Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950–2019: a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2•72 (95% uncertainty interval [UI] 2•66–2•79) in 2000 to 2•31 (2•17–2•46) in 2019. Global annual livebirths increased from 134•5 million (131•5–137•8) in 2000 to a peak of 139•6 million (133•0–146•9) in 2016. Global livebirths then declined to 135•3 million (127•2–144•1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2•1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27•1% (95% UI 26•4–27•8) of global livebirths. Global life expectancy at birth increased from 67•2 years (95% UI 66•8–67•6) in 2000 to 73•5 years (72•8–74•3) in 2019. The total number of deaths increased from 50•7 million (49•5–51•9) in 2000 to 56•5 million (53•7–59•2) in 2019. Under-5 deaths declined from 9•6 million (9•1–10•3) in 2000 to 5•0 million (4•3–6•0) in 2019. Global population increased by 25•7%, from 6•2 billion (6•0–6•3) in 2000 to 7•7 billion (7•5–8•0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58•6 years (56•1–60•8) in 2000 to 63•5 years (60•8–66•1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation: Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global burden of 87 risk factors in 204 countries and territories, 1990�2019: a systematic analysis for the Global Burden of Disease Study 2019

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. Methods: GBD 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 age-sex-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 tobacco smoking and lead exposure. The largest increases in risk exposure were for ambient particulate matter pollution, drug use, high fasting plasma glucose, and high body-mass index. In 2019, the leading Level 2 risk factor globally for attributable deaths was high systolic blood pressure, which accounted for 10·8 million (95 uncertainty interval UI 9·51�12·1) deaths (19·2% 16·9�21·3 of all deaths in 2019), followed by tobacco (smoked, second-hand, and chewing), which accounted for 8·71 million (8·12�9·31) deaths (15·4% 14·6�16·2 of all deaths in 2019). The leading Level 2 risk factor for attributable DALYs globally in 2019 was child and maternal malnutrition, which largely affects health in the youngest age groups and accounted for 295 million (253�350) DALYs (11·6% 10·3�13·1 of all global DALYs that year). The risk factor burden varied considerably in 2019 between age groups and locations. Among children aged 0�9 years, the three leading detailed risk factors for attributable DALYs were all related to malnutrition. Iron deficiency was the leading risk factor for those aged 10�24 years, alcohol use for those aged 25�49 years, and high systolic blood pressure for those aged 50�74 years and 75 years and older. Interpretation: Overall, the record for reducing exposure to harmful risks over the past three decades is poor. Success with reducing smoking and lead exposure through regulatory policy might point the way for a stronger role for public policy on other risks in addition to continued efforts to provide information on risk factor harm to the general public. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Rosuvastatin improves pulse wave reflection by restoring endothelial function

One of the major indicators of intact endothelial function is basal nitric oxide (NO) activity. Further, it seems to be likely that statin therapy exerts beneficial effects on vascular function, at least in part via an improvement of NO bioavailability. In the present double-blind crossover study 29 hypercholesterolemic patients were randomly assigned to receive rosuvastatin and placebo for 42 days. Pulse wave analysis was assessed after 30 min of rest (baseline) and after infusion of NG-monomethyl-l-arginine (l-NMMA) at the end of 42 days treatment period. The magnitude of the increase in central augmentation index (cAIx) in response to inhibition of NO synthase (NOS) by l-NMMA is indicative of basal NO activity. CAIx was significantly lower (18.3 ± 10 versus 21.9 ± 12%, p = 0.027) with rosuvastatin compared to placebo. There was no increment of cAIx in response to l-NMMA in placebo group. In contrast, cAIx increased significantly in response to l-NMMA (20.5 ± 11 versus 25.7 ± 10 mm Hg, p = 0.001) in rosuvastatin group. The percentage of increase of cAIx tended to be more pronounced after treatment with rosuvastatin compared to placebo (53.7 ± 92 versus 14.1 ± 36%, p = 0.087). Pulse pressure amplification (PPA) improved (1.31 ± 0.2 versus 1.26 ± 0.2%, p = 0.016) after rosuvastatin compared to placebo. Regression analyses revealed that both LDL-cholesterol and CRP-levels are independent determinants of basal NO activity improvement, which itself is an independent determinant of vascular function, expressed by an improvement of pulse wave reflection and PPA. In this placebo controlled study, treatment with rosuvastatin improved vascular and endothelial function. Determinants for improved NO production in patients with hypercholesterolemia were the achieved levels of LDL-cholesterol and CRP. Overall, in patients without CV disease, rosuvastatin exerted beneficially effect on vascular dysfunction, one of the earliest manifestation of atherosclerosis

Impaired sodium excretion during mental stress in mild essential hypertension

In hypertensive rats, environmental stress causes sodium retention by an exaggerated increase in renal sympathetic nerve activity, which is modulated by angiotensin II. We tested whether similar effects can be observed in humans. In 66 normotensive subjects (half of them with a family history of hypertension) and 36 subjects with mild essential hypertension, urinary sodium excretion and renal hemodynamics were examined at rest and during mental stress treated either with placebo or ACE inhibition in a double-blind, randomized, cross-over design. Despite a marked increase in glomerular filtration rate in response to mental stress (Deltaglomerular filtration rate, 4.3+/-7.7 mL/min in normotensives without versus 5.6+/-8.4 mL/min in normotensives with a family history versus 10.1+/-5.7 mL/min in patients with mild essential hypertension; P:<0.002), the increase in urinary sodium excretion was blunted in patients with mild essential hypertension (Deltaurinary sodium excretion, 0.12+/-0.17 mmol/min versus 0.10+/-0.14 mmol/min versus 0.05+/-0.14 mmol/min; P:<0.05). ACE inhibition corrected the natriuretic response to mental stress in subjects with mild essential hypertension (Deltaurinary sodium excretion, 0.05+/-0.14 mmol/min with placebo versus 0.13+/-0.19 mmol/min with ACE inhibition; P:<0.01); thus, after ACE inhibition, urinary sodium excretion increased similarly in all 3 groups. In conclusion, impaired sodium excretion occurs during mental stress in human essential hypertension but not in subjects with positive family history of hypertension. This abnormality in sodium handling during activation of the sympathetic nervous system appears to be mediated by angiotensin II

Effects of nitric oxide synthase inhibition and L-arginine on renal haemodynamics in young patients at high cardiovascular risk

<p><b>Background:</b> Aging and a variety of cardiovascular risk factors are associated with oxidative stress and impaired endothelial function. Whether such an association is already evident in the renal vascular bed in young patients at high cardiovascular risk has not yet been determined.</p> <p><b>Methods:</b> We compared renal haemodynamics in 23 young (age 30 ± 5 years) male patients at high cardiovascular risk with impaired lipid metabolism and elevated blood pressure with 23 matched, healthy control subjects (age 28 ± 3 years) without cardiovascular risk factors at baseline and following infusions of the nitric oxide (NO) synthase inhibitor NG-monomethyl-l-arginine (l-NMMA: 4.25 mg/kg), the substrate of NO synthase l-arginine (100 mg/kg) and the antioxidant Vitamin C (3 g, co-infused with l-arginine 100 mg/kg).</p> <p><b>Results:</b> Baseline renal haemodynamics did not differ between the two groups. Infusion of l-NMMA decreased renal plasma flow (RPF) in both groups to a similar extent (−113 ± 95 ml/min versus −128 ± 133 ml/min, p = NS). The response of RPF to infusion of l-arginine was more pronounced in high risk patients than in control subjects (+123 ± 64.4 ml/min versus +75.6 ± 60.2 ml/min, p = 0.012) and further exaggerated during co-infusion of l-arginine and Vitamin C (+299 ± 164 ml/min versus +175 ± 148 ml/min, p = 0.003).</p> <p><b>Conclusions:</b> Basal NO activity of the renal vasculature appears to be unaltered in young patients at high cardiovascular risk. However, the greater response of RPF to l-arginine and to Vitamin C co-infused with l-arginine in these young patients suggests that decreased substrate availability for NO synthase and oxidative stress are key factors for alterations in endothelium-dependent vasodilation of the renal vasculature in this young high risk group of patients.</p&gt

Association of (pro)renin receptor gene polymorphism with blood pressure in Caucasian men

The renin-angiotensin system is a major regulatory system of cardiovascular and renal function. Recently, (pro)renin receptor [(P)RR] was identified as new component of the renin-angiotensin system. The IVS5+169C>T polymorphism of the (P)RR gene was shown to be associated with blood pressure (BP) in Japanese men, but no data are available for Caucasians. Hence, we genotyped the IVS5+169C >T polymorphism of the (P)RR gene in 266 Caucasian men with normal or mildly elevated BP and without any medication. Office BP was measured according to current guidelines. Office and resting systolic BP was lower in C-allele than in T-allele carriers (P<0.05) of the (P)RR gene, with no difference in diastolic BP and heart rate. Serum aldosterone was also lower in C-allele than in T-allele carriers (P<0.05). These findings indicate that C-allele carriers have lower systolic BP than T-allele carriers. Thus, our data suggest that (P)RR influences BP regulation in Caucasian men, potentially through altered aldosterone release

Analysis of retinal arteriolar structure in never-treated patients with essential hypertension

The changes in arteriolar structure of retinal vessels in our study cohort revealed a similar pattern to that observed previously by other investigators in subcutaneous small arteries in essential hypertension. Blood pressure emerged as an important and independent determinant of wall-to-lumen ratio of retinal arterioles

Altered aldosterone response to salt intake and angiotensin II infusion in young normotensive men with parental history of arterial hypertension

Our findings suggest that young normotensive subjects with parental history of arterial hypertension are characterized by an inadequate suppression of aldosterone production in response to salt loading and an exaggerated and prolonged hyper-responsiveness of aldosterone secretion in response to Ang II. This might contribute to the increased risk for the development of essential hypertension in subjects with positive family history of arterial hypertension

Wall-to-lumen ratio of retinal arterioles is related with urinary albumin excretion and altered vascular reactivity to infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine

<p>Objective: We hypothesized that wall-to-lumen ratio (WLR) of retinal arterioles might serve as an in-vivo parameter of vascular damage. To test this hypothesis we examined whether WLR of retinal arterioles is related with increased urinary albumin excretion and altered vascular reactivity to infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine (L-NMMA).</p> <p>Methods: Thirty-nine never-treated male patients aged 18-65 years with a body mass index at least 25 kg/m<sup>2</sup> and without diabetes mellitus or secondary or stage 3 arterial hypertension were examined. WLR of retinal arterioles was assessed using scanning laser Doppler flowmetry. Urinary albumin-to-creatinine ratio (UACR) was measured from first morning spot urine. Vascular reactivity was measured by the change of aortic augmentation index (aAIx) to infusion of L-NMMA.</p> <p>Results: UACR was related with WLR of retinal arterioles (r = 0.352, P = 0.032). In response to L-NMMA infusion aAIx increased (from 10.7 ± 11 to 19.7 ± 11%, P < 0.001). The change of aAIx to L-NMMA infusion was inversely related with WLR of retinal arterioles (r = -0.462, P = 0.003) even after adjustment for changes of hemodynamic parameters to L-NMMA infusion (partial r = -0.475, P = 0.005). The relationships of UACR and the change of aAIx to L-NMMA infusion with WLR of retinal arterioles were found to be independently of other cardiovascular risk factors (ß = 0.386, P = 0.006; β = -0.369, P = 0.004, respectively) in multiple regression analyses with separate models for both parameters.</p> <p>Conclusion: Increased WLR of retinal arterioles may thus serve as an in-vivo marker of vascular damage.</p&gt