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The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age–sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6–6·6), from 65·3 years (65·0–65·6) in 1990 to 71·5 years (71·0–71·9) in 2013, HALE at birth rose by 5·4 years (4·9–5·8), from 56·9 years (54·5–59·1) to 62·3 years (59·7–64·8), total DALYs fell by 3·6% (0·3–7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6–29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non–communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition—in which increasing sociodemographic status brings structured change in disease burden—is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions. Bill & Melinda Gates Foundation.

Abstract Context Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the management of PA patients. Objectives To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS. Design and settings In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes. Results AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as <25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P < 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria. Conclusion Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020)

Chiea Chuen Khor, Tin Aung, Francesca Pasutto, Janey Wiggs and colleagues report a global genome-wide association study of exfoliation syndrome and a fine-mapping analysis of a previously identified disease-associated locus, LOXL1 . They identify a rare protective variant in LOXL1 exclusive to the Japanese population and five new common variant susceptibility loci. Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A , have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1 , which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10 −14 ) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci ( P < 5 × 10 −8 ). We identified association signals at 13q12 ( POMP ), 11q23.3 ( TMEM136 ), 6p21 ( AGPAT1 ), 3p24 ( RBMS3 ) and 5q23 (near SEMA6A ). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Background and Objectives Uncertainty exists regarding the optimal dosing regimen for vancomycin in different patient populations, leading to a plethora of subgroup-specific pharmacokinetic models and derived dosing regimens. We aimed to investigate whether a single model for vancomycin could be developed based on a broad dataset covering the extremes of patient characteristics. Furthermore, as a benchmark for current dosing recommendations, we evaluated and optimised the expected vancomycin exposure throughout life and for specific patient subgroups. Methods A pooled population-pharmacokinetic model was built in NONMEM based on data from 14 different studies in different patient populations. Steady-state exposure was simulated and compared across patient subgroups for two US Food and Drug Administration/European Medicines Agency-approved drug labels and optimised doses were derived. Results The final model uses postmenstrual age, weight and serum creatinine as covariates. A 35-year-old, 70-kg patient with a serum creatinine level of 0.83 mg dL −1 (73.4 µmol L −1 ) has a V 1 , V 2 , CL and Q 2 of 42.9 L, 41.7 L, 4.10 L h −1 and 3.22 L h −1 . Clearance matures with age, reaching 50% of the maximal value (5.31 L h −1  70 kg −1 ) at 46.4 weeks postmenstrual age then declines with age to 50% at 61.6 years. Current dosing guidelines failed to achieve satisfactory steady-state exposure across patient subgroups. After optimisation, increased doses for the Food and Drug Administration label achieve consistent target attainment with minimal (± 20%) risk of under- and over-dosing across patient subgroups. Conclusions A population model was developed that is useful for further development of age and kidney function-stratified dosing regimens of vancomycin and for individualisation of treatment through therapeutic drug monitoring and Bayesian forecasting.

PURPOSE: Family members of patients who die in the intensive care unit (ICU) may experience symptoms of stress, anxiety, depression, posttraumatic stress disorder (PTSD), and/or prolonged grief. We evaluated whether grief symptoms were alleviated if the physician and the nurse in charge at the time of death sent the closest relative a handwritten condolence letter.METHODS: Multicenter randomized trial conducted among 242 relatives of patients who died at 22 ICUs in France between December 2014 and October 2015. Relatives were randomly assigned to receiving (n = 123) or not receiving (n = 119) a condolence letter. The primary endpoint was the Hospital Anxiety and Depression Score (HADS) at 1 month. Secondary endpoints included HADS, complicated grief (ICG), and PTSD-related symptoms (IES-R) at 6 months. Observers were blinded to group allocation.RESULTS: At 1 month, 208 (85.9%) relatives completed the HADS; median score was 16 [IQR, 10-22] with and 14 [8-21.5] without the letter (P = 0.36). Although scores were higher in the intervention group, there were no significant differences regarding the HADS-depression subscale (8 [4-12] vs. 6 [2-12], mean difference 1.1 [-0.5 to 2.6]; P = 0.09) and prevalence of depression symptoms (56.0 vs. 42.4%, RR 0.76 [0.57-1.00]; P = 0.05). At 6 months, 190 (78.5%) relatives were interviewed. The intervention significantly increased the HADS (13 [7-19] vs. 10 [4-17.5], P = 0.04), HADS-depression subscale (6 [2-10] vs. 3 [1-9], P = 0.02), prevalence of depression symptoms (36.6 vs. 24.7%, P = 0.05) and PTSD-related symptoms (52.4 vs. 37.1%, P = 0.03).CONCLUSIONS: In relatives of patients who died in the ICU, a condolence letter failed to alleviate grief symptoms and may have worsened depression and PTSD-related symptoms. Trial registration Clinicaltrials.gov Identifier: NCT02325297.

Objectives: Large studies are needed to update risk factors of bronchiolitis hospitalization. We performed a nationwide analysis of hospitalization rates for bronchiolitis over four consecutive bronchiolitis seasons to identify underlying medical disorders at risk of bronchiolitis hospitalization and assess their frequency.Methods: Data were retrieved from the French National Hospital Discharge database. Of all infants discharged alive from maternity wards from January 2008 to December 2013 in France (N = 3,884,791), we identified four consecutive cohorts at risk of bronchiolitis during the seasons of 2009–2010 to 2012–2013. The main outcome was bronchiolitis hospitalization during a season. Individual risk factors were collected.Results: Among infants, 6.0% were preterm and 2.0% had ≥1 chronic condition including 0.2% bronchopulmonary dysplasia (BPD) and 0.2% hemodynamically significant congenital heart disease (HS-CHD). Bronchiolitis hospitalization rates varied between seasons (min: 1.26% in 2010–2011; max: 1.48% in 2012–2013; p<0.001). Except omphalocele, the following conditions were associated with an increased risk for bronchiolitis hospitalization: solid organ (9.052; 95% CI, 4.664–17.567) and stem cell transplants (6.012; 95% CI, 3.441–10.503), muscular dystrophy (4.002; 95% CI, 3.1095–5.152), cardiomyopathy (3.407; 95% CI, 2.613–4.442), HS-CHD (3.404; 95% CI, 3.153–3.675), congenital lung disease and/or bronchial abnormalities, Down syndrome, congenital tracheoesophageal fistula, diaphragmatic hernia, pulmonary hypertension, chromosomal abnormalities other than Down syndrome, hemodynamically non-significant CHD, congenital abnormalities of nervous system, cystic fibrosis, cleft palate, cardiovascular disease occurring during perinatal period, and BPD.Conclusion: Besides prematurity, BPD, and HS–CHD, eighteen underlying conditions were associated with a significant increased risk for bronchiolitis hospitalization in a nationwide population.

Purpose The prevalence of parental burnout, a condition that has severe consequences for both parents and children, varies dramatically across countries and is highest in Western countries characterized by high individualism. Method In this study, we examined the mediators of the relationship between individualism measured at the country level and parental burnout measured at the individual level in 36 countries (16,059 parents). Results The results revealed three mediating mechanisms, that is, self-discrepancies between socially prescribed and actual parental selves, high agency and self-directed socialization goals, and low parental task sharing, by which individualism leads to an increased risk of burnout among parents. Conclusion The results confirm that the three mediators under consideration are all involved, and that mediation was higher for self-discrepancies between socially prescribed and actual parental selves, then parental task sharing, and lastly self-directed socialization goals. The results provide some important indications of how to prevent parental burnout at the societal level in Western countries.

Aging is accompanied by a drop in the level of health and autonomy, within Western countries more and more people being cared for in nursing homes (NH). The nutritional data in NH in France remain poor, not exhaustive and not representative. The objective of the study was to assess the nutritional status, dementia and mobility patterns among residents of NH in the Limousin territory of France. The study was cross-sectional, descriptive and exhaustive, conducted with the residents of 13 voluntary NH. Undernutrition was identified using French High Authority for Health criteria, and obesity if Body Mass Index >30, in the absence undernutrition criterion. The Mini Mental State examination scores was used for dementia assessment at the threshold of 24. The Mini Nutritional AssessmentTM was used for mobilitity assessment. The statistics were significant at the 5% threshold. 866 residents (70.6% women) included with an average age of 85.3 ± 9.3 years. Undernutrition was 27.5%, obesity 22.9%, dementia 45.7% and very low mobility 68.9%. Women were older than men, more often undernourished, more often demented and more often had very low mobility (p<0.01). Undernutrition (p<0.0001) and low mobility (p<0.0001) were significantly higher among those with dementia versus those without dementia. Very low mobility was higher among undernourished (p<0.05). Undernutrition and obesity are important problems in NH in France. Being a woman, having dementia and having a very low mobility may induce undernutrition.

Few studies have examined the consumption trajectories of inmates after entry to prison. The aim of this study was to assess the changes in the consumption of psychoactive substance between the period before detention and during incarceration and to characterize the profiles of prisoners with similar consumption trajectories during incarceration. A multicenter, cross-sectional study was performed in all of the prisons from one region of France. All prisoners incarcerated during their 3rd months, over 18 years old, and with a sufficient level of French fluency to participate in the study were recruited over a period of 12 months. A total of 800 prisoners were recruited. All prisoners were interviewed face-to-face by a trained interviewer. A majority of prisoners had used at least one psychoactive substance in the weeks prior to incarceration. During incarceration, a substantial reduction in alcohol and illicit drug consumption was observed. The initiation of consumption and an increase in consumption were primarily related to medications. Five different profiles of consumption before incarceration were identified. These profiles all had a high probability of migrating to a similar profile during detention, characterized by less severe consumption of psychoactive substances. Based on their consumption profile prior to incarceration, most prisoners would benefit from a specific medical evaluation as soon as possible following entry into detention. Prison could be an opportunity for reduced consumption and/or the initiation of treatment for the majority of prisoners, despite the pejorative development observed for a minority of prisoners during incarceration.