critical in controlling the viral spread. Telemedicine offers an opportunity to improve health systems delivery, access, and efficiency. This article critically examines the current telemedicine landscape and challenges in its adoption, toward remote/tele-delivery of care, across various medical specialties. The current consortium provides a roadmap and/or framework, along with recommendations, for telemedicine uptake and implementation in clinical practice during and beyond COVID-19.
Keywords: COVID-19; coronavirus disease 2019; telemedicine; teleneurology; telepsychiatry; telerehabilitation.
22. Calic Z, Nham B, Bradshaw AP, Young AS, Bhaskar S, D’Souza M, Anderson CS, Cappelen-Smith C, Cordato D, Welgampola MS. Separating posterior-circulation stroke from vestibular neuritis with quantitative vestibular testing. Clin Neurophysiol. 2020 Aug;131(8):2047-2055. DOI: 10.1016/j.clinph.2020.04.173. Epub 2020 Jun 8. PubMed PMID: 32600960.
Objective: To separate vestibular neuritis (VN) from posteriorcirculation stroke (PCS) using quantitative tests of canal and otolith function.
Methods: Video Head-Impulse tests (vHIT) were used to assess all three semicircular canal pairs; vestibulo-ocular reflex (VOR) gain and saccade metrics were examined. Cervical and ocular-Vestibular-Evoked Myogenic Potentials (c- and oVEMP) and Subjective Visual Horizontal (SVH) were used to assess otolith function.
Results: For controls (n = 40), PCS (n = 22), and VN (n = 22), mean horizontal-canal VOR-gains were 0.96 ± 0.1, 0.85 ± 0.3 and 0.40 ± 0.2, refixation-saccade prevalence was 71.9 ± 41, 90.7 ± 57, 209.2 ± 62 per 100 impulses and cumulative-saccade amplitudes were 0.9 ± 0.4°, 2.4 ± 2.2°, 8.0 ± 3.5°. Abnormality-rates for cVEMP, oVEMP and SVH were 38%, 9%, 72% for PCS, and 43%, 50%, 91% for VN. A gain ≤0.68, refixation-saccade prevalence of ≥135% and cumulative-saccade amplitudes ≥5.3° separated VN from PCS with sensitivities of 95.5%, 95.5%, and 81.8%, and specificities of 68.2%, 86.4% and 95.5%. VOR-gain and saccade prevalence when combined, separated VN from PCS with a sensitivity and specificity of 90.9%. Abnormal oVEMP asymmetry-ratios were of low sensitivity (50%) but high specificity (90.9%) for separating VN from PCS.
Conclusion: vHIT provided the best separation of VN from PCS. VOR-gain, refixation-saccade prevalence and amplitude were effective discriminators of VN from PCS.
Significance: vHIT and oVEMP could assist early identification of the aetiology of Acute Vestibular Syndrome in the Emergency Room.
Keywords: Acute vestibular syndrome; Posterior circulation stroke; Saccades; Vestibular neuritis; Vestibulo-ocular reflex; Video head impulse test.
21. Bhaskar S**, Sinha A, Banach M, Mittoo S, Weissert R, Kass JS, Rajagopal S, Pai AR, Kutty S. Cytokine Storm in COVID-19-Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper. Front Immunol. 2020;11:1648. DOI: 10.3389/fimmu.2020.01648. eCollection 2020. PubMed PMID: 32754159; PubMed Central PMCID: PMC7365905.
Cytokine storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure. The phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19. Critically ill COVID-19 patients experiencing cytokine storm are believed to have a worse prognosis and increased fatality rate. In SARS-CoV-2 infected patients, cytokine storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult). Understanding the pathogenesis of cytokine storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease. In this article, we present an overview of the cytokine storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy. Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on cytokine storm from both a prognostic and therapeutic standpoint.
Keywords: COVID-19; autoimmunity; critical care; cytokine storm; guidelines; immunological mechanisms; immunotherapies; neuroimmunology.
20. Bhaskar S**, Bradley S, Israeli-Korn S, Menon B, Chattu VK, Thomas P, Chawla J, Kumar R, Prandi P, Ray D, Golla S, Surya N, Yang H, Martinez S, Ozgen MH, Codrington J, González EMJ, Toosi M, Hariya Mohan N, Menon KV, Chahidi A, Mederer Hengstl S. Chronic Neurology in COVID-19 Era: Clinical Considerations and Recommendations From the REPROGRAM Consortium. Front Neurol. 2020;11:664. DOI: 10.3389/fneur.2020.00664. eCollection 2020. PubMed PMID: 32695066; PubMed Central PMCID: PMC7339863.
With the rapid pace and scale of the emerging coronavirus 2019 (COVID-19) pandemic, a growing body of evidence has shown a strong association of COVID-19 with pre- and post- neurological complications. This has necessitated the need to incorporate targeted neurological care for this subgroup of patients which warrants further reorganization of services, healthcare workforce, and ongoing management of chronic neurological cases. The social distancing and the shutdown imposed by several nations in the midst of COVID-19 have severely impacted the ongoing care, access and support of patients with chronic neurological conditions such as Multiple Sclerosis, Epilepsy, Neuromuscular Disorders, Migraine, Dementia, and Parkinson disease. There is a pressing need for governing bodies including national and international professional associations, health ministries and health institutions to harmonize policies, guidelines, and recommendations relating to the management of chronic neurological conditions. These harmonized guidelines should ensure patient continuity across the spectrum of hospital and community care including the well-being, safety, and mental health of the patients, their care partners and the health professionals involved. This article provides an in-depth analysis of the impact of COVID-19 on chronic neurological conditions and specific recommendations to minimize the potential harm to those at high risk.
Keywords: chronic neurological disease; coronavirus disease 2019 (COVID-19); guidelines; healthcare services; neurodegenerative disorders; pandemics; protocols; recommendations.
19. Bhaskar S**, Rastogi A, Chattu VK, Adisesh A, Thomas P, Alvarado N, Riahi AD, Varun CN, Pai AR, Barsam S, Walker AH. Key Strategies for Clinical Management and Improvement of Healthcare Services for Cardiovascular Disease and Diabetes Patients in the Coronavirus (COVID-19) Settings: Recommendations From the REPROGRAM Consortium. Front Cardiovasc Med. 2020;7:112. DOI: 10.3389/fcvm.2020.00112. eCollection 2020. PubMed PMID: 32613010; PubMed Central PMCID: PMC7308556.
Patients with cardiovascular disease and diabetes are at potentially higher risk of infection and fatality due to COVID-19. Given the social and economic costs associated with disability due to these conditions, it is imperative that specific considerations for clinical management of these patients be observed. Moreover, the reorganization of health services around the pandemic response further exacerbates the growing crisis around limited access, treatment compliance, acute medical needs, and mental health of patients in this specific subgroup. Existing recommendations and guidelines emanating from respective bodies have addressed some of the pressure points; however, there are variations and limitations vis a vis patient with multiple comorbidities such as obesity. This article will pull together a comprehensive assessment of the association of cardiovascular disease, diabetes, obesity and COVID-19, its impact on the health systems and how best health systems can respond to mitigate current challenges and future needs. We anticipate that in the context of this pandemic, the cardiovascular disease and diabetes patients need a targeted strategy to ensure the harm to this group does not translate to huge costs to society and to the economy. Finally, we propose a triage and management protocol for patients with cardiovascular disease and diabetes in the COVID-19 settings to minimize harm to patients, health systems and healthcare workers alike.
Keywords: cardiovascular diseases (CVDs); clinical algorithm; coronavirus disease 2019 (COVID-19); diabetes; healthcare services; obesity; personal protective equipment (PPE).
18. Bhaskar S**, Sharma D, Walker AH, McDonald M, Huasen B, Haridas A, Mahata MK, Jabbour P. Acute Neurological Care in the COVID-19 Era: The Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium Pathway. Front Neurol. 2020;11:579. DOI: 10.3389/fneur.2020.00579. eCollection 2020. PubMed PMID: 32574252; PubMed Central PMCID: PMC7273748.
The management of acute neurological conditions, particularly acute ischemic stroke, in the context of Coronavirus disease 2019 (COVID-19), is of importance, considering the risk of infection to the healthcare workers and patients and emerging evidence of the neuroinvasive potential of the virus. There are variations in expert guidelines further complicating the picture for clinicians in acute settings. In this light, there is a compelling need for further formulation of recommendations that compile these variations seen in the numerous guidelines present. Health system protocols for managing ongoing acute neurological care and intervention need consideration of safety and well-being of the frontline healthcare workers and the patients. We examine existing pathways and their efficacy to mitigate viral exposure to the healthcare workers and patients and synthesize a systemic approach to manage patients with acute neurological conditions in the COVID-19 scenario. Early experiences with a COVID-19 positive stroke patient treated with endovascular thrombectomy is presented to highlight the urgent need for adequate personal protective equipment (PPE) during acute neuro-interventional procedures.
Keywords: Coronavirus disease 2019 (COVID-19); Personal Protective Equipment (PPE); acute stroke; guidelines; neurointervention; reperfusion; safety; surgery.
17. Delcourt C, Carcel C, Zheng D, Sato S, Arima H, Bhaskar S, Janin P, Al-Shahi Salman R, Cao Y, Zhang S, Heeley E, Davies L, Chalmers J, Anderson CS. Comparison of ABC Methods with Computerized Estimates of Intracerebral Hemorrhage Volume: The INTERACT2 Study. Cerebrovasc Dis Extra. 2019;9(3):148-154. DOI: 10.1159/000504531. Epub 2019 Dec 13. PubMed PMID: 31838472; PubMed Central PMCID: PMC6940457.
Background and purpose: Hematoma volume is a key determinant of outcome in acute intracerebral hemorrhage (ICH). We aimed to compare estimates of ICH volume between simple (ABC/2, length, width, and height) and gold standard planimetric software approaches.
Methods: Data are from the second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Multivariable linear regression was used to compare ICH volumes on baseline CT scans using the ABC/2, modified ABC/2 (mABC/2), and MIStar software. Other aspects of ICH morphology examined included location, irregularity, heterogeneity, intraventricular and subarachnoid hemorrhage extension (SAH) of hematoma, and associated white matter lesions and brain atrophy.
Results: In 2,084 patients with manual and semiautomated measurements, median (IQR) ICH volumes for each approach were: ABC/2 11.1 (5.11-20.88 mL), mABC/2 7.8 (3.88-14.11 mL), and MIStar 10.7 (5.59-18.66 mL). Median differences between ABC/2 and MIStar, and mABC/2 and MIStar were 0.34 (-1.01 to 2.96) and -2.4 (-4.95 to -0.7416), respectively. Hematoma volumes differed significantly with irregular shape (ABC/2 and MIStar, p < 0.001; mABC/2 and MIStar, p = 0.007) and larger volumes (mABC/2 and MIStar, p < 0.001; ABC/2 and MIStar, p = 0.07). ICH with SAH showed a significant discrepancy between ABC/2 and MIStar (p < 0.001).
Conclusions: Overall, ABC/2 performs better than mABC/2 in estimating ICH volume. The largest discrepancies were evidenced against automated software for irregular-shaped and large ICH with SAH, but the clinical significance of this is uncertain.
Keywords: Hematoma size; Imaging, stroke; Intracerebral hemorrhage; Stroke outcome measures.
16. Phua C, Bhaskar S, Calic Z. Hemiprosopometamorphopsia: a Case of Impaired Facial Perception Restricted to the Eye. SN Comprehensive Clinical Medicine. 2019 October; 1(11):931-933. DOI: 10.1007/s42399-019-00161-7.
Prosopometamorphopsia is a rare condition of perceptual facial distortion, with no impairment in facial recognition. We report a case of hemiprosopometamorphopsia restricted only to the eye. A 42-year-old male pilot presented with an acute onset visual disturbance consistent with hemiprosopometamorphopsia. While looking at faces, he observed a distorted image with the left eye appearing lower than the right. Faces resembled the paintings of Picasso. He had preserved insight and could recognize faces. Neurological and ophthalmological examination revealed no abnormalities. A brain MRI performed on day 3 of symptom onset demonstrated an area of acute infarct in the right occipital lobe involving the right posterior cerebral artery territory. Carotid CT angiogram and circle of Willis were unremarkable. Further workup did not reveal an underlying cause. Secondary stroke prevention with aspirin and statin was initiated. An event recorder was implanted. He was discharged on day 8 with near complete resolution of presenting symptom. While various facial distortions have been reported from prosopometamorphopsia, our case was restricted to only the eye and could have been easily overlooked or misdiagnosed as a migraine phenomenon. In patients presenting with perceptual facial distortion, clinicians should consider the possibility of stroke.
15. Bhaskar S**. Impact of obesity-induced type 2 diabetes on long-term outcomes following stroke. Clin Sci (Lond). 2019 Jul 31;133(14):1603-1607. DOI: 10.1042/CS20190492. Print 2019 Jul 31. PubMed PMID: 31331992.
Diabetes is associated with poor recovery profiles following stroke. The pathophysiological mechanisms by which diabetes mediates neurological recovery after stroke are debatable. A recent paper published in the Clinical Science by Pintana et al. (Clinical Science (2019)133, 1367-1386) provides a possible explanation for the underlying mechanisms of poor long-term motor recovery after stroke in obesity-induced diabetes animal model. Authors report that stroke-induced neurogenesis and parvalbumin (PV)+ interneuron-mediated neuroplasticity is severely impaired due to obesity-induced type 2 diabetes (T2D). Poor long-term motor recovery after stroke in comorbid obese and diabetic mice was not associated with stroke-induced grey or white matter damage. Understanding these mechanisms is crucial to develop therapeutic strategies to improve recovery in the obesity-induced diabetic population. The strength of the present study lies in the use of a comorbid obese/diabetic animal model, which is more likely to reflect the clinical scenario. However, these findings should be understood from the context of this specific animal model and whether these findings hold true for another variant of the obesity/T2D model warrants further consideration. This is an interesting study from the perspective of understanding the stroke pathology in T2D; however, the interaction of microvascular changes (including vascular modelling, angiogenesis), oxidative stress and insulin resistance (IR) associated with T2D and poor recovery profile merit further discussions. Given the increasing burden of obesity, diabetes and/or stroke globally, understanding of mechanisms may be useful in developing cardiovascular risk management pathways in this subgroup of population who are at increased risk of poor clinical outcomes following acute stroke.
Keywords: Angiogenesis; Diabetes; Recovery; Stroke; neurogenesis; synaptogenesis.
14. Bhaskar S**, Thomas P, Cheng Q, Clement N, McDougall A, Hodgkinson S, Cordato D. Trends in acute stroke presentations to an emergency department: implications for specific communities in accessing acute stroke care services. Postgrad Med J. 2019 May;95(1123):258-264. DOI: 10.1136/postgradmedj-2019-136413. Epub 2019 May 16. PubMed PMID: 31097575.
Background and purpose: South Western Sydney comprises of a culturally and linguistically diverse (CALD) and lower socioeconomic status population group within the state of New South Wales. Geographic location and sociodemographic factors play important roles in access to healthcare and may be crucial in the success of time-critical acute stroke intervention. The aim of this study was to examine the trends in the delayed presentation to emergency department (ED) and identify factors associated with prehospital delay for an acute stroke/transient ischaemic attack (TIA) at a comprehensive stroke centre.
Methods: Patient health-related data were extracted for stroke/TIA discharges for the period 2009-2017. Electronic medical record data were used to determine sociodemographic characteristics and prehospital factors, and their associations with delayed presentation≥4.5 hours from stroke onset were studied.
Results: During the 9-year period, population-adjusted stroke/TIA discharge rates increased from 540 to 676 per 100 000. A significant reduction in the proportion of patients presenting to ED<4.5 hours (56% in 2009 versus 46% in 2017, p<0.001) was observed. Younger patients aged 55-64 and 65-74 years, those belonging to Polynesia, South Asia and Mainland Southeast Asia, and those not using state ambulance as the mode of arrival to the hospital were at increased risk of prehospital delay.
Conclusions: Comprehensive reappraisal of educational programmes for early stroke recognition is required in our region due to delayed ED presentations of younger and specific CALD communities of stroke/TIA patients.
Keywords: culturally and linguistically diverse (CALD) population; delayed presentation; emergency department; health equity; health policy; health promotion; health systems; healthcare access; stroke.
13. Bhaskar S**, Saab J, Cappelen-Smith C, Killingsworth M, Wu XJ, Cheung A, Manning N, Aouad P, McDougall A, Hodgkinson S, Cordato D. Clot Histopathology in Ischemic Stroke with Infective Endocarditis. Can J Neurol Sci. 2019 May;46(3):331-336. DOI: 10.1017/cjn.2019.8. Epub 2019 Mar 14. PubMed PMID: 30867075.
Background: Endovascular thrombectomy (EVT) has shown efficacy in acute ischemic stroke (AIS) patients with infective endocarditis (IE). The possibility to undertake advanced histopathological clot analysis following EVT offers a new avenue to establish the etiological basis of the stroke – which is often labelled “cryptogenic.” In this paper, we present our findings from four consecutive patients with IE who underwent EVT following an AIS at our tertiary referral comprehensive stroke centre.
Methods: Comprehensive histopathological analysis of clot retrieved after EVT, including morphology, was undertaken.
Results: The consistent observation was the presence of dense paucicellular fibrinoid material mixed/interspersed with clusters of bacterial cocci. This clot morphology may be specific to septic embolus due to IE unlike incidental bacteraemia and could possibly explain the refractoriness of such clots to systemic thrombolysis.
Conclusion: Detailed morphological and histopathological analysis of EVT-retrieved clots including Gram staining can assist in etiological classification of the clot. Understanding the composition of the clot may be of clinical value in early diagnostics and mapping treatment planning in IE.
Keywords: Clot histopathology; Endovascular thrombectomy; Infective endocarditis; Ischemic stroke.
12. Venkat A, Cappelen-Smith C, Askar S, Thomas PR, Bhaskar S, Tam A, McDougall AJ, Hodgkinson SJ, Cordato DJ. Factors Associated with Stroke Misdiagnosis in the Emergency Department: A Retrospective Case-Control Study. Neuroepidemiology. 2018;51(3-4):123-127. DOI: 10.1159/000491635. Epub 2018 Aug 9. PubMed PMID: 30092562.
Background: Failure to recognise acute stroke may result in worse outcomes due to missed opportunity for acute stroke therapies. Our study examines factors associated with stroke misdiagnosis in patients admitted to a large comprehensive stroke centre.
Methods: Retrospective review comparing 156 consecutive stroke patients misdiagnosed in emergency department (ED) with 156 randomly selected stroke controls matched for age, gender, language spoken and stroke subtype for the period 2014-2016.
Results: There were 141 ischemic and 15 hemorrhagic misdiagnosed strokes (median age: 77 years, male:female = 1.3: 1). Symptom resolution, altered mental status, nausea/vomiting, dizziness and vertigo favored misdiagnosis (p < 0.05). Hemiparesis and dysarthria favored an accurate diagnosis (p < 0.05). Misdiagnosed patients were more commonly triaged into a lower ED category (62 vs. 42%, p = 0.001), clinically assessed as Face, Arm, Speech and Time (FAST) – negative (78 vs. 22%, p < 0.001) and underwent delayed CT imaging (median 4.1 vs. 1.5 h, p < 0.001). Misdiagnosed patients were more likely to have posterior circulation stroke (PCS; 39 vs. 22%, p = 0.01) and be admitted under non-neurological services (35 vs. 11%, p < 0.001) with worse discharge outcomes including increased mortality.
Conclusions: Patients with stroke misdiagnosis were commonly FAST-negative with nonspecific symptoms including altered mental status, dizziness and nausea/vomiting often associated with PCS. Improved diagnostic accuracy may increase access to acute therapies.
Keywords: Emergency department; Misdiagnosis; Stroke.
11. Beran R, Bhaskar S. Concussion within the Military. Journal of Military & Veterans’ Health. 2018 July; 26(3):20-27.
Concussion or mild traumatic brain injury (mTBI) is associated with long-term impairments in military personnel. Diagnosis of the condition remains clinically challenging. Neurological examination and cognitive symptoms may not accurately map the nature and severity of underlying brain injury. Neuroimaging techniques, such as diffusion tensor imaging (DTI), show promise as an effective tool in delineating the microstructural neural changes and corresponding clinical consequences following mTBI. This paper discusses the diagnosis and management of concussion, in the military context, using two cases of veterans who suffered blast-related mTBI. Insights on an integrated approach to concussion in the military, incorporating thorough neurological and neuropsychological examination and application of advanced neuroimaging are presented.
Key Words: Concussion, Military, Traumatic Brain Injury (TBI), Imaging, Simoa, Chronic traumatic encephalopathy (CTE)
10. Bhaskar S**, Stanwell P, Cordato D, Attia J, Levi C. Reperfusion therapy in acute ischemic stroke: dawn of a new era?. BMC Neurol. 2018 Jan 16;18(1):8. DOI: 10.1186/s12883-017-1007-y. Review. PubMed PMID: 29338750; PubMed Central PMCID: PMC5771207.
Following the success of recent endovascular trials, endovascular therapy has emerged as an exciting addition to the arsenal of clinical management of patients with acute ischemic stroke (AIS). In this paper, we present an extensive overview of intravenous and endovascular reperfusion strategies, recent advances in AIS neurointervention, limitations of various treatment paradigms, and provide insights on imaging-guided reperfusion therapies. A roadmap for imaging guided reperfusion treatment workflow in AIS is also proposed. Both systemic thrombolysis and endovascular treatment have been incorporated into the standard of care in stroke therapy. Further research on advanced imaging-based approaches to select appropriate patients, may widen the time-window for patient selection and would contribute immensely to early thrombolytic strategies, better recanalization rates, and improved clinical outcomes.
Keywords: Endovascular treatment; Neurointervention; Prognosis; Reperfusion therapy; Stroke.
9. Bhaskar S**, Cordato D, Cappelen-Smith C, Cheung A, Ledinghaxxm D, Celermajer D, Levi C. Clarion call for histopathological clot analysis in “cryptogenic” ischemic stroke: implications for diagnosis and treatment. Ann Clin Transl Neurol. 2017 Dec;4(12):926-930. DOI: 10.1002/acn3.500. eCollection 2017 Dec. PubMed PMID: 29296623; PubMed Central PMCID: PMC5740241. [First report on inclusion of routine histopathological analyses including Gram-staining of clots retrieved after endovascular clot retrieval in stroke patients especially those with valvular heart disease]
Diagnosis, treatment, and secondary management of cryptogenic stroke patients pose a formidable challenge. The scenario is further complicated in patients with native and prosthetic valvular heart disease. We present a case study of a 36-year-old man who received intravenous thrombolysis (IV-tPA) and endovascular thrombectomy (EVT) for presumed “cryptogenic” complete middle cerebral artery infarction who made a surprisingly excellent clinical recovery despite poor baseline and postintervention neuroimaging. Retrospective gram stain of his clot confirmed a diagnosis of infective endocarditis. This raises an important issue regarding need for more routine histopathological analysis of clot retrieved after EVT in “cryptogenic” stroke patients particularly those with valvular heart disease.
8. Bhaskar S**, Stanwell P, Bivard A, Spratt N, Walker R, Kitsos GH, Parsons MW, Evans M, Jordan L, Nilsson M, Attia J, Levi C. The influence of initial stroke severity on mortality, overall functional outcome and in-hospital placement at 90 days following acute ischemic stroke: A tertiary hospital stroke register study. Neurol India. 2017 Nov-Dec;65(6):1252-1259. DOI: 10.4103/0028-3886.217947. PubMed PMID: 29133696. [Evidence to include stroke severity in clinical-decision making, and administrative/system assessments]
Sruthi SN, Sylaja PN. Neurol India. 2017 doi: 10.4103/0028-3886.217982. PMID: 29133697
Prasad K, Singh N.Neurol India. 2017 doi: 10.4103/0028-3886.217998
Background and purpose: Epidemiological studies on the extent of the interaction and/or influence of stroke severity on clinical outcomes are important. The aim of the present study was to investigate the putative (and degree of) impact of initial stroke severity in predicting the overall functional outcome, in-hospital placement, and mortality in acute ischemic stroke (AIS) in comparison with age, admission to the stroke unit and thrombolytic treatment.
Materials and methods: The John Hunter Hospital acute stroke register was used to collect a retrospective cohort of AIS patients being assessed for reperfusion therapy and admitted between January 2006 and December 2013. Univariate and multivariate logistic regression and receiver operating characteristics analyses were used to assess associations with functional outcome, in-hospital placement, and mortality at 90 days.
Results: 608 AIS patients with complete datasets were included in the study. On univariate analysis, initial stroke severity showed the strongest independent association to the risk of death within 90 days (Odds ratio (OR) =1.15; P < 0.001; 95% confidence interval (CI) = [1.11, 1.18]); age was a less significant independent influence (OR = 1.02; P = 0.049; 95% CI = [1.00, 1.03]). Multivariate logistic regression analysis demonstrated that initial stroke severity independently predicted the 90 day mortality (OR = 1.16; 95% CI = [1.12, 1.2]; P < 0.0001) and unfavorable outcome (OR = 1.16; 95% CI = [1.13, 1.2]; P < 0.0001). Higher National Institute of Health Stroke Scale at admission was significantly associated with longer in-hospital placement (P < 0.0001).
Conclusions: In this acute stroke cohort, initial stroke severity had a major impact on the likelihood of death following an AIS and appears to be the dominant influence on the overall stroke outcome and in-hospital placement.
7. Bhaskar S*, Bivard A, Stanwell P, Parsons M, Attia JR, Nilsson M, Levi C. Baseline collateral status and infarct topography in post-ischaemic perilesional hyperperfusion: An arterial spin labelling study. J Cereb Blood Flow Metab. 2017 Mar;37(3):1148-1162. DOI: 10.1177/0271678X16653133. Epub 2016 Jul 21. PubMed PMID: 27256323; PubMed Central PMCID: PMC5363484.
[The first study to delineate the underlying pathophysiological mechanism behind post-ischemic perilesional hyperperfusion and role of arterial collaterals using non-invasive ASL MRI]
Focal hyperperfusion after acute ischaemic stroke could be of prognostic value depending upon its spatial localisation and temporal dynamics. Factors associated with late stage (12-24 h) perilesional hyperperfusion, identified using arterial spin labelling, are poorly defined. A prospective cohort of acute ischaemic stroke patients presenting within 4.5 h of symptom onset were assessed with multi-modal computed tomography acutely and magnetic resonance imaging at 24 ± 8 h. Multivariate logistic regression analysis and receiver operating characteristics curves were used. One hundred and nineteen hemispheric acute ischaemic stroke patients (mean age = 71 ± 12 years) with 24 h arterial spin labelling imaging were included. Forty-two (35.3%) patients showed perilesional hyperperfusion on arterial spin labelling at 24 h. Several factors were independently associated with perilesional hyperperfusion: good collaterals (71% versus 29%, P < 0.0001; OR = 5, 95% CI = [1.6, 15.7], P = 0.005), major reperfusion (81% versus 48%, P = < 0.0001; OR = 7.5, 95% CI = [1.6, 35.1], P = 0.01), penumbral salvage (76.2% versus 47%, P = 0.002; OR = 6.6, 95% CI = [1.8, 24.5], P = 0.004), infarction in striatocapsular (OR = 9.5, 95% CI = [2.6, 34], P = 0.001) and in cortical superior division middle cerebral artery (OR = 4.7, 95% CI = [1.4, 15.7], P = 0.012) territory. The area under the receiver operating characteristic curve was 0.91. Our results demonstrate good arterial collaterals, major reperfusion, penumbral salvage, and infarct topographies involving cortical superior middle cerebral artery and striatocapsular are associated with perilesional hyperperfusion.
Keywords: Stroke; arterial spin labelling; collaterals; hyperperfusion; perfusion imaging; topography.
2016 and Prior
6. Bhaskar S*, Bivard A, Parsons M, Nilsson M, Attia JR, Stanwell P, Levi C. Delay of late-venous phase cortical vein filling in acute ischemic stroke patients: Associations with collateral status. J Cereb Blood Flow Metab. 2017 Feb;37(2):671-682. DOI: 10.1177/0271678X16637611. Epub 2016 Jul 20. PubMed PMID: 26965242; PubMed Central PMCID: PMC5381457.
[The first study to establish delayed-cortical venous flow as a novel biomarker and its association with poor collaterals]
Evaluation of the venous system may be useful in stroke prognostication and patient selection for acute intervention strategies. We report a novel phenomenon, delayed-late venous phase cortical vein filling, observed on dynamic computed tomography angiography obtained using multidetector computed tomography scanner, in acute ischemic stroke patients. The aim of this study was to examine the frequency of delayed-late venous phase cortical vein filling and assess its association to baseline collateral status. Dynamic computed tomography angiography images of acute ischemic stroke patients, being assessed for reperfusion therapy, were prospectively studied. Delayed-late venous phase cortical vein filling was defined by late venous phase opacification of cortical veins despite contrast clearance from contralateral cortical veins on dynamic computed tomography angiography. Time to peak of maximum arterial enhancement was recorded. A total of 117 patients (mean age = 70.6 ± 13.3 years; males = 48%) with hemispheric ischemic stroke who underwent acute dynamic computed tomography angiography were included in the study. Overall, 56 (48%) demonstrated delayed-late venous phase cortical vein filling. Poor collateralization (OR = 13.50; 95% CI = (4.2, 43); p ≤ 0.0001) and longer time to peak of maximum arterial enhancement (OR = 3.2; 95% CI = (1.96, 5.3); p ≤ 0.0001) were positively associated with delayed-late venous phase cortical vein filling. Delayed-late venous phase cortical vein filling was independently associated with poor baseline collateral status (75% vs. 15%, p ≤ 0.0001; OR = 14.38; 95% CI = (4.33, 47.8); p ≤ 0.0001). Delayed-late venous phase cortical vein filling is frequently seen in patients with acute ischemic stroke and is associated with poor baseline collateralization.
Keywords: CTA; Stroke; angiography; collateral flow; venous flow.
5. Bhaskar S*, Bivard A, Stanwell P, Attia JR, Parsons M, Nilsson M, Levi C. Association of Cortical Vein Filling with Clot Location and Clinical Outcomes in Acute Ischaemic Stroke Patients. Sci Rep. 2016 Dec 5;6:38525. doi: 10.1038/srep38525. PubMed PMID: 27917948; PubMed Central PMCID: PMC5137111.
[The first study to report the existence of delayed cortical venous filling in acute focal ischemia and its prognostic impact]
Delay in cortical vein filling during the late-venous phase (delayed-LCVF) is characterized by opacification of cerebral veins despite contrast clearance from contralateral veins on dynamic computed tomography angiography (dCTA) in acute ischemic stroke (AIS) patients. The aim of the study was to investigate the associations of delayed-LCVF with clot location, reperfusion status at 24 hours, and 90-days functional outcome in AIS patients who received reperfusion therapy. A prospective cohort of AIS patients treated with intravenous thrombolysis was studied. Groupwise comparison, univariate, and multivariate regression analyses were used to study the association of delayed-LCVF with clot location and clinical outcomes. Of 93 patients (mean age = 72 ± 12 years) with hemispheric AIS included in the study, 46 (49%) demonstrated delayed-LCVF. Patients with delayed-LCVF demonstrated a significantly higher proportion of proximal occlusion (72% vs 13%, P =< 0.0001), and poor reperfusion at 24 hours (41% vs 11%, P = 0.001). The proportion of poor functional outcome at 90 days was not significantly different (22/56 (48%) vs 17/61 (36%), P = 0.297). The appearance of delayed-LCVF on baseline dCTA may be a surrogate for large vessel occlusion, and an early marker for poor 24-hour angiographic reperfusion.
4. Bhaskar S*, Saeidi K, Borhani P, Amiri H. Recent progress in migraine pathophysiology: role of cortical spreading depression and magnetic resonance imaging. Eur J Neurosci. 2013 Dec;38(11):3540-51. DOI: 10.1111/ejn.12368. Epub 2013 Sep 30. Review. PubMed PMID: 24118449.
Migraine is characterised by debilitating pain, which affects the quality of life in affected patients in both the western and the eastern worlds. The purpose of this article is to give a detailed outline of the pathophysiology of migraine pain, which is one of the most confounding pathologies among pain disorders in clinical conditions. We critically evaluate the scientific basis of various theories concerning migraine pathophysiology, and draw insights from brain imaging approaches that have unraveled the prevalence of cortical spreading depression (CSD) in migraine. The findings supporting the role of CSD as a physiological substrate in clinical pain are discussed. We also give an exhaustive overview of brain imaging approaches that have been employed to solve the genesis of migraine pain, and its possible links to the brainstem, the neocortex, genetic endophenotypes, and pathogenetic factors (such as dopaminergic hypersensitivity). Furthermore, a roadmap is proposed to provide a better understanding of pain pathophysiology in migraine, to enable the development of strategies using leads from brain imaging studies for the identification of early biomarkers, efficient prognosis, and treatment planning, which eventually may help in alleviating some of the devastating impact of pain morbidity in patients afflicted with migraine.
Keywords: CSD; DTI; fMRI; headache; neuroimaging.
3. Bhaskar S*, Tian F, Stoeger T, Kreyling W, de la Fuente JM, Grazú V, Borm P, Estrada G, Ntziachristos V, Razansky D. Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging. Part Fibre Toxicol. 2010 Mar 3;7:3. DOI: 10.1186/1743-8977-7-3. Review. PubMed PMID: 20199661; PubMed Central PMCID: PMC2847536.
Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer’s, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered.
2. Hermann PC, Bhaskar S, Cioffi M, Heeschen C. Cancer stem cells in solid tumors. Semin Cancer Biol. 2010 Apr;20(2):77-84. DOI: 10.1016/j.semcancer.2010.03.004. Epub 2010 Apr 3. Review. PubMed PMID: 20371287.
According to the cancer progression model, several events are required for the progression from normal epithelium to carcinoma. Due to their extended life span, stem cells would represent the most likely target for the accumulation of these genetic events but this has not been formally proven for most of solid cancers. Even more importantly, cancer stem cells seem to harbor mechanisms protecting them from standard cytotoxic therapy. While cancer stem cells have been demonstrated to be responsible for therapy resistance in glioblastoma and pancreatic cancer, further evidence now points to similar mechanisms in colon cancer stem cells. Therefore, it appears reasonable to conclude that there is sufficient evidence now for the existence of cancer stem cells in several epithelial tumors and that these cancer stem cells pose a significant threat via their resistance to standard therapies. Accumulating evidence suggests, however, that novel approaches targeting cancer stem cells are capable of overcoming these resistance mechanisms. To further foster our understanding of in vivo cancer stem cell biology, novel imaging modalities in conjunction with clinically most relevant cancer stem cell models need to be developed and utilized. These studies will then pave the way to better elucidate the underlying regulatory mechanisms of cancer stem cells and develop platforms for targeted theragnostics, which may eventually help improving the prognosis of our patients suffering from these deadly diseases.
1. Montesano L, Díaz M, Bhaskar S, Minguez J. Towards an intelligent wheelchair system for users with cerebral palsy. IEEE Trans Neural Syst Rehabil Eng. 2010 Apr;18(2):193-202. DOI: 10.1109/TNSRE.2009.2039592. Epub 2010 Jan 12. PubMed PMID: 20071276.
This paper describes and evaluates an intelligent wheelchair, adapted for users with cognitive disabilities and mobility impairment. The study focuses on patients with cerebral palsy, one of the most common disorders affecting muscle control and coordination, thereby impairing movement. The wheelchair concept is an assistive device that allows the user to select arbitrary local destinations through a tactile screen interface. The device incorporates an automatic navigation system that drives the vehicle, avoiding obstacles even in unknown and dynamic scenarios. It provides the user with a high degree of autonomy, independent from a particular environment, i.e., not restricted to predefined conditions. To evaluate the rehabilitation device, a study was carried out with four subjects with cognitive impairments, between 11 and 16 years of age. They were first trained so as to get acquainted with the tactile interface and then were recruited to drive the wheelchair. Based on the experience with the subjects, an extensive evaluation of the intelligent wheelchair was provided from two perspectives: 1) based on the technical performance of the entire system and its components and 2) based on the behavior of the user (execution analysis, activity analysis, and competence analysis). The results indicated that the intelligent wheelchair effectively provided mobility and autonomy to the target population.
Bhaskar, S., Banach, M., Weissert, R., Mittoo, S., Nurtazina, A., eds. (2021). Telemedicine during and beyond COVID-19. Lausanne: Frontiers Media SA. https://doi.org/10.3389/978-2-88966-739-0
1. Bhaskar S, Calic Z. The predictive value of collateral score in posterior circulation stroke. EUROPEAN JOURNAL OF NEUROLOGY 2020;27:117.
2. Phua CS, Cheah B, Bhaskar S, et al. Prosoometamorphopsia:’I am seeing Picasso faces’. In: International Journal of Stroke. 2019:26-26.
3. Bhaskar S, Saab J, Cappelen-Smith C, et al. Erythrocyte-rich clots are associated with cardioembolic aetiology, reduced number of manoeuvres, and improved clinical outcome in acute ischemic stroke patients. In: European Journal of Neurology. 2019:180-180.
4. Bhaskar S, Saab J, Cappelen-Smith C, et al. Cryptogenic stroke is linked to cardioembolic aetiology: a histopathological study of thrombus retrieved after endovascular thrombectomy. In: European Journal of Neurology. 2019:20-20.
5. Stevens, E, Graham, P, Alsahli, K, Cheung, A, Wenderoth, J, Cappelen-Smith, C, Cordato, D, McDougall, A, Zagami, AS, Bhaskar, S & Manning, NW 2018, ‘Carotid stenting in endovascular thrombectomy: comparison of outcomes between patients treated before and after six hours of stroke symptom onset’, International Journal of Stroke, vol. 13, no. 1S, 238, pp. 27.
6. Kohli, A, Graham, PL, Alsahli, K, Cheung, A, Wenderoth, J, Cordato, D, Cappelen-Smith, C, McDougall, A, Zagami, AS, Bhaskar, S & Manning, NW 2018, ‘Haemorrhagic transformation in acute ischaemic stroke patients requiring carotid stenting’, International Journal of Stroke, vol. 13, no. 1S, 247, pp. 29.
7. Kohli A; Bhaskar S; Cordato D; Alsahli K; Cheung A; Wenderoth J; Cappelen-Smith C; McDougall A; Zagami A; Manning NW, 2018, ‘Use of anti-platelet drugs in emergent carotid stenting for acute ischaemic stroke: Safety and efficacy analysis’, in International Journal of Stroke, pp. 27 – 27,
8. Kohli, A., Graham, P. L., Alsahli, K., Cheung, A., Wenderoth, J., Cordato, D., Cappelen-Smith, C., Kohli, A, Graham, PL, Alsahli, K, Cheung, A, Wenderoth, J, Cordato, D, Cappelen-Smith, C, McDougall, A, Zagami, AS, Bhaskar, S & Manning, NW 2018, ‘Haemorrhagic transformation in acute ischaemic stroke patients requiring carotid stenting’, International Journal of Stroke, vol. 13, no. 1S, 247, pp. 29.
9. Bhaskar S, Thomas P, Cappelen-Smith C, et al. Factors associated with delayed hospital presentation for acute stroke events in South Western Sydney. In: International Journal of Stroke. 2018:24-24.
10. Jordan L, Bhaskar S, Russell M, et al. Stroke mortality prognosis: Understanding risk. International Journal of Stroke 2014;9.
11. Evans M, Bhaskar S, Kitsons G. ABREAST Study (Abnormal Blood REsults Acute STroke). International Journal of Stroke 2014;9.
12. Bhaskar S, Evans M, Kitsos G, et al. The influence of initial stroke severity on the likelihood of death at 90 days following acute stroke: A tertiary hospital stroke register study. International Journal of Stroke 2014;9.