Evaluation of offspring sex ratio, sex hormones and antioxidant enzymes following exposure to methyl tertiary butyl ether in adult male Sprague-Dawley rats

Methyl tertiary butyl ether (MTBE) is an oxygenated fuel additive which has been used widely in many parts of the world. This experiment was performed to determine the effect of MTBE on offspring sex ratio, sex hormones and antioxidant enzymes. A total of 20 adult Sprague-Dawley male rats were divided into four groups and received 0, 400, 800 and 1600 mg/kg/day MTBE by gavages for 30 consecutive days. At the end of the experiment, blood samples were taken for determination of sex hormones and antioxidant enzymes. Then, male rats were mated with healthy unexposed female rats and sex of offspring was determined after birth. Sex ratio was 0.48, 0.50, 0.43 and 0.50 in 0, 400, 800 and 1600 mg/kg/day MTBE groups, respectively (P = 0.91). There was significant decreasing trend for luteinizing hormone (LH) and testosterone in experimental groups (rs = -0.50, P = 0.030 and rs = -0.67, P = 0.002, respectively). No changes were observed for superoxide dismutase. However, decrease in glutathione peroxidase (GPX) was observed in all treatment groups compared with control which was significant in 400 mg/kg/day MTBE group (P = 0.016). The present study showed that paternal exposure to oral MTBE has no effect on offspring sex ratio; while, MTBE exposure could exert dose-dependent changes in serum testosterone and LH in treatment groups. The results of the present study, need to be clarified in the future studies

Ultrazvučne značajke maternice i jajnika za vrijeme estrusa i njihov odnos sa stopom gravidnosti u mliječnih krava

It was hypothesized that the accumulation of fluids in the uterine lumen reduces fertility in dairy cows. Therefore, the purpose of the present study was an evaluation of the ultrasound characteristics of the reproductive tract, including the accumulation of fluids in the uterine lumen during estrus, and the effect of these findings on pregnancy rates in dairy cows. The study was conducted on 486 lactating Holstein cows detected to be in estrous, on a large commercial dairy herd in Shiraz, Iran. Transrectal ultrasound was performed at the time of artificial insemination. Reproductive tract characteristics, comprising follicle diameters, the presence of corpus luteum in ovaries, the thickness, folding and edema of the uterus, and intrauterine fluid, were visualized and scored by ultrasonography. The cows were followed after insemination and their pregnancy rate determined. The effect of ultrasound findings were investigated in relation to pregnancy rates. The data were analyzed using logistic regression analyses. The results indicated that the pregnancy rate was significantly higher in cows with follicle size >14 mm (38.8%) compared with ≤14 mm (27.3%), after adjusting for the parity of the animals, days in milk and mean daily milk production (OR = 1.84, P = 0.005). No association between pregnancy rate and other ultrasound characteristics of the reproductive tract during estrus was observed in this study (P>0.05). In conclusion, follicle size is positively associated with the pregnancy rate of dairy cows in estrus. However, other ultrasound findings of the uterus, including intrauterine fluid, did not show any association with pregnancy rates.Pretpostavlja se da nakupljanje tekućine u materničnoj šupljini smanjuje plodnost u mliječnih krava. Cilj je ovoga istraživanja stoga bio procijeniti ultrazvučne značajke reproduktivnog sustava, uključujući nakupljanje tekućine u maternici za vrijeme estrusa, te njihov utjecaj na stopu gravidnost u mliječnih krava. Istraživanje je provedeno na 486 holštajnskih krava uzgajanih u velikom komercijalnom stadu, u Shirazu, Iran. Sve krave su bile u laktaciji i s otkrivenim estrusom. Transrektalni ultrazvuk učinjen je u vrijeme umjetnog osjemenjivanja. Značajke reproduktivnog sustava, koje su obuhvatile promjer folikula, prisutnost žutog tijela u jajnicima, debljinu, nabor i edem maternice te intrauterinu tekućinu, promatrane su i procijenjene ultrazvučno. Krave su nakon osjemenjivanja praćene te im je određena stopa gravidnosti. Analiziran je utjecaj pokazatelja određenih ultrazvukom na stopu gravidnosti. Podaci su obrađeni logističkom regresijskom analizom. Rezultati su pokazali da je stopa gravidnosti, nakon prilagođavanja pariteta životinja te dnevne količine mlijeka i srednje dnevne količine proizvodnje (OR = 1,84, P = 0,005), bila znakovito veća u krava s folikulima većima od 14 mm (38,8 %) u usporedbi s onima od 14 mm i manjima (27,3 %). Nije uočena povezanost između stope gravidnosti i drugih ultrazvučnih značajki reproduktivnog sustava za vrijeme estrusa praćenog u ovom istraživanju (P>0,05). Zaključeno je da je veličina folikula pozitivno povezana s stopom gravidnosti mliječnih krava u estrusu. Kakogod, drugi ultrazvučni nalazi maternice, uključujući intrauterinu tekućinu, nisu pokazali povezanost sa stopom gravidnosti

Serumski srčani troponin I kao biljeg srčane degeneracije uzrokovane pokusnim trovanjem ovaca salinomicinom.

Salinomycin is an ionophore with antimicrobial properties. It is a dietary additive used as a growth promoter for ruminants and as a coccidiostat in chickens. However, over-dosage or misuse situations can lead to a series of toxic syndromes. Cardiac troponin I (cTnI) is the part of the troponin complex (I, C and T) within the sarcomere in myocardial cells that regulates contraction of the heart muscle. cTnI is released from injured myocardiocytes into circulation, so it can be a specifific biomarker in myocardial necrosis. The purpose of this study is to propose cTnI for diagnostic cardiac degeneration induced by experimental toxicosis with salinomycin in sheep. Twenty Iranian mixed breed adult female fat-tailed sheep (BW: 33.3 ± 3.4 kg) were used in this study. The sheep were randomly divided in to five equal groups. Group I (control) received 20 mL normal Saline. Groups II, III, IV and V were orally administered 1 mg/kg (twice a day for two days), 2, 3 and 4 mg/kg (once a day for two days) salinomycin, respectively. Following drug administration, blood samples were collected at different time intervals (2, 5, 8, 14 and 21 days) in order to determine various biochemical parameters (cTnI, CK, LDH, ALT and AST). In all groups, the heart sounds of the animals were carefully heard and electrocardiogram (ECG) was taken to determine the type of probable arrhythmia. The results illustrated a significant increase in the activity of cTnI. Numerous arrhythmias were recorded, such as: sinus tachycardia, supraventricular tachycardia, sinus arrhythmia and supraventricular premature contraction. All animals with arrhythmias showed a significant increase in the activity of cTnI. Cardiac muscle necrosis observed macroscopically on post mortem examination revealed myocardial degeneration. Overall, the results of this study indicate that cTnI may be considered as a valuable biomarker in diagnosing cardiac degeneration due to salinomycin toxicosis.Salinomicin je ionofor s antimikrobnim svojstvima. Rabi se kao dodatak hrani koji u preživača ima ulogu promotora rasta, a u pilića ulogu kokcidiostatika. Prevelike količine i pogrešna uporaba salinomicina mogu dovesti do teških sindroma trovanja. Srčani troponin I (cTnI) je dio troponinskog kompleksa (I, C i T), unutar sarkomere srčanih mišićnih stanica, koji regulira kontrakcije srčanog mišića. Budući da se oslobađa iz oštećenih miokardiocita u krvotok, cTnI može biti specifičan biomarker kod nekroze srčanog mišića. Svrha istraživanja bila je predložiti da se cTnI primjeni u dijagnostici srčane degeneracije uzrokovane pokusnim trovanjem ovaca salinomicinom. U istraživanje je bilo uključeno 20 odraslih, masnorepih ovaca, križanki iranskih pasmina (TM: 33,3 ± 3,4 kg). Ovce su metodom slučajnog izbora bile podijeljene u pet skupina iste veličine. Skupina I (kontrola) dobila je 20 mL otopine soli. Skupine II, III, IV i V dobile su oralnim putem salinomicin i to u količini od 1 mg/kg (dva puta dnevno kroz dva dana), odnosno 2, 3 i 4 mg/kg (jednom dnevno kroz dva dana). Odmah nakon toga uzimani su uzorci krvi u različitim vremenskim razmacima (2, 5, 8, 14 i 21 dana) s ciljem određivanja različitih biokemijskih pokazatelja (cTnI, CK, LDH, ALT i AST). U svim skupinama pažljivo su osluškivani srčani tonovi i određivan elektrokardiogram s ciljem otkrivanja tipa moguće srčane aritmije. Rezultati pokazuju značajno povećanje aktivnosti cTnI. Zabilježene su i mnoge aritmije kao što su sinusna tahikardija, supraventrikularna tahikardija, sinusna aritmija i supraventrikularna preuranjena kontrakcija. Sve su životinje uz aritmiju očitovale i značajno povećanje aktivnosti cTnI. Razudbom nakon uginuća makroskopski je opažena nekroza i degeneracija srčanog mišića. Zaključno, rezultati istraživanja pokazuju da cTnI može biti vrijedan biomarker u dijagnostici srčane degeneracije prouzročene trovanjem salinomicinom

Dijagnostičke vrijednosti proteina akutne faze u iranskoga domaćega goveda invadiranoga praživotinjom Theileria annulata

This study was conducted to assess the pattern of changes and the relative value of acute phase proteins (APP) including haptoglobin (Hp), serum amyloid A (SAA), ceruloplasmin and fi brinogen in Iranian indigenous cattle infected with Theileria annulata. The diseased group comprised 24 Iranian indigenous dairy cattle, 2-3 years old, naturally infected with Theileria annulata. The infected animals were divided into 4 subgroups with different parasitemia rates (<1% and 1-3%). As a control group, 10 uninfected cattle were also sampled. Blood samples were collected and all measurements were made using validated methods. There were significant differences in red blood cells (RBCs), packed cell volume (PCV), hemoglobin (Hb) and concentrations of Hp, SAA, ceruloplasmin and fibrinogen between healthy cattle and those infected with T. annulata with different parasitemia rates (P<0.05). As the parasitemia rate increased in infected cattle, a signifi cant decrease was observed in RBCs, PCV and Hb. In contrast, with the increase in the parasitemia rate, a significant increase in Hp, SAA, ceruloplasmin and fibrinogen was evident. The optimal cut-off point was set by the receiver operating characteristics (ROC) method to >5.68 μg/mL for SAA, >0.09 g/L for Hp, >0.049 g/L for ceruloplasmin and >1.90 g/L for fibrinogen, with corresponding 71.50% sensitivity and 100% specificity for SAA, 83.30% sensitivity and 70% specificity for Hp, 50% sensitivity and 90% specificity for ceruloplasmin and 71.30% sensitivity and 80% specificity for fi brinogen. In conclusion, measuring SAA with the highest sensitivity, specificity and AUC compared to other APPs, can be a suitable indicator of inflammatory reactions in indigenous cattle infected with Theileria annulata.Istraživanje je provedeno s potrebom da se utvrdi dinamika promjena i relativne vrijednosti proteina akutne faze, uključujući haptoglobin (Hp), serumski amiloid A, ceruloplazmin i fibrinogen, u iranskoga domaćega goveda invadiranoga praživotinjom Theileria annulata. Skupina pokusnih životinja sadržavala je ukupno 24 iranska domaća mliječna goveda u dobi od dvije do tri godine invadirana praživotinjom Theileria annulata. Invadirane životinje bile su podijeljene u četiri podskupine s obzirom na različite razine parazitemije (5,68 μg/mL za serumski amiloid A, >0,09 za haptoglobin, >0,049 g/L za ceruloplazmin i >1,90 g/L za fibrinogen. Za serumski je amiloid osjetljivost iznosila 71,50% dok je specifičnost bila 100%. Osjetljivost je za haptoglobin iznosila 83,30% dok je specifičnost iznosila 70%. Za ceruloplazmin je osjetljivost iznosila 50%, a specifičnost 90%. Za fibrinogen je osjetljivost iznosila 71,30% dok je specifičnost iznosila 80%. Zaključno se može reći da mjerenje vrijednosti serumskoga amiloida A može biti prikladan pokazatelj upale uzrokovane praživotinjom Theileria annulata jer se u odnosu na ostale proteine akutne faze odlikuje najvišom razinom osjetljivosti, specifičnosti i AUC

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs 1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). Interpretation: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury

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

Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. Methods: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. Findings: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. Interpretation: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

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

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Accurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios. Methods: To estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline. Findings: During the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction. Interpretation: Fertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world. Funding: Bill & Melinda Gates Foundation