Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with nonhypoxic ischaemic acute brain injuries and conditions in the intensive care unit (Mega-ROX Brains)

Background: The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults who have nonhypoxic ischaemic encephalopathy acute brain injuries and conditions and are receiving invasive mechanical ventilation in the intensive care unit (ICU) is uncertain. Objective: The objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Brains trial. Design, setting, and participants: Mega-ROX Brains is an international randomised clinical trial, which will be conducted within an overarching 40,000-participant, registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We expect to enrol between 7500 and 9500 participants with nonhypoxic ischaemic encephalopathy acute brain injuries and conditions who are receiving unplanned invasive mechanical ventilation in the ICU. Main outcome measures: The primary outcome is in-hospital all-cause mortality up to 90 d from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of participants discharged home. Results and conclusions: Mega-ROX Brains will compare the effect of conservative vs. liberal oxygen therapy regimens on 90-day in-hospital mortality in adults in the ICU with acute brain injuries and conditions. The protocol and planned analyses are reported here to mitigate analysis bias. Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN 12620000391976)

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

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

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

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. FUNDING Bill & Melinda Gates Foundation

Elevated myocardial oxygen consumption during cutaneous cold stress in young adult overweight and obese Africans

Exaggerated sympathetic-mediated cardiovascular responses to stressful stimuli (such as cold exposure) has been linked to the development of hypertension and cardiovascular disease, which in turn has been demonstrated to predict the development of future hypertension. The aim of the present study was to test the hypothesis that enhanced change in myocardial oxygen consumption (MVO2) to cutaneous cold stress may be one potential mechanism that predisposes overweight/obese individuals in Africa to developing hypertension. The Rate-Pressure-Product (a non-invasive determinant of MVO2) was measured in normotensive young individuals aged between 18 and 25 years at baseline and during sympathetic activation elicited by cutaneous cold stimulation (CCS). Following CCS, there was a significant enhanced rate pressure product (RPP) change in overweight individuals (P=0.019). Furthermore, multivariate regression analysis showed that body mass index, but not body weight had a significant influence on RPP variation following CCS. Thus, it can be concluded that normotensive overweight or obese individuals have an exaggerated RPP response to the CCS. However, exposure to cold may augment sympathetic reactivity in overweight/obese individuals, which may contribute to increased risk of developing myocardial dysfunction, even in young normotensive individuals

Preventive effects of L-glutamine on gestational fructose-induced cardiac hypertrophy: Involvement of pyruvate dehydrogenase kinase-4

Gestational fructose exposure has detrimental health consequences on both the maternal and fetus or offspring in the early or later life, contributing to epidemic rise in cardiometabolic syndrome including cardiac events. l-Glutamine has been shown to mitigate cardiac metabolic stress. However, the effect of l-glutamine on cardiac hypertrophy induced by gestational fructose exposure is not known. We therefore hypothesized that l-glutamine would prevent gestational fructose-induced cardiac hypertrophy, possibly by suppression of pyruvate dehydrogenase kinase-4 (PDK-4). Pregnant Wistar rats were allotted into the control, l-glutamine, gestational fructose exposure, and gestational fructose exposure plus l-glutamine groups (6 rats in each group). The groups received distilled water (vehicle, per os), 1 g/kg body weight l-glutamine (per os), 10% fructose (w/v) and 10% fructose (w/v) plus 1 g/kg l-glutamine (per os), respectively, daily for 19 days. Data from this study showed that gestational fructose-enriched drink caused cardiac hypertrophy with correspondent body weight gain, glucose dysregulation, increased cardiac PDK-4, triglyceride, glycogen, lactate, and uric acid production. On the other hand, defective glutathione-dependent antioxidant barrier was also observed in pregnant rats taking fructose-enriched drink. However, the gestational fructose-induced cardiac hypertrophy and its correlates were attenuated by l-glutamine. The present results demonstrate that gestational fructose-enriched drink induces cardiac hypertrophy that is accompanied by increased PDK-4. The findings also suggest that the inhibitory effect of l-glutamine on PDK-4 prevents the development of cardiac hypertrophy, thereby implying that PDK-4 may be a potential novel therapeutic intervention for cardiac hypertrophy especially in pregnancy.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Neck circumference is independently associated with relative systemic hypertension in young adults with sickle cell anaemia

Abstract Background A seemingly interesting observation in patients with sickle cell anaemia (SCA) is that they usually have lower systemic blood pressures (BP) and insulin resistance than persons in the general population in spite of chronic inflammation and vasculopathy. However, relative systemic hypertension (rHTN) has been linked to pulmonary hypertension, increased blood viscosity and renal insufficiency, which could indicate a risk of developing cardiometabolic disorder (CMD) in SCA. We therefore hypothesized that neck circumference (NC) and CMD marker; triglyceride glucose (TyG) index would independently predict rHTN in young adults with SCA in steady state. Methods We compared the anthropometrical, hematological, hemorheological and CMD markers between SCA patients with normal BP < 120/70 mmHg; nHTN, n = 65) and those with rHTN (BP ≥ 120/70 mmHg, n = 32). Results Our results showed that SCA with rHTN had significantly higher body weight, waist circumference, NC, plasma viscosity, systolic and diastolic BP. Results also indicated that NC (OR: 2.98; 95% CI 1.46 to 6.10, p < 0.01) was a predictor of rHTN in SCA independent of gender, age, weight, waist circumference, BMI, blood viscosity, triglyceride or TyG. A receiver operating characteristic curve analysis also showed that NC was the most efficient predictor of rHTN than other CMD markers. Conclusion The present study demonstrates that increased NC is a salient risk factors that is independently associated with rHTN in SCA. The finding therefore underscores the utility of NC in early detection and stratification of systemic hypertension, particularly in individuals with SCA

Artesunate-induced hemolysis and hypoglycemia in rats: Gender implication and role of antioxidant enzymes

Introduction: The gender implication of the effects of artesunate on hematological parameters and blood glucose is not well understood. The present study investigated the effects of artesunate on some hematological parameters, blood glucose, and antioxidant enzymes in both the sexes. Materials And Methods: A total of 35 male and 35 female Wistar rats were randomly divided into five groups (n = 7). Group one rats received distilled water; groups two and three received 2.90 mg/kg artesunate on the first day and 1.45 mg/kg artesunate from the second day until the fifth and fifteenth days, respectively; and groups four and five received 8.70 mg/kg artesunate on the first day and 4.35 mg/kg artesunate from the second day until the fifth and fifteenth days, respectively. Results: The results of this study showed that an increase in G-6-PD activity alone prevented hemolysis in the male, but not in the female rats following a short duration of treatment. However, after a longer duration of treatment, a synergy between gucose-6-phosphate dehydrogenase (G-6-PD) and catalase prevented hemolysis in the female rats, whereas hemolysis occurred in the male rats due to the absence of an increased G-6-PD activity. Probably due to hormonal differences, artesunate reduced fasting blood glucose in the females, but it was either hypoglycemic (at low dose) or hyperglycemic (at high dose) in the male rats. Discussion: In conclusion, the present study suggests that a duration-dependent difference exists in the onset of artesunate-induced hemolysis and the response of antioxidant enzymes in the male and female rats and that following longer duration of treatment, hypoglycemia could be sustained in the female rats while counterregulatory mechanism(s) could be triggered in the male rats

Uric acid is a key player in salt-induced endothelial dysfunction: the therapeutic role of Stigma maydis (corn silk) extract

Hyperuricemia has been implicated in the pathogenesis and complications of cardiovascular diseases with associated elevated oxidant events. There is evidence that excessive salt intake results in cardiometabolic disturbances but the mechanism is elusive. Also, Stigma maydis (corn silk) is noted for its antioxidant properties among other beneficial roles. This study, therefore, aimed to establish the effect of high-salt diet (SD) on uric acid (UA) production and the role of S. maydis in salt-induced phenotypes. Four groups of randomly selected rats (n = 5) were fed with normal rat feed, corn silk extract (500 mg/kg), SD (8%) and corn silk extract plus high-salt feed. After 6 weeks of the experimental procedure, each animal was anesthetized by exposure to chloroform vapor and blood samples collected by cardiac puncture. Data were expressed in means ± SEM and p values <0.05 were accepted as significant. SD resulted in reduced plasma superoxide dismutase (SOD), nitric oxide (NO), and glutathione peroxidase (GPx) but not endothelial nitric oxide synthase. Also, plasma UA and vascular cell adhesion molecule-1 (VCAM-1) increased in the SD group compared with control. However, S. maydis extract in the SD-exposed group increased NO and GPx and not SOD. Also, S. maydis extract attenuated UA and VCAM-1. In conclusion, high-salt intake may initiate deleterious cardiovascular events through UA-dependent mechanism and S. maydis extract has therapeutic potential in high-salt–induced oxidative damage and/or UA-dependent endothelial pathologies.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author