Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding: Bill & Melinda Gates Foundation

Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980�2015: the Global Burden of Disease Study 2015

Background Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015. Methods For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification. Findings Global HIV incidence reached its peak in 1997, at 3·3 million new infections (95 uncertainty interval UI 3·1�3·4 million). Annual incidence has stayed relatively constant at about 2·6 million per year (range 2·5�2·8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38·8 million (95% UI 37·6�40·4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1·8 million deaths (95% UI 1·7�1·9 million) in 2005, to 1·2 million deaths (1·1�1·3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections. Interpretation Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030. Funding Bill & Melinda Gates Foundation, and National Institute of Mental Health and National Institute on Aging, National Institutes of Health. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990�2015: a systematic analysis for the Global Burden of Disease Study 2015

Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Findings Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2·9 years (95 uncertainty interval 2·9�3·0) for men and 3·5 years (3·4�3·7) for women, while HALE at age 65 years improved by 0·85 years (0·78�0·92) and 1·2 years (1·1�1·3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Interpretation Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum. Funding Bill & Melinda Gates Foundation. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Probiotic Supplementation in Morbid Obese Patients Undergoing One Anastomosis Gastric Bypass-Mini Gastric Bypass (OAGB-MGB) Surgery: a Randomized, Double-Blind, Placebo-Controlled, Clinical Trial

Background: Bariatric surgery is known as one of the most effective treatments for sustainable weight loss; however, it may be associated with some complications. This study was designed to examine the effects of probiotic supplementation on some morbidities related to this surgery. Methods: This was a placebo-controlled, double-blind, randomized clinical trial on morbid obese patients referred for One Anastomosis Gastric Bypass- Mini Gastric Bypass (OAGB-MGB) surgery to a tertiary referral center. Patients were assigned to receive a probiotic supplement (Familact®) or placebo from 4 weeks prior to surgery to 12 weeks after surgery. Anthropometric, biochemical, and inflammatory indices were evaluated at the beginning and the end of the study. Results: At the end of study, significant improvements in some serum inflammatory markers, vitamin D status, and anthropometric measurements were observed (p &lt; 0.05), which were significantly more in probiotic group rather than placebo group (p &lt; 0.05). Moreover, significant improvements in glycemic indices and lipid profile were observed in both groups; however, these changes were not significantly different between the groups. There was no significant difference in serum levels of vitamin B12, folate, and homocysteine between groups at week 16 of the study. Discussion: Our results indicate that probiotic supplementation promotes inflammatory markers, body weight loss, and status of vitamin D in patients undergoing OAGB-MGB bypass. Whether these findings will sustain in longer treatment duration remained to be elucidated in future studies. Trial Registration: This study has been registered at Clinicaltrial.gov with registration number NCT02708589. © 2018, Springer Science+Business Media, LLC, part of Springer Nature

Probiotic Supplementation in Morbid Obese Patients Undergoing One Anastomosis Gastric Bypass-Mini Gastric Bypass (OAGB-MGB) Surgery: a Randomized, Double-Blind, Placebo-Controlled, Clinical Trial

Background: Bariatric surgery is known as one of the most effective treatments for sustainable weight loss; however, it may be associated with some complications. This study was designed to examine the effects of probiotic supplementation on some morbidities related to this surgery. Methods: This was a placebo-controlled, double-blind, randomized clinical trial on morbid obese patients referred for One Anastomosis Gastric Bypass- Mini Gastric Bypass (OAGB-MGB) surgery to a tertiary referral center. Patients were assigned to receive a probiotic supplement (Familact®) or placebo from 4 weeks prior to surgery to 12 weeks after surgery. Anthropometric, biochemical, and inflammatory indices were evaluated at the beginning and the end of the study. Results: At the end of study, significant improvements in some serum inflammatory markers, vitamin D status, and anthropometric measurements were observed (p &lt; 0.05), which were significantly more in probiotic group rather than placebo group (p &lt; 0.05). Moreover, significant improvements in glycemic indices and lipid profile were observed in both groups; however, these changes were not significantly different between the groups. There was no significant difference in serum levels of vitamin B12, folate, and homocysteine between groups at week 16 of the study. Discussion: Our results indicate that probiotic supplementation promotes inflammatory markers, body weight loss, and status of vitamin D in patients undergoing OAGB-MGB bypass. Whether these findings will sustain in longer treatment duration remained to be elucidated in future studies. Trial Registration: This study has been registered at Clinicaltrial.govwith registration number NCT02708589. © 2018 Springer Science+Business Media, LLC, part of Springer Natur

Associations between cms's clinical performance measures project benchmarks, profit structure, and mortality in dialysis units

Prior studies observing greater mortality in for-profit dialysis units have not captured information about benchmarks of care. This study was undertaken to examine the association between profit status and mortality while achieving benchmarks. Utilizing data from the US Renal Data System and the Centers for Medicare & Medicaid Services' end-stage renal disease (ESRD) Clinical Performance Measures project, hemodialysis units were categorized as for-profit or not-for-profit. Associations with mortality at 1 year were estimated using Cox regression. Two thousand six hundred and eighty-five dialysis units (31515 patients) were designated as for-profit and 1018 (15085 patients) as not-for-profit. Patients in for-profit facilities were more likely to be older, black, female, diabetic, and have higher urea reduction ratio (URR), hematocrit, serum albumin, and transferrin saturation. Patients (19.4 and 18.6%) in for-profit and not-for-profit units died, respectively. In unadjusted analyses, profit status was not associated with mortality (hazard ratio (HR)= 1.04, P=0.09). When added to models with profit status, the following resulted in a significant association between profit status (for-profit vs not-for-profit) and increasing mortality risk: URR, hematocrit, albumin, and ESRD Network. In adjusted models, patients in for-profit facilities had a greater death risk (HR 1.09, P = 0.004). More patients in for-profit units met clinical benchmarks. Survival among patients in for-profit units was similar to not-for-profit units. This suggests that in the contemporary era, interventions in for-profit dialysis units have not impaired their ability to deliver performance benchmarks and do not affect survival

Associations between cms's clinical performance measures project benchmarks, profit structure, and mortality in dialysis units

Prior studies observing greater mortality in for-profit dialysis units have not captured information about benchmarks of care. This study was undertaken to examine the association between profit status and mortality while achieving benchmarks. Utilizing data from the US Renal Data System and the Centers for Medicare & Medicaid Services' end-stage renal disease (ESRD) Clinical Performance Measures project, hemodialysis units were categorized as for-profit or not-for-profit. Associations with mortality at 1 year were estimated using Cox regression. Two thousand six hundred and eighty-five dialysis units (31515 patients) were designated as for-profit and 1018 (15085 patients) as not-for-profit. Patients in for-profit facilities were more likely to be older, black, female, diabetic, and have higher urea reduction ratio (URR), hematocrit, serum albumin, and transferrin saturation. Patients (19.4 and 18.6%) in for-profit and not-for-profit units died, respectively. In unadjusted analyses, profit status was not associated with mortality (hazard ratio (HR)= 1.04, P=0.09). When added to models with profit status, the following resulted in a significant association between profit status (for-profit vs not-for-profit) and increasing mortality risk: URR, hematocrit, albumin, and ESRD Network. In adjusted models, patients in for-profit facilities had a greater death risk (HR 1.09, P = 0.004). More patients in for-profit units met clinical benchmarks. Survival among patients in for-profit units was similar to not-for-profit units. This suggests that in the contemporary era, interventions in for-profit dialysis units have not impaired their ability to deliver performance benchmarks and do not affect survival

Associations between cms\u27s clinical performance measures project benchmarks, profit structure, and mortality in dialysis units

Prior studies observing greater mortality in for-profit dialysis units have not captured information about benchmarks of care. This study was undertaken to examine the association between profit status and mortality while achieving benchmarks. Utilizing data from the US Renal Data System and the Centers for Medicare & Medicaid Services\u27 end-stage renal disease (ESRD) Clinical Performance Measures project, hemodialysis units were categorized as for-profit or not-for-profit. Associations with mortality at 1 year were estimated using Cox regression. Two thousand six hundred and eighty-five dialysis units (31515 patients) were designated as for-profit and 1018 (15085 patients) as not-for-profit. Patients in for-profit facilities were more likely to be older, black, female, diabetic, and have higher urea reduction ratio (URR), hematocrit, serum albumin, and transferrin saturation. Patients (19.4 and 18.6%) in for-profit and not-for-profit units died, respectively. In unadjusted analyses, profit status was not associated with mortality (hazard ratio (HR)= 1.04, P=0.09). When added to models with profit status, the following resulted in a significant association between profit status (for-profit vs not-for-profit) and increasing mortality risk: URR, hematocrit, albumin, and ESRD Network. In adjusted models, patients in for-profit facilities had a greater death risk (HR 1.09, P = 0.004). More patients in for-profit units met clinical benchmarks. Survival among patients in for-profit units was similar to not-for-profit units. This suggests that in the contemporary era, interventions in for-profit dialysis units have not impaired their ability to deliver performance benchmarks and do not affect survival

Supplementary Material for: Association of Monocyte Chemoattractant Protein-1 with Death and Atherosclerotic Events in Chronic Kidney Disease

<b><i>Background:</i></b> Monocyte chemoattractant protein-1 ­(MCP-1), a marker of inflammation and monocyte recruitment to atherosclerotic plaques, is associated with cardiovascular (CV) outcomes in patients with acute coronary syndrome. Although plasma levels are elevated in chronic kidney disease (CKD), associations with reduced kidney function or outcomes in CKD have not been explored. <b><i>Methods:</i></b> In this population-based, probability-sampled, longitudinal cohort of 3,257 participants, including 286 (8.8%) patients with CKD, we studied the association of plasma MCP-1 with estimated glomerular filtration rate (eGFR), albuminuria, death, and intermediate and hard CV outcomes in CKD and non-CKD individuals. Cox proportional hazards regression assessed associations of baseline MCP-1 with all-cause death and atherosclerotic events. <b><i>Results:</i></b> MCP-1 was higher in CKD than non-CKD participants (<i>p</i> < 0.001), and negatively associated with eGFR (<i>r</i> = –0.23, <i>p</i> < 0.0001) but not albuminuria in CKD. MCP-1 was associated with pulse wave velocity and coronary artery calcification in non-CKD but not CKD individuals. At 13.5 years, there were 230 (7.7%) deaths and 168 (6.4%) atherosclerotic events in the non-CKD vs. 97 (34.0%) deaths and 62 (27.9%) events in the CKD group (<i>p</i> < 0.001 for each). MCP-1 was associated with death (hazards ratio [HR] 2.0 [1.4–2.9] per log-unit increase) and atherosclerotic events (1.7 [1.0–2.9]) in CKD individuals. The HR for death in CKD remained significant (1.6 [1.1–2.3]) after adjusting for CV risk factors. <b><i>Conclusions:</i></b> Although plasma MCP-1 increased with decreased eGFR, it remained an independent risk factor for death in CKD. MCP-1 did not correlate with intermediate CV outcomes, implicating pathways other than atherosclerosis in the association of MCP-1 with death in CKD