Background In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries.Methods GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution.Findings Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990-2010 time period, with the greatest annualised rate of decline occurring in the 0-9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10-24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the...

Background Rigorous analysis of levels and trends in exposure to leading risk factors and quantification of their effect on human health are important to identify where public health is making progress and in which cases current efforts are inadequate. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a standardised and comprehensive assessment of the magnitude of risk factor exposure, relative risk, and attributable burden of disease. MethodsGBD 2019 estimated attributable mortality, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 87 risk factors and combinations of risk factors, at the global level, regionally, and for 204 countries and territories. GBD uses a hierarchical list of risk factors so that specific risk factors (eg, sodium intake), and related aggregates (eg, diet quality), are both evaluated. This method has six analytical steps. (1) We included 560 risk-outcome pairs that met criteria for convincing or probable evidence on the basis of research studies. 12 risk-outcome pairs included in GBD 2017 no longer met inclusion criteria and 47 risk-outcome pairs for risks already included in GBD 2017 were added based on new evidence. (2) Relative risks were estimated as a function of exposure based on published systematic reviews, 81 systematic reviews done for GBD 2019, and meta-regression. (3) Levels of exposure in each age-sex-location-year included in the study were estimated based on all available data sources using spatiotemporal Gaussian process regression, DisMod-MR 2.1, a Bayesian meta-regression method, or alternative methods. (4) We determined, from published trials or cohort studies, the level of exposure associated with minimum risk, called the theoretical minimum risk exposure level. (5) Attributable deaths, YLLs, YLDs, and DALYs were computed by multiplying population attributable fractions (PAFs) by the relevant outcome quantity for each agesex-location-year. (6) PAFs and attributable burden for combinations of risk factors were estimated taking into account mediation of different risk factors through other risk factors. Across all six analytical steps, 30 652 distinct data sources were used in the analysis. Uncertainty in each step of the analysis was propagated into the final estimates of attributable burden. Exposure levels for dichotomous, polytomous, and continuous risk factors were summarised with use of the summary exposure value to facilitate comparisons over time, across location, and across risks. Because the entire time series from 1990 to 2019 has been re-estimated with use of consistent data and methods, these results supersede previously published GBD estimates of attributable burden. Findings The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure. Global declines also occurred for tobac...

OBJECTIVE-Emerging evidence suggests that dietary phytoestrogens can have beneficial effects on obesity and diabetes, although their mode of action is not known. Here, we investigate the mechanisms mediating the action of dietary phytoestrogens on lipid and glucose metabolism in rodents.RESEARCH DESIGN AND METHODS-Male CD-1 mice were fed from conception to adulthood with either a high soycontaining diet or a soy-free diet. Serum levels of circulating isoflavones, ghrelin, leptin, free fatty acids, triglycerides, and cholesterol were quantified. Tissue samples were analyzed by quantitative RT-PCR and Western blotting to investigate changes of gene expression and phosphorylation state of key metabolic proteins. Glucose and insulin tolerance tests and euglycemichyperinsulinemic clamp were used to assess changes in insulin sensitivity and glucose uptake. In addition, insulin secretion was determined by in situ pancreas perfusion.RESULTS-In peripheral tissues of soy-fed mice, especially in white adipose tissue, phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase was increased, and expression of genes implicated in peroxisomal fatty acid oxidation and mitochondrial biogenesis was upregulated. Soy-fed mice also showed reduced serum insulin levels and pancreatic insulin content and improved insulin sensitivity due to increased glucose uptake into skeletal muscle. Thus, mice fed with a soy-rich diet have improved adipose and glucose metabolism. A better understanding of the factors regulating lipid and glucose metabolism are of eminent interest due to the pandemic development of obesity and its related metabolic disorders. Preventive strategies to control excess body weight and insulin resistance have mainly focused on physical exercise and total caloric intake. Over the past years, however, an increasing body of evidence indicates that estrogens are important regulators of glucose and adipose metabolism. They are known to modulate the distribution of body fat and adipose tissue metabolism either through the direct regulation of adipogenesis and lypolysis or indirectly via modulation of the energy balance (rev. in 1). Similarly, estrogens play an important role in glucose homeostasis and are known to modulate insulin sensitivity (2). Postmenopausal women develop visceral obesity and insulin resistance and are at an increased risk for diabetes; estrogen replacement therapy normalizes these abnormalities (3,4). In rodent models of type 2 diabetes, female mice are protected against hyperglycemia unless they are ovariectomized, whereas in male animals, estrogen perfusion reverses diabetes (5). Finally, estrogen receptor (ER)␣ or aromatase-knockout mice display several phenotypes associated with the metabolic syndrome, such as increased adiposity, glucose intolerance, and insulin resistance (6,7), demonstrating the fundamental implication of estrogens in these metabolic processes. CONCLUSIONS-DietaryPhytoestrogens are nonsteroidal compounds of natural origin that can bind to both ER␣ and ER␤ and ...

Summary Noise induced hearing loss (NIHL) is a debilitating sensory impairment affecting 10–15% of the population caused primarily through damage to the sensory hair cells or to the auditory neurons. Once lost, these never regenerate [1] and no effective drugs are available [2, 3]. Emerging evidence point towards an important contribution of synaptic ribbons in the long-term coupling of the inner hair cell and afferent neuron synapse to maintain hearing [4]. Here we show in mice (nocturnal) that night noise overexposure triggers permanent hearing loss whereas mice overexposed during the day recover to normal auditory thresholds. In view of this time-dependent sensitivity, we identified a self-sustained circadian rhythm in the isolated cochlea, as evidenced by circadian expression of clock genes and ample PERIOD2::LUCIFERASE oscillations, originating mainly from the primary auditory neurons and hair cells. The transcripts of the otoprotecting brain-derived neurotrophic factor (BDNF) showed higher levels in response to day noise versus night noise, suggesting that BDNF-mediated signaling regulates noise sensitivity throughout the day. Administration of an agonist of the selective BDNF receptor TrkB in the night protected the inner hair cell’s synaptic ribbons and subsequent full recovery of hearing thresholds after night noise overexposure. The TrkB agonist shifted the phase and boosted the amplitude of circadian rhythms in the isolated cochlea. These findings highlight the coupling of circadian rhythmicity and TrkB receptor for the successful prevention and treatment of NIHL.

ImportanceTo date, no systematic review has taken a meta-analytic approach to estimating the prevalence and incidence of tinnitus in the general population.ObjectiveTo provide frequency estimates of tinnitus worldwide.Data SourcesAn umbrella review followed by a traditional systematic review was performed by searching PubMed-MEDLINE and Embase from inception through November 19, 2021.Study SelectionResearch data from the general population were selected, and studies based on patients or on subgroups of the population with selected lifestyle habits were excluded. No restrictions were applied according to date, age, sex, and country.Data Extraction and SynthesisRelevant extracted information included type of study, time and location, end point, population characteristics, and tinnitus definition. The study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline.Main Outcomes and MeasuresPooled prevalence estimates of any tinnitus, severe tinnitus, chronic tinnitus, and diagnosed tinnitus as well as incidence of tinnitus were obtained using random-effects meta-analytic models; heterogeneity between studies was controlled using the χ2 test, and inconsistency was measured using the I2 statistic.ResultsAmong 767 publications, 113 eligible articles published between 1972 and 2021 were identified, and prevalence estimates from 83 articles and incidence estimates from 12 articles were extracted. The pooled prevalence of any tinnitus among adults was 14.4% (95% CI, 12.6%-16.5%) and ranged from 4.1% (95% CI, 3.7%-4.4%) to 37.2% (95% CI, 34.6%-39.9%). Prevalence estimates did not significantly differ by sex (14.1% [95% CI, 11.6%-17.0%] among male individuals; 13.1% [95% CI, 10.5%-16.2%] among female individuals), but increased prevalence was associated with age (9.7% [95% CI, 7.4%-12.5%] among adults aged 18-44 years; 13.7% [95% CI, 11.0%-17.0%] among those aged 45-64 years; and 23.6% [95% CI, 19.4%-28.5%] among those aged ≥65 years; P < .001 among age groups). The pooled prevalence of severe tinnitus was 2.3% (95% CI, 1.7%-3.1%), ranging from 0.5% (95% CI, 0.3%-0.7%) to 12.6% (95% CI, 11.1%-14.1%). The pooled prevalence of chronic tinnitus was 9.8% (95% CI, 4.7%-19.3%) and the pooled prevalence of diagnosed tinnitus was 3.4% (95% CI, 2.1%-5.5%). The pooled incidence rate of any tinnitus was 1164 per 100 000 person-years (95% CI, 479-2828 per 100 000 person-years).Conclusions and RelevanceDespite the substantial heterogeneity among studies, this comprehensive systematic review on the prevalence and incidence of tinnitus suggests that tinnitus affects more than 740 million adults globally and is perceived as a major problem by more than 120 million people, mostly aged 65 years or older. Health policy makers should consider the global burden of tinnitus, and greater effort should be devoted to boost research on tinnitus.