Publications

Abstract

Leptomeningeal collaterals (LMCs) are crucial in mitigating the impact of acute ischemic stroke (AIS) by providing alternate blood flow routes when primary arteries are obstructed. This article explores the evolutionary pathophysiology of LMCs, highlighting their critical function in stroke and the genetic and molecular mechanisms governing their development and remodelling. We address the translational challenges of applying animal model findings to human clinical scenarios, emphasizing the need for further research to validate emerging therapies-such as pharmacological agents, gene therapy and mechanical interventions-in clinical settings, aimed at enhancing collateral perfusion. Computational modelling emerges as a promising method for integrating experimental data, which requires precise parameterization and empirical validation. We introduce the ‘Evolucollateral Dynamics’ hypothesis, proposing a novel framework that incorporates evolutionary biology principles into therapeutic strategies, offering new perspectives on enhancing collateral circulation. This hypothesis emphasizes the role of genetic predispositions and environmental influences on collateral circulation, which may impact therapeutic strategies and optimize treatment outcomes. Future research must incorporate human clinical data to create robust treatment protocols, thereby maximizing the therapeutic potential of LMCs and improving outcomes for stroke patients.

Abstract

Atrial fibrillation (AF) is a severe condition associated with high morbidity and mortality, including an increased risk of stroke and poor outcomes poststroke. Our understanding of the prognosis in AF remains poor. Machine learning (ML) has been applied to the diagnosis, management, and prognosis of AF in the context of stroke but remains suboptimal for clinical use. This article endeavors to provide a comprehensive overview of current ML applications to AF patients at risk of stroke, as well as poststroke patients without AF. Strategies to develop effective ML involve the validation of a variety of ML algorithms across internal and external datasets as well as exploring their predictive powers in hypothetical and realistic settings. Recent literature of this rapidly evolving field has displayed much promise. However, further testing and innovation of medical artificial intelligence are required before its imminent introduction to ensure complete patient trust within the community. Prioritizing this research is imperative for advancing the optimization of ongoing care for AF patients, as well as the management of stroke patients with AF.

Keywords: artificial intelligence; atrial fibrillation; diagnosis; machine learning; management; prognosis; stroke.

Abstract

Background/Objective: Atrial fibrillation (AF) complicates the management of acute ischemic stroke (AIS), necessitating precise predictive models to enhance clinical outcomes. This meta-analysis evaluates the efficacy of machine learning (ML) models in three key areas: stroke prognosis in AF patients, stroke prediction in AF patients, and AF prediction in stroke patients. The study aims to assess the accuracy and variability of ML models in forecasting AIS outcomes and detecting AF in stroke patients, while exploring the clinical benefits and limitations of integrating these models into practice. Methods: We conducted a systematic search of PubMed, Embase, and Cochrane databases up to June 2024, selecting studies that evaluated ML accuracy in stroke prognosis and prediction in AF patients and AF prediction in stroke patients. Data extraction and quality assessment were performed independently by two reviewers, with random-effects modeling applied to estimate pooled accuracy metrics. Results: The meta-analysis included twenty-four studies comprising 7,391,645 patients, categorized into groups for stroke prognosis in AF patients (eight studies), stroke prediction in AF patients (thirteen studies), and AF prediction in stroke patients (three studies). The pooled AUROC was 0.79 for stroke prognosis and 0.68 for stroke prediction in AF, with higher accuracy noted in short-term predictions. The mean AUROC across studies was 0.75, with models such as Extreme Gradient Boosting (XGB) and Random Forest (RF) showing superior performance. For stroke prognosis in AF, the mean AUROC was 0.78, whereas stroke prediction yielded a mean AUROC of 0.73. AF prediction post-stroke had an average AUROC of 0.75. These findings indicate moderate predictive capability of ML models, underscoring the need for further refinement and standardization. The absence of comprehensive sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) metrics limited the ability to conduct full meta-analytic modeling. Conclusions: While ML models demonstrate potential for enhancing stroke prognosis and AF prediction, they have yet to meet the clinical standards required for widespread adoption. Future efforts should focus on refining these models and validating them across diverse populations to improve their clinical utility.

Abstract

Background: Up-to-date estimates of stroke burden and attributable risks and their trends at global, regional, and national levels are essential for evidence-based health care, prevention, and resource allocation planning. We aimed to provide such estimates for the period 1990-2021.

Methods: We estimated incidence, prevalence, death, and disability-adjusted life-year (DALY) counts and age-standardised rates per 100 000 people per year for overall stroke, ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage, for 204 countries and territories from 1990 to 2021. We also calculated burden of stroke attributable to 23 risk factors and six risk clusters (air pollution, tobacco smoking, behavioural, dietary, environmental, and metabolic risks) at the global and regional levels (21 GBD regions and Socio-demographic Index [SDI] quintiles), using the standard GBD methodology. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline.

Findings: In 2021, stroke was the third most common GBD level 3 cause of death (7·3 million [95% UI 6·6-7·8] deaths; 10·7% [9·8-11·3] of all deaths) after ischaemic heart disease and COVID-19, and the fourth most common cause of DALYs (160·5 million [147·8-171·6] DALYs; 5·6% [5·0-6·1] of all DALYs). In 2021, there were 93·8 million (89·0-99·3) prevalent and 11·9 million (10·7-13·2) incident strokes. We found disparities in stroke burden and risk factors by GBD region, country or territory, and SDI, as well as a stagnation in the reduction of incidence from 2015 onwards, and even some increases in the stroke incidence, death, prevalence, and DALY rates in southeast Asia, east Asia, and Oceania, countries with lower SDI, and people younger than 70 years. Globally, ischaemic stroke constituted 65·3% (62·4-67·7), intracerebral haemorrhage constituted 28·8% (28·3-28·8), and subarachnoid haemorrhage constituted 5·8% (5·7-6·0) of incident strokes. There were substantial increases in DALYs attributable to high BMI (88·2% [53·4-117·7]), high ambient temperature (72·4% [51·1 to 179·5]), high fasting plasma glucose (32·1% [26·7-38·1]), diet high in sugar-sweetened beverages (23·4% [12·7-35·7]), low physical activity (11·3% [1·8-34·9]), high systolic blood pressure (6·7% [2·5-11·6]), lead exposure (6·5% [4·5-11·2]), and diet low in omega-6 polyunsaturated fatty acids (5·3% [0·5-10·5]).

Interpretation: Stroke burden has increased from 1990 to 2021, and the contribution of several risk factors has also increased. Effective, accessible, and affordable measures to improve stroke surveillance, prevention (with the emphasis on blood pressure, lifestyle, and environmental factors), acute care, and rehabilitation need to be urgently implemented across all countries to reduce stroke burden.

Funding: Bill & Melinda Gates Foundation.

Abstract

Background: Antimicrobial resistance (AMR) poses an important global health challenge in the 21st century. A previous study has quantified the global and regional burden of AMR for 2019, followed with additional publications that provided more detailed estimates for several WHO regions by country. To date, there have been no studies that produce comprehensive estimates of AMR burden across locations that encompass historical trends and future forecasts.

Methods: We estimated all-age and age-specific deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 22 pathogens, 84 pathogen-drug combinations, and 11 infectious syndromes in 204 countries and territories from 1990 to 2021. We collected and used multiple cause of death data, hospital discharge data, microbiology data, literature studies, single drug resistance profiles, pharmaceutical sales, antibiotic use surveys, mortality surveillance, linkage data, outpatient and inpatient insurance claims data, and previously published data, covering 520 million individual records or isolates and 19 513 study-location-years. We used statistical modelling to produce estimates of AMR burden for all locations, including those with no data. Our approach leverages the estimation of five broad component quantities: the number of deaths involving sepsis; 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 antibiotic of interest; and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden attributable to and associated with AMR, which we define based on two counterfactuals; respectively, an alternative scenario in which all drug-resistant infections are replaced by drug-susceptible infections, and an alternative scenario in which all drug-resistant infections were replaced by no infection. Additionally, we produced global and regional forecasts of AMR burden until 2050 for three scenarios: a reference scenario that is a probabilistic forecast of the most likely future; a Gram-negative drug scenario that assumes future drug development that targets Gram-negative pathogens; and a better care scenario that assumes future improvements in health-care quality and access to appropriate antimicrobials. We present final estimates aggregated to the global, super-regional, and regional level.

Findings: In 2021, we estimated 4·71 million (95% UI 4·23-5·19) deaths were associated with bacterial AMR, including 1·14 million (1·00-1·28) deaths attributable to bacterial AMR. Trends in AMR mortality over the past 31 years varied substantially by age and location. From 1990 to 2021, deaths from AMR decreased by more than 50% among children younger than 5 years yet increased by over 80% for adults 70 years and older. AMR mortality decreased for children younger than 5 years in all super-regions, whereas AMR mortality in people 5 years and older increased in all super-regions. For both deaths associated with and deaths attributable to AMR, meticillin-resistant Staphylococcus aureus increased the most globally (from 261 000 associated deaths [95% UI 150 000-372 000] and 57 200 attributable deaths [34 100-80 300] in 1990, to 550 000 associated deaths [500 000-600 000] and 130 000 attributable deaths [113 000-146 000] in 2021). Among Gram-negative bacteria, resistance to carbapenems increased more than any other antibiotic class, rising from 619 000 associated deaths (405 000-834 000) in 1990, to 1·03 million associated deaths (909 000-1·16 million) in 2021, and from 127 000 attributable deaths (82 100-171 000) in 1990, to 216 000 (168 000-264 000) attributable deaths in 2021. There was a notable decrease in non-COVID-related infectious disease in 2020 and 2021. Our forecasts show that an estimated 1·91 million (1·56-2·26) deaths attributable to AMR and 8·22 million (6·85-9·65) deaths associated with AMR could occur globally in 2050. Super-regions with the highest all-age AMR mortality rate in 2050 are forecasted to be south Asia and Latin America and the Caribbean. Increases in deaths attributable to AMR will be largest among those 70 years and older (65·9% [61·2-69·8] of all-age deaths attributable to AMR in 2050). In stark contrast to the strong increase in number of deaths due to AMR of 69·6% (51·5-89·2) from 2022 to 2050, the number of DALYs showed a much smaller increase of 9·4% (-6·9 to 29·0) to 46·5 million (37·7 to 57·3) in 2050. Under the better care scenario, across all age groups, 92·0 million deaths (82·8-102·0) could be cumulatively averted between 2025 and 2050, through better care of severe infections and improved access to antibiotics, and under the Gram-negative drug scenario, 11·1 million AMR deaths (9·08-13·2) could be averted through the development of a Gram-negative drug pipeline to prevent AMR deaths.

Interpretation: This study presents the first comprehensive assessment of the global burden of AMR from 1990 to 2021, with results forecasted until 2050. Evaluating changing trends in AMR mortality across time and location is necessary to understand how this important global health threat is developing and prepares us to make informed decisions regarding interventions. Our findings show the importance of infection prevention, as shown by the reduction of AMR deaths in those younger than 5 years. Simultaneously, our results underscore the concerning trend of AMR burden among those older than 70 years, alongside a rapidly ageing global community. The opposing trends in the burden of AMR deaths between younger and older individuals explains the moderate future increase in global number of DALYs versus number of deaths. Given the high variability of AMR burden by location and age, it is important that interventions combine infection prevention, vaccination, minimisation of inappropriate antibiotic use in farming and humans, and research into new antibiotics to mitigate the number of AMR deaths that are forecasted for 2050.

Funding: UK Department of Health and Social Care’s Fleming Fund using UK aid, and the Wellcome Trust.

Abstract

Objective: This study aims to develop and validate the Futile Recanalization Prediction Score (FRPS), a novel tool designed to predict the severity risk of FR and aid in pre- and post-EVT risk assessments. Methods: The FRPS was developed using a rigorous process involving the selection of predictor variables based on clinical relevance and potential impact. Initial equations were derived from previous meta-analyses and refined using various statistical techniques. We employed machine learning algorithms, specifically random forest regression, to capture nonlinear relationships and enhance model performance. Cross-validation with five folds was used to assess generalizability and model fit. Results: The final FRPS model included variables such as age, sex, atrial fibrillation (AF), hypertension (HTN), diabetes mellitus (DM), hyperlipidemia, cognitive impairment, pre-stroke modified Rankin Scale (mRS), systolic blood pressure (SBP), onset-to-puncture time, sICH, and NIHSS score. The random forest model achieved a mean R-squared value of approximately 0.992. Severity ranges for FRPS scores were defined as mild (FRPS < 66), moderate (FRPS 66–80), and severe (FRPS > 80). Conclusions: The FRPS provides valuable insights for treatment planning and patient management by predicting the severity risk of FR. This tool may improve the identification of candidates most likely to benefit from EVT and enhance prognostic accuracy post-EVT. Further clinical validation in diverse settings is warranted to assess its effectiveness and reliability.

Despite remarkable strides in the diagnosis and treatment of cardiac and neurological conditions, significant disparities persist, particularly in regions often categorized as the Global South. These disparities are multifaceted, arising from challenges such as restricted access to healthcare resources, poor screening programs, and an unequal distribution of treatment modalities. Patients in these regions face worse health outcomes than those in more affluent countries, underscoring the urgent need for targeted interventions and equitable healthcare initiatives.

Abstract

Background: Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.

Methods: We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.

Findings: Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378-521), affecting 3·40 billion (3·20-3·62) individuals (43·1%, 40·5-45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7-26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6-38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5-32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7-2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.

Interpretation: As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed.

Abstract

Background: Posterior circulation stroke (PCS) accounts for approximately 20% of all acute ischemic strokes. The optimal reperfusion therapy for PCS management remains uncertain.

Purpose: To evaluate the prevalence and outcomes of intravenous thrombolysis (IVT), endovascular thrombectomy (EVT), and bridging therapy in PCS patients.

Material and methods: We conducted a meta-analysis of 19 studies examining reperfusion therapy outcomes in PCS patients, including 9765 individuals. We pooled prevalence data and assessed associations between reperfusion therapies and clinical, safety, and recanalization outcomes using random-effects models.

Results: The pooled prevalence of reperfusion therapies post-acute PCS was 39% for IVT, 54% for EVT, and 48% for bridging therapy. EVT was associated with significantly higher odds of favorable functional outcomes (modified Rankin Score [mRS] 0-3) at 90 days compared to standard medical therapy (odds ratio [OR] = 5.68; 95% confidence interval [CI]=2.07-15.59; P = 0.001). Conversely, bridging therapy was linked to reduced odds of favorable functional outcomes at 90 days compared to EVT (OR = 0.35; 95% CI=0.26-0.47; P < 0.001). Bridging therapy was also significantly associated with lower odds of good functional outcomes (mRS 0-2) (OR = 0.25; 95% CI=0.11-0.54; P < 0.001), reduced risk of symptomatic intracranial hemorrhage (OR = 0.26; 95% CI=0.07-0.68; P = 0.009), lower mortality (OR = 0.13; 95% CI=0.04-0.44; P = 0.001), and less successful recanalization (OR = 0.35; 95% CI=0.13-0.94; P = 0.038) relative to EVT.

Conclusion: Our meta-analysis underscores the favorable outcomes associated with EVT in PCS cases. With notable reperfusion rates, understanding factors influencing PCS outcomes can inform patient selection and prognostic considerations.

Keywords: Posterior circulation stroke; endovascular thrombectomy; intravenous thrombolysis; mortality; symptomatic intracranial hemorrhage.

Abstract

Background

The Australian population aged 70 and above is increasing and imposing new challenges for policy makers and providers to deliver accessible, appropriate and affordable health care. We examine pre-COVID patterns of health loss between 1990 and 2019 to inform policies and practices.

Methods

Using the standardised methodology framework and analytical strategies from GBD 2019 methodologies, we estimated mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life years (DALYs), life expectancy at age 70 and above (LE-70), and healthy life expectancy (HALE-70) in Australia comparing them globally and with high socio-demographic index (SDI) groups.

Findings

DALY rates have been improving steadily over the past 30 years among Australians aged 70 and above. Decreases in DALY rates were primarily attributed to a fall in YLLs attributable to cardiovascular diseases (60%) and chronic respiratory disorders (30.2%) and transport injuries (56.9%), while the non-fatal burden remained stable from 1990 to 2019. According to the DALY rates, the top five leading causes are ischemic heart disease, Alzheimer’s disease, COPD, stroke, and falls, where falls exhibited the largest increase since 1990.

Interpretation

This study provides an in-depth report on the main causes of mortality and disability in Australia’s population aged 70 and above. It sheds light on the shifts in burden over three decades, emphasising the need for the Australian health system to enhance its readiness in addressing the escalating demands of an ageing population. These findings establish pre-COVID baseline estimates for Australia’s population aged 70 and above, informing healthcare preparedness.

Abstract

The brain-heart axis denotes the intricate bidirectional communication vital for maintaining overall physiological balance, or homeostasis. Numerous studies underscore the profound impact of cardiovascular conditions on brain health. Conditions such as atrial fibrillation and left ventricular hypertrophy have been identified as potential contributors to cerebrovascular diseases and cognitive impairment. Utilizing of tools such as the electrocardiogram (ECG) are instrumental in identifying atrial fibrillation and left ventricular hypertrophy. Notably, findings from such diagnostic tests correlate with cortical microinfarcts and diminished cerebral blood flow. An elevated P-wave terminal force in lead V1 on an ECG has emerged as a promising indicator of left atrial abnormalities, serving as a potential precursor to atrial fibrillation and cognitive impairment. Ultrasound modalities, such as echocardiography and carotid ultrasound, offer additional insights into the intricate relationship between cardiac function and cognitive dysfunction. In addition to imaging techniques, blood-based markers of cardiac disease, including N-terminal pro-B-type natriuretic peptide (proBNP), high-sensitivity cardiac troponin T, and Growth Differentiation Factor 15, have been associated with cognitive impairment, emphasizing an intricate heart-brain connection. Although exploring the roles of these biomarkers holds significant promise for future research, the interconnectivity between cardiac biomarkers and the brain remains poorly elucidated. The numerous underlying mechanisms linking the heart and the brain continue to elude our understanding and warrant further investigation.

Abstract

Background

Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic.

Methods

The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic.

Findings

Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021.

Interpretation

Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades.

Abstract

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050.

Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline.

Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8-63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0-45·0] in 2050) and south Asia (31·7% [29·2-34·1] to 15·5% [13·7-17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4-40·3) to 41·1% (33·9-48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6-25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5-43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5-17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7-11·3) in the high-income super-region to 23·9% (20·7-27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5-6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2-26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [-0·6 to 3·6]).

Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions.

Abstract

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021.

Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk-outcome pairs. Pairs were included on the basis of data-driven determination of a risk-outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk-outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk-outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate’s distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws.

Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7-9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4-9·2]), smoking (5·7% [4·7-6·8]), low birthweight and short gestation (5·6% [4·8-6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8-6·0]). For younger demographics (ie, those aged 0-4 years and 5-14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9-27·7]) and environmental and occupational risks (decrease of 22·0% [15·5-28·8]), coupled with a 49·4% (42·3-56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9-21·7] for high BMI and 7·9% [3·3-12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6-1·9) for high BMI and 1·3% (1·1-1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4-78·8) for child growth failure and 66·3% (60·2-72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP).

Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions.

Abstract

Non-communicable chronic diseases (NCDs) have become a major global health concern. They constitute the leading cause of disabilities, increased morbidity, mortality, and socio-economic disasters worldwide. Medical condition-specific digital biomarker (DB) panels have emerged as valuable tools to manage NCDs. DBs refer to the measurable and quantifiable physiological, behavioral, and environmental parameters collected for an individual through innovative digital health technologies, including wearables, smart devices, and medical sensors. By leveraging digital technologies, healthcare providers can gather real-time data and insights, enabling them to deliver more proactive and tailored interventions to individuals at risk and patients diagnosed with NCDs. Continuous monitoring of relevant health parameters through wearable devices or smartphone applications allows patients and clinicians to track the progression of NCDs in real time. With the introduction of digital biomarker monitoring (DBM), a new quality of primary and secondary healthcare is being offered with promising opportunities for health risk assessment and protection against health-to-disease transitions in vulnerable sub-populations. DBM enables healthcare providers to take the most cost-effective targeted preventive measures, to detect disease developments early, and to introduce personalized interventions. Consequently, they benefit the quality of life (QoL) of affected individuals, healthcare economy, and society at large. DBM is instrumental for the paradigm shift from reactive medical services to 3PM approach promoted by the European Association for Predictive, Preventive, and Personalized Medicine (EPMA) involving 3PM experts from 55 countries worldwide. This position manuscript consolidates multi-professional expertise in the area, demonstrating clinically relevant examples and providing the roadmap for implementing 3PM concepts facilitated through DBs.

Abstract

Background: Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations.

Methods: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds.

Findings: The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles.

Interpretation: Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere.

Abstract

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020-21 COVID-19 pandemic period.

Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution.

Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5-65·1] decline), and increased during the COVID-19 pandemic period (2020-21; 5·1% [0·9-9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98-5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50-6·01) in 2019. An estimated 131 million (126-137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7-17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8-24·8), from 49·0 years (46·7-51·3) to 71·7 years (70·9-72·5). Global life expectancy at birth declined by 1·6 years (1·0-2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67-8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4-52·7]) and south Asia (26·3% [9·0-44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations.

Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic.

Funding: Bill & Melinda Gates Foundation.

Background: To estimate global and regional trends from 2000 to 2020 of the number of persons visually impaired by cataract and their proportion of the total number of vision-impaired individuals.

Methods: A systematic review and meta-analysis of published population studies and gray literature from 2000 to 2020 was carried out to estimate global and regional trends. We developed prevalence estimates based on modeled distance visual impairment and blindness due to cataract, producing location-, year-, age-, and sex-specific estimates of moderate to severe vision impairment (MSVI presenting visual acuity <6/18, ≥3/60) and blindness (presenting visual acuity <3/60). Estimates are age-standardized using the GBD standard population.

Results: In 2020, among overall (all ages) 43.3 million blind and 295 million with MSVI, 17.0 million (39.6%) people were blind and 83.5 million (28.3%) had MSVI due to cataract blind 60% female, MSVI 59% female. From 1990 to 2020, the count of persons blind (MSVI) due to cataract increased by 29.7%(93.1%) whereas the age-standardized global prevalence of cataract-related blindness improved by -27.5% and MSVI increased by 7.2%. The contribution of cataract to the age-standardized prevalence of blindness exceeded the global figure only in South Asia (62.9%) and Southeast Asia and Oceania (47.9%).

Conclusions: The number of people blind and with MSVI due to cataract has risen over the past 30 years, despite a decrease in the age-standardized prevalence of cataract. This indicates that cataract treatment programs have been beneficial, but population growth and aging have outpaced their impact. Growing numbers of cataract blind indicate that more, better-directed, resources are needed to increase global capacity for cataract surgery.

© 2024. The Author(s).

Abstract

Background: Accurate assessments of current and future fertility-including overall trends and changing population age structures across countries and regions-are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios.

Methods: To estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10-54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression-Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values-a metric assessing gain in forecasting accuracy-by comparing predicted versus observed ASFRs from the past 15 years (2007-21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline.

Findings: During the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63-5·06) to 2·23 (2·09-2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137-147), declining to 129 million (121-138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1-canonically considered replacement-level fertility-in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7-29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59-2·08) in 2050 and 1·59 (1·25-1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world’s livebirths in 2100, to 41·3% (39·6-43·1) in 2050 and 54·3% (47·1-59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions-decreasing, for example, in south Asia from 24·8% (23·7-25·8) in 2021 to 16·7% (14·3-19·1) in 2050 and 7·1% (4·4-10·1) in 2100-but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40-1·92) in 2050 and 1·62 (1·35-1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction.

Interpretation: Fertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world.

Funding: Bill & Melinda Gates Foundation.

Abstract

Aim: Chronic Kidney Disease (CKD) is a common comorbidity among acute ischaemic stroke (AIS) patients undergoing reperfusion therapies, including intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT). Acknowledging CKD’s prevalence in this cohort and understanding its influence on outcomes is crucial for prognosis and optimizing care. This study aims to determine the prevalence of CKD among anterior circulation AIS (acAIS) patients undergoing reperfusion therapies and to analyse the role of CKD in mediating outcomes.

Methods: A random-effects meta-analysis was conducted to pool and examine prevalence data. A total of 263 633 patients were included in the meta-analysis. The study assessed CKD’s association with functional outcomes, symptomatic intracranial haemorrhage (sICH) and mortality.

Results: The overall pooled prevalence of CKD among acAIS ranged from 30% to 56% in IVT-treated patients and 16%-42% for EVT-treated patients. CKD was associated with increased odds of unfavourable functional outcome at 90 days in both IVT (OR 1.837; 95% CI: [1.599; 2.110]; p < .001) and EVT (OR 1.804; 95% CI: [1.525; 2.133]; p < .001) groups. In IVT-treated patients, CKD was associated with increased odds of 30-day mortality (OR 6.211; 95% CI: [1.105; 34.909]; p = .038). CKD in IVT-treated patients exhibited increased odds of sICH, albeit statistically non-significant (OR 1.595; 95% CI: [0.567; 3.275]).

Conclusions: The high prevalence of CKD and its significant impact on outcomes in acAIS patients treated with reperfusion therapies underscore its clinical significance. This insight can guide personalised care strategies and potentially improve the prognosis in the management of acAIS.

Keywords: chronic kidney disease; endovascular thrombectomy; reperfusion therapy; stroke; thrombolysis.

Abstract

Reperfusion therapy in the form of intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) has revolutionised the field of stroke medicine. Atrial fibrillation (AF) patients constitute a major portion of the overall stroke population; however, the prevalence of AF amongst acute ischemic stroke (AIS) patients receiving reperfusion therapy remains unclear. Limitations in our understanding of prevalence in this group of patients are exacerbated by difficulties in appropriately diagnosing AF. Additionally, the benefits of reperfusion therapy are not consistent across all subgroups of AIS patients. More specifically, AIS patients with AF often tend to have poor prognoses despite treatment relative to those without AF. This article aims to present an overview of the diagnostic and therapeutic management of AF and how it mediates outcomes following stroke, most specifically in AIS patients treated with reperfusion therapy. We provide unique insights into AF prevalence and outcomes that could allow healthcare professionals to optimise the treatment and prognosis for AIS patients with AF. Specific indications on acute neurovascular management and secondary stroke prevention in AIS patients with AF are also discussed.

Abstract

Background: Cerebral microbleeds (CMBs), a notable neuroimaging finding often associated with cerebral microangiopathy, demonstrate a heightened prevalence in patients diagnosed with acute ischemic stroke (AIS), which is in turn linked to less favourable clinical prognoses. Nevertheless, the exact prevalence of CMBs and their influence on post-reperfusion therapy outcomes remain inadequately elucidated.

Materials and methods: Through systematic searches of PubMed, Embase and Cochrane databases, studies were identified adhering to specific inclusion criteria: (a) AIS patients, (b) age ≥ 18 years, (c) CMBs at baseline, (d) availability of comparative data between CMB-positive and CMB-negative groups, along with relevant post-reperfusion therapy outcomes. The data extracted were analysed using forest plots of odds ratios, and random-effects modelling was applied to investigate the association between CMBs and symptomatic intracerebral haemorrhage (sICH), haemorrhagic transformation (HT), 90-day functional outcomes, and 90-day mortality post-reperfusion therapy.

Results: In a total cohort of 9776 AIS patients who underwent reperfusion therapy, 1709 had CMBs, with a pooled prevalence of 19% (ES 0.19; 95% CI: 0.16, 0.23, p < 0.001). CMBs significantly increased the odds of sICH (OR 2.57; 95% CI: 1.72; 3.83; p < 0.0001), HT (OR 1.53; 95% CI: 1.25; 1.88; p < 0.0001), as well as poor functional outcomes at 90 days (OR 1.59; 95% CI: 1.34; 1.89; p < 0.0001) and 90-day mortality (OR 1.65; 95% CI: 1.27; 2.16; p < 0.0001), relative to those without CMBs, in AIS patients undergoing reperfusion therapy (encompassing intravenous thrombolysis [IVT], endovascular thrombectomy [EVT], either IVT or EVT, and bridging therapy). Variations in the level of association can be observed among different subgroups of reperfusion therapy.

Conclusions: This meta-analysis underscores a significant association between CMBs and adverse postprocedural safety outcomes encompassing sICH, HT, poor functional outcome, and increased mortality in AIS patients undergoing reperfusion therapy. The notable prevalence of CMBs in both the overall AIS population and those undergoing reperfusion therapy emphasizes their importance in post-stroke prognostication.

Keywords: cerebral microbleeds; haemorrhage; meta-analysis; prevalence; reperfusion therapy; stroke.

Promoting holistic outcomes in health is a crucial imperative for healthcare systems globally, including those in the G20 nations. This approach encompasses not only addressing physical health concerns but also acknowledging the social, emotional, and economic factors that profoundly influence an individual’s overall well-being. Low-income and marginalised communities are particularly vulnerable to poor health outcomes. These groups often have limited access to healthcare services and face a range of social determinants of health that can negatively impact their physical and mental well-being. This policy brief discusses key issues concerning fragmented health systems within the G20. It offers actionable recommendations to confront these challenges and improve holistic health outcomes, with particular emphasis on uplifting vulnerable communities. The brief argues that the promotion of holistic outcomes in health for vulnerable communities is a complex and ongoing task that requires collaboration between healthcare providers, community organisations, and policymakers.

Abstract

Background: Futile recanalization (FR) continues to raise concern despite the success of endovascular thrombectomy (EVT) in acute ischemic stroke (AIS). Understanding the prevalence of FR and identifying associated factors are crucial for refining patient prognoses and optimizing management strategies.

Objectives: This study aims to comprehensively assess the pooled prevalence of FR, explore the diverse factors connected with FR, and establish the association of FR with long-term clinical outcomes among AIS patients undergoing EVT. Materials and Methods: Incorporating studies focusing on FR following EVT in AIS patients, we conducted a random-effect meta-analysis to assess the pooled prevalence and its association with various clinical and imaging risk factors linked to FR. Summary estimates were compiled and study heterogeneity was explored.

Results: Our comprehensive meta-analysis, involving 11,700 AIS patients undergoing EVT, revealed a significant pooled prevalence of FR at 51%, with a range of 48% to 54% (Effect Size [ES]: 51%; 95% Confidence Interval [CI]: 48–54%; z = 47.66; p < 0.001). Numerous clinical factors demonstrated robust correlations with FR, including atrial fibrillation (Odds Ratio [OR]: 1.39, 95% CI 1.22 1.59; p < 0.001), hypertension (OR 1.65, 95% CI 1.41 1.92; p < 0.001), diabetes mellitus (OR 1.71, 95% CI 1.47 1.99; p < 0.001), previous stroke or transient ischemic attack (OR 1.298, 95% CI 1.06 1.59; p = 0.012), prior anticoagulant usage (OR 1.33, 95% CI 1.08 1.63; p = 0.007), cardioembolic strokes (OR 1.34, 95% CI 1.10 1.63; p = 0.003), and general anesthesia (OR 1.53, 95% CI 1.35 1.74; p < 0.001). Conversely, FR exhibited reduced likelihoods of smoking (OR 0.66, 95% CI 0.57 0.77; p < 0.001), good collaterals (OR 0.33, 95% CI 0.23 0.49; p < 0.001), male sex (OR 0.87, 95% CI 0.77 0.97; p = 0.016), and intravenous thrombolysis (IVT) (OR 0.75, 95% CI 0.66 0.86; p < 0.001). FR was strongly associated with increasing age (standardized mean difference [SMD] 0.49, 95% CI 0.42 0.56; p < 0.0001), baseline systolic blood pressure (SMD 0.20, 95% CI 0.13 0.27; p < 0.001), baseline National Institute of Health Stroke Severity Score (SMD 0.75, 95% CI: 0.65 0.86; p < 0.001), onset-to-treatment time (SMD 0.217, 95% CI 0.13 0.30; p < 0.001), onset-to-recanalization time (SMD 0.38, 95% CI 0.19; 0.57; p < 0.001), and baseline blood glucose (SMD 0.31, 95% CI 0.22 0.41; p < 0.001), while displaying a negative association with reduced baseline Alberta Stroke Program Early CT Score (ASPECTS) (SMD −0.37, 95% CI −0.46 −0.27; p < 0.001). Regarding clinical outcomes, FR was significantly associated with increased odds of symptomatic intracranial hemorrhages (OR 7.37, 95% CI 4.89 11.12; p < 0.001), hemorrhagic transformations (OR 2.98, 95% CI 2.37 3.75; p < 0.001), and 90-day mortality (OR 19.24, 95% CI 1.57 235.18; p = 0.021).

Conclusions: The substantial prevalence of FR, standing at approximately 51%, warrants clinical consideration. These findings underscore the complexity of FR in AIS patients and highlight the importance of tailoring management strategies based on individual risk factors and clinical profiles.

Abstract

Atrial fibrillation (AF) significantly contributes to acute ischaemic stroke (AIS), yet its precise influence on clinical outcomes post-intravenous thrombolysis (IVT) and post-endovascular thrombectomy (EVT) has remained elusive. Furthermore, the overall prevalence of AF in AIS patients undergoing reperfusion therapy has not been clearly determined. Employing random-effects meta-analyses, this research aimed to estimate the pooled prevalence of AF among AIS patients undergoing reperfusion therapy, while also examining the association between AF and clinical outcomes such as functional outcomes, symptomatic intracerebral haemorrhage (sICH) and mortality. Studies comparing AF and non-AF patient groups undergoing reperfusion therapy were identified and included following an extensive database search. Forty-nine studies (n = 66,887) were included. Among IVT patients, the prevalence of AF was 31% (Effect Size [ES] 0.31 [95%CI 0.28-0.35], p < 0.01), while in EVT patients, it reached 42% (ES 0.42 [95%CI 0.38-0.46], p < 0.01), and in bridging therapy (BT) patients, it stood at 36% (ES 0.36 [95%CI 0.28-0.43], p < 0.01). AF was associated with significantly lower odds of favourable 90-day functional outcomes post IVT (Odds Ratio [OR] 0.512 [95%CI 0.376-0.696], p < 0.001), but not post EVT (OR 0.826 [95%CI 0.651-1.049], p = 0.117). Our comprehensive meta-analysis highlights the varying prevalence of AF among different reperfusion therapies and its differential impact on patient outcomes. The highest pooled prevalence of AF was observed in EVT patients, followed by BT and IVT patients. Interestingly, our analysis revealed that AF was significantly associated with poorer clinical outcomes following IVT. Such an association was not observed following EVT.

Keywords: atrial fibrillation; outcomes; prevalence; reperfusion therapy; stroke; thrombectomy; thrombolysis.

Abstract

Background: Peripheral artery disease is a growing public health problem. We aimed to estimate the global disease burden of peripheral artery disease, its risk factors, and temporospatial trends to inform policy and public measures.

Methods: Data on peripheral artery disease were modelled using the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019 database. Prevalence, disability-adjusted life years (DALYs), and mortality estimates of peripheral artery disease were extracted from GBD 2019. Total DALYs and age-standardised DALY rate of peripheral artery disease attributed to modifiable risk factors were also assessed.

Findings: In 2019, the number of people aged 40 years and older with peripheral artery disease was 113 million (95% uncertainty interval [UI] 99·2-128·4), with a global prevalence of 1·52% (95% UI 1·33-1·72), of which 42·6% was in countries with low to middle Socio-demographic Index (SDI). The global prevalence of peripheral artery disease was higher in older people, (14·91% [12·41-17·87] in those aged 80-84 years), and was generally higher in females than in males. Globally, the total number of DALYs attributable to modifiable risk factors in 2019 accounted for 69·4% (64·2-74·3) of total peripheral artery disease DALYs. The prevalence of peripheral artery disease was highest in countries with high SDI and lowest in countries with low SDI, whereas DALY and mortality rates showed U-shaped curves, with the highest burden in the high and low SDI quintiles.

Interpretation: The total number of people with peripheral artery disease has increased globally from 1990 to 2019. Despite the lower prevalence of peripheral artery disease in males and low-income countries, these groups showed similar DALY rates to females and higher-income countries, highlighting disproportionate burden in these groups. Modifiable risk factors were responsible for around 70% of the global peripheral artery disease burden. Public measures could mitigate the burden of peripheral artery disease by modifying risk factors.

Funding: Bill & Melinda Gates Foundation.

Abstract

Background: The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019.

Methods: We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends.

Findings: In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of -0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC = -0.41), inflammatory bowel disease (AAPC = -0.72), multiple sclerosis (AAPC = -0.26), psoriasis (AAPC = -0.77), and atopic dermatitis (AAPC = -0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR.

Interpretation: The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively.

Funding: The Global Burden of Disease Study is funded by the Bill and Melinda Gates Foundation. The project funded by Scientific Research Fund of Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital (2022QN38).

Abstract

Background: Although meningitis is largely preventable, it still causes hundreds of thousands of deaths globally each year. WHO set ambitious goals to reduce meningitis cases by 2030, and assessing trends in the global meningitis burden can help track progress and identify gaps in achieving these goals. Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we aimed to assess incident cases and deaths due to acute infectious meningitis by aetiology and age from 1990 to 2019, for 204 countries and territories.

Methods: We modelled meningitis mortality using vital registration, verbal autopsy, sample-based vital registration, and mortality surveillance data. Meningitis morbidity was modelled with a Bayesian compartmental model, using data from the published literature identified by a systematic review, as well as surveillance data, inpatient hospital admissions, health insurance claims, and cause-specific meningitis mortality estimates. For aetiology estimation, data from multiple causes of death, vital registration, hospital discharge, microbial laboratory, and literature studies were analysed by use of a network analysis model to estimate the proportion of meningitis deaths and cases attributable to the following aetiologies: Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, group B Streptococcus, Escherichia coli, Klebsiella pneumoniae, Listeria monocytogenes, Staphylococcus aureus, viruses, and a residual other pathogen category.

Findings: In 2019, there were an estimated 236 000 deaths (95% uncertainty interval [UI] 204 000-277 000) and 2·51 million (2·11-2·99) incident cases due to meningitis globally. The burden was greatest in children younger than 5 years, with 112 000 deaths (87 400-145 000) and 1·28 million incident cases (0·947-1·71) in 2019. Age-standardised mortality rates decreased from 7·5 (6·6-8·4) per 100 000 population in 1990 to 3·3 (2·8-3·9) per 100 000 population in 2019. The highest proportion of total all-age meningitis deaths in 2019 was attributable to S pneumoniae (18·1% [17·1-19·2]), followed by N meningitidis (13·6% [12·7-14·4]) and K pneumoniae (12·2% [10·2-14·3]). Between 1990 and 2019, H influenzae showed the largest reduction in the number of deaths among children younger than 5 years (76·5% [69·5-81·8]), followed by N meningitidis (72·3% [64·4-78·5]) and viruses (58·2% [47·1-67·3]).

Interpretation: Substantial progress has been made in reducing meningitis mortality over the past three decades. However, more meningitis-related deaths might be prevented by quickly scaling up immunisation and expanding access to health services. Further reduction in the global meningitis burden should be possible through low-cost multivalent vaccines, increased access to accurate and rapid diagnostic assays, enhanced surveillance, and early treatment.

Funding: Bill & Melinda Gates Foundation.

Abstract

Background: Diabetes is one of the leading causes of death and disability worldwide, and affects people regardless of country, age group, or sex. Using the most recent evidentiary and analytical framework from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), we produced location-specific, age-specific, and sex-specific estimates of diabetes prevalence and burden from 1990 to 2021, the proportion of type 1 and type 2 diabetes in 2021, the proportion of the type 2 diabetes burden attributable to selected risk factors, and projections of diabetes prevalence through 2050.

Methods: Estimates of diabetes prevalence and burden were computed in 204 countries and territories, across 25 age groups, for males and females separately and combined; these estimates comprised lost years of healthy life, measured in disability-adjusted life-years (DALYs; defined as the sum of years of life lost [YLLs] and years lived with disability [YLDs]). We used the Cause of Death Ensemble model (CODEm) approach to estimate deaths due to diabetes, incorporating 25 666 location-years of data from vital registration and verbal autopsy reports in separate total (including both type 1 and type 2 diabetes) and type-specific models. Other forms of diabetes, including gestational and monogenic diabetes, were not explicitly modelled. Total and type 1 diabetes prevalence was estimated by use of a Bayesian meta-regression modelling tool, DisMod-MR 2.1, to analyse 1527 location-years of data from the scientific literature, survey microdata, and insurance claims; type 2 diabetes estimates were computed by subtracting type 1 diabetes from total estimates. Mortality and prevalence estimates, along with standard life expectancy and disability weights, were used to calculate YLLs, YLDs, and DALYs. When appropriate, we extrapolated estimates to a hypothetical population with a standardised age structure to allow comparison in populations with different age structures. We used the comparative risk assessment framework to estimate the risk-attributable type 2 diabetes burden for 16 risk factors falling under risk categories including environmental and occupational factors, tobacco use, high alcohol use, high body-mass index (BMI), dietary factors, and low physical activity. Using a regression framework, we forecast type 1 and type 2 diabetes prevalence through 2050 with Socio-demographic Index (SDI) and high BMI as predictors, respectively.

Findings: In 2021, there were 529 million (95% uncertainty interval [UI] 500-564) people living with diabetes worldwide, and the global age-standardised total diabetes prevalence was 6·1% (5·8-6·5). At the super-region level, the highest age-standardised rates were observed in north Africa and the Middle East (9·3% [8·7-9·9]) and, at the regional level, in Oceania (12·3% [11·5-13·0]). Nationally, Qatar had the world’s highest age-specific prevalence of diabetes, at 76·1% (73·1-79·5) in individuals aged 75-79 years. Total diabetes prevalence-especially among older adults-primarily reflects type 2 diabetes, which in 2021 accounted for 96·0% (95·1-96·8) of diabetes cases and 95·4% (94·9-95·9) of diabetes DALYs worldwide. In 2021, 52·2% (25·5-71·8) of global type 2 diabetes DALYs were attributable to high BMI. The contribution of high BMI to type 2 diabetes DALYs rose by 24·3% (18·5-30·4) worldwide between 1990 and 2021. By 2050, more than 1·31 billion (1·22-1·39) people are projected to have diabetes, with expected age-standardised total diabetes prevalence rates greater than 10% in two super-regions: 16·8% (16·1-17·6) in north Africa and the Middle East and 11·3% (10·8-11·9) in Latin America and Caribbean. By 2050, 89 (43·6%) of 204 countries and territories will have an age-standardised rate greater than 10%.

Interpretation: Diabetes remains a substantial public health issue. Type 2 diabetes, which makes up the bulk of diabetes cases, is largely preventable and, in some cases, potentially reversible if identified and managed early in the disease course. However, all evidence indicates that diabetes prevalence is increasing worldwide, primarily due to a rise in obesity caused by multiple factors. Preventing and controlling type 2 diabetes remains an ongoing challenge. It is essential to better understand disparities in risk factor profiles and diabetes burden across populations, to inform strategies to successfully control diabetes risk factors within the context of multiple and complex drivers.

Funding: Bill & Melinda Gates Foundation.

Abstract

The underlying aetiopathophysiology of cancer-related strokes and thromboembolisms differs from that of non cancer-related strokes, which makes treating cancer-related strokes and thromboembolisms a distinct clinical challenge. This necessitates the development of novel, individualised diagnostic and treatment strategies. However, limited guidelines are available for the management of cancer-related strokes and the prevention of acute strokes or other thromboembolic events in this patient population. In this article, we present an updated overview of the therapeutic and preventive strategies for strokes in cancer settings. These strategies include acute reperfusion therapy, anticoagulant therapy, antiplatelet therapy, and lifestyle management options. We also outline comprehensive pathways and highlight gaps in the evidence-based clinical management of cancer-related strokes or thromboembolisms. Additionally, future recommendations for the management of strokes in cancer patients are provided.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Objective

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.

Methods

This is a retrospective study involving 93 patients and 33 Neurosurgery physicians who anonymously participated in the survey about their experience with telemedicine visits.

Results

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%).

Conclusion

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.

Keywords

Neurosurgery, Telemedicine, COVID-19, Patient Experience, Physicians, Health Systems

Abstract

Background

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.

Objective

This meta-analysis sought to examine the effect of NLR on functional outcomes, mortality and adverse outcomes in AIS patients receiving RT.

Methods

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.

Results

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.

Conclusion

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

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

Background

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.

Objectives

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.

Design

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.

Results

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).

Conclusion

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

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

Abstract

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.

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

Bill & Melinda Gates Foundation and Gates Ventures.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Keywords: COVID-19; SARS-CoV2; cerebrovascular disease; global health; infectious disease; meta-analysis; mucormycosis; public health.

Abstract

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.

Abstract

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.

Abstract

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

Abstract

Introduction:
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.

Results:
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).

Conclusions:
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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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) (AUC_CTP : 0.90 [95% CI 0.87-0.92] vs. AUC_NCCT : 0.96 [95% CI 0.94-0.97]); however, with higher pooled sensitivity (SENS_CTP : 72% [95% CI 57%-83%] vs. SENS_NCCT : 25% [95% CI 17%-35%]) and lower specificity (SPEC_CTP : 90% [95% CI 83%-94%] vs. SPEC_NCCT : 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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

Introduction:
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.

Results:
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.

Conclusions:
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%.

Abstract

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.

Abstract

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.

Keywords: COVID-19; digital health; policy; public health; telemedicine.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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).

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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).

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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)

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.