Background Tuberculosis is a major contributor to the global burden of disease, causing more than a million deaths annually. Given an emphasis on equity in access to diagnosis and treatment of tuberculosis in global health targets, evaluations of differences in tuberculosis burden by sex are crucial. We aimed to assess the levels and trends of the global burden of tuberculosis, with an emphasis on investigating differences in sex by HIV status for 204 countries and territories from 1990 to 2019. MethodsWe used a Bayesian hierarchical Cause of Death Ensemble model (CODEm) platform to analyse 21 505 siteyears of vital registration data, 705 site-years of verbal autopsy data, 825 site-years of sample-based vital registration data, and 680 site-years of mortality surveillance data to estimate mortality due to tuberculosis among HIV-negative individuals. We used a population attributable fraction approach to estimate mortality related to HIV and tuberculosis coinfection. A compartmental meta-regression tool (DisMod-MR 2.1) was then used to synthesise all available data sources, including prevalence surveys, annual case notifications, population-based tuberculin surveys, and tuberculosis cause-specific mortality, to produce estimates of incidence, prevalence, and mortality that were internally consistent. We further estimated the fraction of tuberculosis mortality that is attributable to independent effects of risk factors, including smoking, alcohol use, and diabetes, for HIV-negative individuals. For individuals with HIV and tuberculosis coinfection, we assessed mortality attributable to HIV risk factors including unsafe sex, intimate partner violence (only estimated among females), and injection drug use. We present 95% uncertainty intervals for all estimates.Findings Globally, in 2019, among HIV-negative individuals, there were 1•18 million (95% uncertainty interval 1•08-1•29) deaths due to tuberculosis and 8•50 million (7•45-9•73) incident cases of tuberculosis. Among HIV-positive individuals, there were 217 000 (153 000-279 000) deaths due to tuberculosis and 1•15 million (1•01-1•32) incident cases in 2019. More deaths and incident cases occurred in males than in females among HIV-negative individuals globally in 2019, with 342 000 (234 000-425 000) more deaths and 1•01 million (0•82-1•23) more incident cases in males than in females. Among HIV-positive individuals, 6250 (1820-11 400) more deaths and 81 100 (63 300-100 000) more incident cases occurred among females than among males in 2019. Age-standardised mortality rates among HIV-negative males were more than two times greater in 105 countries and age-standardised incidence rates were more than 1•5 times greater in 74 countries than among HIV-negative females in 2019. The fraction of global tuberculosis deaths among HIV-negative individuals attributable to alcohol use, smoking, and diabetes was 4•27 (3•69-5•02), 6•17 (5•48-7•02), and 1•17 (1•07-1•28) times higher, respectively, among males than among females in 2019. Among individuals with HIV and tuberculosi...
SummaryAromatase catalyzes the rate limiting step that converts androgens to estrogens. Postmenopausal women with hormone dependent breast cancer respond to first generation aromatase inhibitors such as aminoglutethimide with a marked suppression of circulating estradiol levels. In contrast, premenopausal women appear to be resistant to first generation aromatase inhibitors. The inability to block ovarian aromatase results from the low affinity of first generation inhibitors for the active site of the enzyme. Under these circumstances, the high substrate levels in the premenopausal ovary compete effectively with these inhibitors and do not allow binding of inhibitor to the active site of the enzyme.Second and third generation aromatase inhibitors with higher affinity for aromatase have now been developed and potentially could block ovarian aromatase. To test this possibility, we administered CGS 20267 (letrozole), a highly potent aromatase inhibitor, to cycling female rats. A dose dependent inhibition of uterine weight occurred with maximum effects produced by the 5 mg/kg/day dosage. During a period of 4 weeks, uterine weight was reduced to levels induced by ovariectomy. Ovarian tissue estradiol levels were inhibited by approximately 80%. As a reflection of inhibition of ovarian aromatase activity, the levels of androstenedione in the ovary increased by an order of magnitude. Both LH and FSH plasma levels increased but not to those observed after ovariectomy. The rise in gonadotropin levels induced a statistically significant but relatively small increase in ovarian weights.These results demonstrate the ability to persistently block ovarian aromatase activity in cycling rats with a potent aromatase inhibitor. This study provides a rationale for clinical trials of potent aromatase inhibitors in pre-menopausal women with breast cancer.
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