The predominance of Human Immunodeficiency Virus type 1 (HIV-1) circulating recombinant form 02 (CRF02_AG) in West Central Africa may be related to its replicative fitness

BACKGROUND: CRF02_AG is the predominant HIV strain circulating in West and West Central Africa. The aim of this study was to test whether this predominance is associated with a higher in vitro replicative fitness relative to parental subtype A and G viruses. Primary HIV-1 isolates (10 CRF02_AG, 5 subtype A and 5 subtype G) were obtained from a well-described Cameroonian cohort. Growth competition experiments were carried out at equal multiplicity of infection in activated T cells and monocyte-derived dendritic cells (MO-DC) in parallel. RESULTS: Dual infection/competition experiments in activated T cells clearly indicated that CRF02_AG isolates had a significant replication advantage over the subtype A and subtype G viruses. The higher fitness of CRF02_AG was evident for isolates from patients with CD4+ T cell counts >200 cells/μL (non-AIDS) or CD4+ T cell counts <200 cells/μL (AIDS), and was independent of the co-receptor tropism. In MO-DC cultures, CRF02_AG isolates showed a slightly but not significantly higher replication advantage compared to subtype A or G isolates. CONCLUSION: We observed a higher ex vivo replicative fitness of CRF02_AG isolates compared to subtype A and G viruses from the same geographic region and showed that this was independent of the co-receptor tropism and irrespective of high or low CD4+ T cell count. This advantage in replicative fitness may contribute to the dominant spread of CRF02_AG over A and G subtypes in West and West Central Africa

Serum Uric Acid and Adiposity: Deciphering Causality Using a Bidirectional Mendelian Randomization Approach

Background: Although the relationship between serum uric acid (SUA) and adiposity is well established, the direction of the causality is still unclear in the presence of conflicting evidences. We used a bidirectional Mendelian randomization approach to explore the nature and direction of causality between SUA and adiposity in a population-based study of Caucasians aged 35 to 75 years. Methods and Findings: We used, as instrumental variables, rs6855911 within the SUA gene SLC2A9 in one direction, and combinations of SNPs within the adiposity genes FTO, MC4R and TMEM18 in the other direction. Adiposity markers included weight, body mass index, waist circumference and fat mass. We applied a two-stage least squares regression: a regression of SUA/adiposity markers on our instruments in the first stage and a regression of the response of interest on the fitted values from the first stage regression in the second stage. SUA explained by the SLC2A9 instrument was not associated to fat mass (regression coefficient [95 % confidence interval]: 0.05 [20.10, 0.19] for fat mass) contrasting with the ordinary least square estimate (0.37 [0.34, 0.40]). By contrast, fat mass explained by genetic variants of the FTO, MC4R and TMEM18 genes was positively and significantly associated to SUA (0.31 [0.01, 0.62]), similar to the ordinary least square estimate (0.27 [0.25, 0.29]). Results were similar for the other adiposity markers. Conclusions: Using a bidirectional Mendelian randomization approach in adult Caucasians, our findings suggest tha

Comparison of micronuclei frequency in bone marrow cells of three rat lines

The aim of this paper is to compare the spontaneous and induced with cyclophosphamide micronucleus indexes in bone marrow cells of the Sprague Dawley, Lewis and Wistar rat lines. Five experimental groups were formed (10 animals of each sex and of each line, in every group). The first group was used as the negative control (intact animals), the second one was exposed to oral administration of drugs; other conditions were the same as for the other groups. The third group was treated with 2 % Tween 65 and the fourth group was treated with 0.9 % NaCl. Both substances were administered by oral way to 2 ml/kg during 14 days. The fifth group was treated intraperitoneally with strong mutagen cyclophosphamide in the dose of 50 mg/kg (10 ml/kg in solution), on 48th and 24th hours before euthanasia. The Sprague Dawley line (both sexes) was significantly different from the other lines. Rats of this line had lower index of spontaneous formation of micronuclei, higher index of cyclophosphamide­induced micronucle formation, percent of micronucleated erythrocytes in bone marrow and the index of cytotoxicity. The results obtained make it possible to identify the most appropriate line of rats as model animals for studies of genotoxicity. It will allow also to obtain more accurate estimates of genotoxicity of various substances.Сравнивали спонтанные и индуцированные циклофосфамидом микроядерные индексы в клетках костного мозга трех линий крыс – Sprague Dawley, Льюис и Вистар. Сформировали пять экспериментальных групп (по 10 животных каждого пола и линии в каждой группе). Первую группу использовали в качестве негативного контроля (интактные животные), вторая служила контролем влияния перорального приема препаратов. Все условия содержания были одинаковыми для всех групп животных. Крыс третьей группы обрабатывали 2 % Tween 65, а четвертой группы – 0,9 % NaCl. Оба вещества вводили перорально в дозе 2 мл/кг в течение 14 дней. Животных пятой группы обрабатывали внутрибрюшинно циклофосфамидом в дозе 50 мг/кг (10 мл/кг раствора), за 48 и 24 ч до эвтаназии. Линия Sprague Dawley (оба пола) существенно отличается от других. Крысы этой линии имели низкие показатели спонтанного образования микроядер и высокий индекс при индукции циклофосфамидом, а также процент эритроцитов с микроядрами в костном мозге и индекс цитотоксичности. Полученные результаты позволяют определить наиболее подходящие линии крыс в качестве модельных животных для изучения генотоксичности. Это также позволит получать более точные оценки генотоксичности различных веществ. Порівнювали спонтанні та індуковані циклофосфамідом мікроядерні індекси в клітинах кісткового мозку трьох ліній щурів – Sprague Dawley, Люіс і Вистар.Сформували п’ять експериментальних груп (по 10 тварин кожної статі і лінії в кожній групі). Першу групу використали як негативний контроль (інтактні тварини), друга слугувала контролем впливу перорального прийому препаратів. Всі умови утримання були однаковими для всіх груп тварин. Щурів третьої групи обробляли 2 % Тween 65, а четвертої групи – 0,9 % NaCl. Обидві речовини вводили перорально в дозі 2 мл/кг впродовж 14 днів. Тварин п’ятої групи обробляли внутрішньочеревно циклофосфамідом в дозі 50 мг/кг (10 мл/кг розчину), за 48 і 24 год до евтаназії. Лінія Sprague Dawley (обидві статі) істотно відрізнялась від інших. Щури цієї лінії мали низькі показники спонтанного утворення мікроядер і високий індекс при індукції циклофосфамідом, а також відсоток еритроцитів з мікроядрами в кістковому мозку та індекс цитотоксичності. Отримані результати дозволяють визначити найбільш відповідні лінії щурів як модельних тварин для вивчення генотоксичності. Це також дозволить отримувати точніші оцінки генотоксичності різних речовин

Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19

Background: We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world’s largest international, standardized data sets concerning hospitalized patients. Methods: The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). Results: Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60 years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. Conclusions: Age was the strongest determinant of risk of death, with a ~30-fold difference between the oldest and youngest groups; each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death. The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death