The Anti-Coronavirus Therapies (ACT) Trials: Design, Baseline Characteristics, and Challenges.

Background: Effective treatments for COVID-19 are urgently needed, but conducting randomized trials during the pandemic has been challenging. Methods: The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3500 outpatients and 2500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine vs usual care, and aspirin vs usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization, it is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine vs usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily vs usual care. The primary outcome for the colchicine randomization is need for high-flow oxygen, need for mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization, it is major thrombotic events, need for high-flow oxygen, need for mechanical ventilation, or death. Results: At the completion of enrollment on February 10, 2022, the outpatient trial had enrolled 3917 patients, and the inpatient trial had enrolled 2611 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals, and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic. Conclusions: The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine, and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban, across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials.

Contexte: Il est urgent de mettre au point des traitements efficaces contre la COVID-19, mais il n'est pas facile de réaliser des essais à répartition aléatoire dans un contexte pandémique. Méthodologie: Les essais internationaux factoriels ACT (Anti-Coronavirus Therapy) avaient un objectif d'inscription de 3 500 patients externes et de 2 500 patients hospitalisés présentant une COVID-19 symptomatique. L'essai mené auprès de patients externes visait à évaluer la colchicine par rapport aux soins habituels, et l'aspirine par rapport aux soins habituels. Le paramètre d'évaluation principal au terme de la répartition aléatoire des patients était l'hospitalisation ou le décès dans le groupe traité par la colchicine, et la thrombose majeure, l'hospitalisation ou le décès dans le groupe traité par l'aspirine. L'essai mené auprès de patients hospitalisés visant à évaluer la colchicine par rapport aux soins habituels, et un traitement associant le rivaroxaban à 2,5 mg deux fois par jour et l'aspirine à 100 mg une fois par jour par rapport aux soins habituels. Le paramètre d'évaluation principal au terme de la répartition aléatoire des patients était le recours à l'oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par la colchicine, et la survenue de manifestations thrombotiques majeures, le recours à l'oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par l'association rivaroxaban-aspirine. Résultats: À la fin de la période d'inscription, le 10 février 2022, 3 917 patients externes et 2 611 patients hospitalisés formaient la population des essais. Certains aspects se sont révélés problématiques, notamment le manque de données préliminaires sur les interventions à évaluer, les incertitudes liées aux taux d'événements prévus, les retards touchant les approbations réglementaires et éthiques et les interventions de recherche, de même que l'évolution de la pandémie de COVID-19. Conclusions: Les essais ACT détermineront l'efficacité du traitement anti-inflammatoire par la colchicine et du traitement antithrombotique par l'aspirine, administrée seule ou en association avec le rivaroxaban, contre la COVID-19 légère, modérée ou sévère. Les leçons tirées de ces essais orienteront la planification d'essais ultérieurs.

Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): a prospective cohort study

BACKGROUND: To our knowledge, no previous study has prospectively documented the incidence of common diseases and related mortality in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) with standardised approaches. Such information is key to developing global and context-specific health strategies. In our analysis of the Prospective Urban Rural Epidemiology (PURE) study, we aimed to evaluate differences in the incidence of common diseases, related hospital admissions, and related mortality in a large contemporary cohort of adults from 21 HICs, MICs, and LICs across five continents by use of standardised approaches. METHODS: The PURE study is a prospective, population-based cohort study of individuals aged 35-70 years who have been enrolled from 21 countries across five continents. The key outcomes were the incidence of fatal and non-fatal cardiovascular diseases, cancers, injuries, respiratory diseases, and hospital admissions, and we calculated the age-standardised and sex-standardised incidence of these events per 1000 person-years. FINDINGS: This analysis assesses the incidence of events in 162 534 participants who were enrolled in the first two phases of the PURE core study, between Jan 6, 2005, and Dec 4, 2016, and who were assessed for a median of 9·5 years (IQR 8·5-10·9). During follow-up, 11 307 (7·0%) participants died, 9329 (5·7%) participants had cardiovascular disease, 5151 (3·2%) participants had a cancer, 4386 (2·7%) participants had injuries requiring hospital admission, 2911 (1·8%) participants had pneumonia, and 1830 (1·1%) participants had chronic obstructive pulmonary disease (COPD). Cardiovascular disease occurred more often in LICs (7·1 cases per 1000 person-years) and in MICs (6·8 cases per 1000 person-years) than in HICs (4·3 cases per 1000 person-years). However, incident cancers, injuries, COPD, and pneumonia were most common in HICs and least common in LICs. Overall mortality rates in LICs (13·3 deaths per 1000 person-years) were double those in MICs (6·9 deaths per 1000 person-years) and four times higher than in HICs (3·4 deaths per 1000 person-years). This pattern of the highest mortality in LICs and the lowest in HICs was observed for all causes of death except cancer, where mortality was similar across country income levels. Cardiovascular disease was the most common cause of deaths overall (40%) but accounted for only 23% of deaths in HICs (vs 41% in MICs and 43% in LICs), despite more cardiovascular disease risk factors (as judged by INTERHEART risk scores) in HICs and the fewest such risk factors in LICs. The ratio of deaths from cardiovascular disease to those from cancer was 0·4 in HICs, 1·3 in MICs, and 3·0 in LICs, and four upper-MICs (Argentina, Chile, Turkey, and Poland) showed ratios similar to the HICs. Rates of first hospital admission and cardiovascular disease medication use were lowest in LICs and highest in HICs. INTERPRETATION: Among adults aged 35-70 years, cardiovascular disease is the major cause of mortality globally. However, in HICs and some upper-MICs, deaths from cancer are now more common than those from cardiovascular disease, indicating a transition in the predominant causes of deaths in middle-age. As cardiovascular disease decreases in many countries, mortality from cancer will probably become the leading cause of death. The high mortality in poorer countries is not related to risk factors, but it might be related to poorer access to health care. (AU)

Psychosocial factors and obesity in 17 high-, middle- and low-income countries: the Prospective Urban Rural Epidemiologic study.

BACKGROUND/OBJECTIVES: Psychosocial stress has been proposed to contribute to obesity, particularly abdominal, or central obesity, through chronic activation of the neuroendocrine systems. However, these putative relationships are complex and dependent on country and cultural context. We investigated the association between psychosocial factors and general and abdominal obesity in the Prospective Urban Rural Epidemiologic study. SUBJECTS/METHODS: This observational, cross-sectional study enrolled 151 966 individuals aged 35-70 years from 628 urban and rural communities in 17 high-, middle- and low-income countries. Data were collected for 125 290 individuals regarding education, anthropometrics, hypertension/diabetes, tobacco/alcohol use, diet and psychosocial factors (self-perceived stress and depression). RESULTS: After standardization for age, sex, country income and urban/rural location, the proportion with obesity (body mass index ≥30 kg m(-)(2)) increased from 15.7% in 40 831 individuals with no stress to 20.5% in 7720 individuals with permanent stress, with corresponding proportions for ethnicity- and sex-specific central obesity of 48.6% and 53.5%, respectively (P<0.0001 for both). Associations between stress and hypertension/diabetes tended to be inverse. Estimating the total effect of permanent stress with age, sex, physical activity, education and region as confounders, no relationship between stress and obesity persisted (adjusted prevalence ratio (PR) for obesity 1.04 (95% confidence interval: 0.99-1.10)). There was no relationship between ethnicity- and sex-specific central obesity (adjusted PR 1.00 (0.97-1.02)). Stratification by region yielded inconsistent associations. Depression was weakly but independently linked to obesity (PR 1.08 (1.04-1.12)), and very marginally to abdominal obesity (PR 1.01 (1.00-1.03)). CONCLUSIONS: Although individuals with permanent stress tended to be slightly more obese, there was no overall independent effect and no evidence that abdominal obesity or its consequences (hypertension, diabetes) increased with higher levels of stress or depression. This study does not support a causal link between psychosocial factors and abdominal obesity.

Psychosocial factors and obesity in 17 high-, middle- andlow-income countries: the Prospective Urban RuralEpidemiologic study

Psychosocial stress has been proposed to contribute to obesity, particularly abdominal, or centralobesity, through chronic activation of the neuroendocrine systems. However, these putative relationships are complex anddependent on country and cultural context. We investigated the association between psychosocial factors and general andabdominal obesity in the Prospective Urban Rural Epidemiologic study.SUBJECTS/METHODS: This observational, cross-sectional study enrolled 151 966 individuals aged 35–70 years from 628 urban andrural communities in 17 high-, middle- and low-income countries. Data were collected for 125 290 individuals regarding education,anthropometrics, hypertension/diabetes, tobacco/alcohol use, diet and psychosocial factors (self-perceived stress and depression).RESULTS: After standardization for age, sex, country income and urban/rural location, the proportion with obesity (body massindex ⩾ 30 kgm−2) increased from 15.7% in 40 831 individuals with no stress to 20.5% in 7720 individuals with permanent stress,with corresponding proportions for ethnicity- and sex-specific central obesity of 48.6% and 53.5%, respectively (Po0.0001 forboth). Associations between stress and hypertension/diabetes tended to be inverse. Estimating the total effect of permanent stresswith age, sex, physical activity, education and region as confounders, no relationship between stress and obesity persisted(adjusted prevalence ratio (PR) for obesity 1.04 (95% confidence interval: 0.99–1.10)). There was no relationship between ethnicityandsex-specific central obesity (adjusted PR 1.00 (0.97–1.02)). Stratification by region yielded inconsistent associations. Depressionwas weakly but independently linked to obesity (PR 1.08 (1.04–1.12)), and very marginally to abdominal obesity (PR 1.01(1.00–1.03)).

Cardiovascular risk and events in 17 low-,middle-, and high-income countries

BACKGROUNDMore than 80% of deaths from cardiovascular disease are estimated to occur inlow-income and middle-income countries, but the reasons are unknown.METHODSWe enrolled 156,424 persons from 628 urban and rural communities in 17 countries(3 high-income, 10 middle-income, and 4 low-income countries) and assessedtheir cardiovascular risk using the INTERHEART Risk Score, a validated score forquantifying risk-factor burden without the use of laboratory testing (with higherscores indicating greater risk-factor burden). Participants were followed for incidentcardiovascular disease and death for a mean of 4.1 years.RESULTSThe mean INTERHEART Risk Score was highest in high-income countries, intermediatein middle-income countries, and lowest in low-income countries (P<0.001).However, the rates of major cardiovascular events (death from cardiovascularcauses, myocardial infarction, stroke, or heart failure) were lower in high-incomecountries than in middle- and low-income countries (3.99 events per 1000 personyearsvs. 5.38 and 6.43 events per 1000 person-years, respectively; P<0.001). Casefatality rates were also lowest in high-income countries (6.5%, 15.9%, and 17.3%in high-, middle-, and low-income countries, respectively; P = 0.01). Urban communitieshad a higher risk-factor burden than rural communities but lower ratesof cardiovascular events (4.83 vs. 6.25 events per 1000 person-years, P<0.001) andcase fatality rates (13.52% vs. 17.25%, P<0.001). The use of preventive medicationsand revascularization procedures was significantly more common in high-incomecountries than in middle- or low-income countries (P<0.001).CONCLUSIONSAlthough the risk-factor burden was lowest in low-income countries, the rates ofmajor cardiovascular disease and death were substantially higher in low-incomecountries than in high-income countries. The high burden of risk factors in highincome...

Treatment of diabetic coma in a tropical environment.

Fourteen patients admitted to Muhimbili Medical Centre, Dar es Salaam in diabetic coma were treated according to a management plan based on the hourly administration of low doses of soluble insulin. The use of this treatment plan resulted in a significant fall in mortality. Three patients died. While these results are still unsatisfactory, the study has shown that combining the treatment plan with enthusiastic and constant medical and nursing care, the results of treatment of diabetic coma in the tropics can approach those of the developed world. The treatment plan is described in detail, since we believe that it can be used in hospitals with only basic facilities.

Cholera-like diseases due to Vibrio parahaemolyticus.

The first seven cases of cholera-like disease due to Vibrio parahaemolyticus, acquired mainly through handling of raw fish from the Indian Ocean, in Dar es Salaam are reported. Five of the patients were young women, two of those being fishmongers. The duration of the disease in six of the patients was short leading to recovery within 24 h. One of the patients took 4 days of intensive rehydration therapy before recovery. Whereas V. parahaemolyticus is the commonest cause of food poisoning in Japan where raw or half cooked salt water fish are a common delicacy, the disease in Tanzania where raw fish is almost never eaten, appears to have resulted mainly from poor personal hygiene in handling raw fish. It is recommended that more studies on the problem should be carried out and the public should be educated on the dangers of unhygienic handling of raw fish.