Metabolomics analysis of type 2 diabetes remission identifies 12 metabolites with predictive capacity: a CORDIOPREV clinical trial study.

Type 2 diabetes mellitus (T2DM) is one of the most widely spread diseases, affecting around 90% of the patients with diabetes. Metabolomics has proven useful in diabetes research discovering new biomarkers to assist in therapeutical studies and elucidating pathways of interest. However, this technique has not yet been applied to a cohort of patients that have remitted from T2DM. All patients with a newly diagnosed T2DM at baseline (n = 190) were included. An untargeted metabolomics approach was employed to identify metabolic differences between individuals who remitted (RE), and those who did not (non-RE) from T2DM, during a 5-year study of dietary intervention. The biostatistical pipeline consisted of an orthogonal projection on the latent structure discriminant analysis (O-PLS DA), a generalized linear model (GLM), a receiver operating characteristic (ROC), a DeLong test, a Cox regression, and pathway analyses. The model identified a significant increase in 12 metabolites in the non-RE group compared to the RE group. Cox proportional hazard models, calculated using these 12 metabolites, showed that patients in the high-score tercile had significantly (p-value < 0.001) higher remission probabilities (Hazard Ratio, HR, high versus low = 2.70) than those in the lowest tercile. The predictive power of these metabolites was further studied using GLMs and ROCs. The area under the curve (AUC) of the clinical variables alone is 0.61, but this increases up to 0.72 if the 12 metabolites are considered. A DeLong test shows that this difference is statistically significant (p-value = 0.01). Our study identified 12 endogenous metabolites with the potential to predict T2DM remission following a dietary intervention. These metabolites, combined with clinical variables, can be used to provide, in clinical practice, a more precise therapy. ClinicalTrials.gov, NCT00924937.The CORDIOPREV study is supported by the Ministerio de Economia y Competitividad, Spain, under the grants AGL2012/39615, PIE14/00005, and PIE14/00031 associated to J.L.-M.; AGL2015-67896-P to J.L.-M. and A.C.; CP14/00114 to A.C.; PI19/00299 to A.C.; DTS19/00007 to A.C.; FIS PI13/00023 to J.D.-L., PI16/01777 to F.P.-J. and P.P.-M.; Antonio Camargo is supported by an ISCIII research contract (Programa Miguel-Servet CPII19/00007); Marina Mora-Ortiz has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 847468; ‘Fundacion Patrimonio Comunal Olivarero’, Junta de Andalucía (Consejería de Salud, Consejeria de Agricultura y Pesca, Consejería de Innovacion, Ciencia y Empresa), ‘Diputaciones de Jaen y Cordoba’, ‘Centro de Excelencia en Investigación sobre Aceite de Oliva y Salud’ and ‘Ministerio de Medio Ambiente, Medio Rural y Marino’, Gobierno de España; ‘Consejeria de Innovación, Ciencia y Empresa, Proyectos de Investigación de Excelencia’, Junta de Andalucía under the grant CVI-7450 obtaiend by J.L.-M.; and we would also like to thank the ‘Fondo Europeo de Desarrollo Regional (FEDER)’.S

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. 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 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

An exploration of the potential benefits of integrated pest management systems and the use of insect resistant potatoes to control the Guatemalan Tuber Moth (Tecia solanivora Povolny) in Ventaquemada, Colombia

CORPOICA and IFPRI implemented a research project in Ventaquemada, Colombia. The project’s goal was to asses the benefits of Integrated Pest Management (IPM) practices and the potential of Genetically Modified insect resistant (Bt) potatoes to manage damage caused by the Guatemalan Tuber Moth (Tecia solanivora Povolny). The Guatemalan Tuber Moth is particularly destructive because field spraying on the adult stage is ineffective and there exists damage specificity to the tubers. Excessive pesticide sprays have resulted in resistance to several insecticides. Insect resistant (Bt) potatoes has been shown an effective means to control other members of the Tuber Moth complex. Thus a Bt potato may play a role in managing Tecia in Colombia. This is an ex ante study as there are no Bt potatoes currently under field conditions in Colombia.. To examine this issue, we conducted a survey in 2003 of 78 farmers in the region to estimate a baseline of traditionally and IPM managed systems. The first year survey was supplemented with focus groups to examine damage and production costs in 2003 and 2004. We also implemented activities such as field verification of IPM practices and damage, a Farmer Field School and other participatory methods. Our analysis uses methods such partial budgeting analysis, a production function input abatement expectations model, and an economic surplus model augmented by stochastic simulations. Results of the analysis presented here outlines estimated losses under field and storage conditions, likely range of benefits accrued by farmers in the region due to the potential adoption of a portfolio of IPM management practices and Bt potatoes. Results from the survey conducted in 2003 show that producers in the area have endured significant field and storage losses within the previous 10 years, but were low in that particular year. Initial results where confirmed by results of focus groups in 2003 and 2004 which show very low field and storage damage. Sustained precipitation explains the observed low levels of damage by the Tuber Moth. Low levels of damage induced zero (or even negative) cost differences between conventional and IPM management. In contrast, using the proposed expectation model to estimate expected payoffs to IPM investments show that even with low levels of damage it still pays for producers to invest in IPM practices. The economic surplus estimates show that even considering variability of field and storage losses, as well as of other critical parameters, the use of Bt potatoes in Colombia creates a positive return to investment to Bt potato research, assuming that damage is present under field conditions. We finalize by discussing some of the institutional and strategic considerations for the potential use of Bt potatoes in the country

CIRCLE-seq: a highly sensitive in vitro screen for genome-wide CRISPR-Cas9 nuclease off-targets

Sensitive detection of off-target effects is important for translating CRISPR-Cas9 nucleases into human therapeutics. In vitro biochemical methods for finding off-targets offer potential advantages of greater reproducibility and scalability while avoiding limitations associated with strategies that require the culture and manipulation of living cells. Here we describe CIRCLE-seq (Circularization for In vitro Reporting of CLeavage Effects by sequencing), a highly sensitive, sequencing-efficient in vitro screening strategy that outperforms existing cell-based or biochemical approaches for identifying CRISPR-Cas9 genome-wide off-target mutations. In contrast to previously described in vitro methods, we show that CIRCLE-seq can be practiced using widely accessible next-generation sequencing technology and does not require reference genome sequence. Importantly, CIRCLE-seq can be used to identify off-target mutations associated with cell-type-specific SNPs, demonstrating the feasibility and importance of generating personalized specificity profiles. CIRCLE-seq provides the most accessible, rapid and comprehensive method for identifying genome-wide off-target mutations of CRISPR-Cas9 described to date

miR-223-3p as a Potential Biomarker and Player for Adipose Tissue Dysfunction Preceding Type 2 Diabetes Onset

Circulating microRNAs (miRNAs) have been proposed as biomarkers for type 2 diabetes (T2D). Adipose tissue (AT), for which dysfunction is widely associated with T2D development, has been reported as a major source of circulating miRNAs. However, the role of dysfunctional AT in the altered pattern of circulating miRNAs associated with T2D onset remains unexplored. Herein, we investigated the relationship between T2D-associated circulating miRNAs and AT function, as well as the role of preadipocytes and adipocytes as secreting cells of candidate circulating miRNAs. Among the plasma miRNAs related to T2D onset in the CORonary Diet Intervention with Olive oil and cardiovascular PREVention (CORDIOPREV) cohort, baseline miR-223-3p levels (diminished in patients who next developed T2D [incident-T2D]) were significantly related to AT insulin resistance (IR). Baseline serum from incident-T2D participants induced inflammation and IR in 3T3-L1 adipocytes. We demonstrated that tumor necrosis factor (TNF)-alpha inhibited miR-223-3p secretion while enhancing miR-223-3p intracellular accumulation in 3T3-L1 (pre)adipocytes. Overexpression studies showed that an intracellular increase of miR-223-3p impaired glucose and lipid metabolism in these cells. Our findings provide mechanistic insights into the alteration of circulating miRNAs preceding T2D, unveiling both preadipocytes and adipocytes as miR-223-3p-secreting cells and suggesting that inflammation promotes miR-223-3p intracellular accumulation, which might contribute to (pre)adipocyte dysfunction and body metabolic dysregulation

miR-223-3p as a potential biomarker and player for adipose tissue dysfunction preceding type 2 diabetes onset

Circulating microRNAs (miRNAs) have been proposed as biomarkers for type 2 diabetes (T2D). Adipose tissue (AT), for which dysfunction is widely associated with T2D development, has been reported as a major source of circulating miRNAs. However, the role of dysfunctional AT in the altered pattern of circulating miRNAs associated with T2D onset remains unexplored. Herein, we investigated the relationship between T2D-associated circulating miRNAs and AT function, as well as the role of preadipocytes and adipocytes as secreting cells of candidate circulating miRNAs. Among the plasma miRNAs related to T2D onset in the CORonary Diet Intervention with Olive oil and cardiovascular PREVention (CORDIOPREV) cohort, baseline miR-223-3p levels (diminished in patients who next developed T2D [incident-T2D]) were significantly related to AT insulin resistance (IR). Baseline serum from incident-T2D participants induced inflammation and IR in 3T3-L1 adipocytes. We demonstrated that tumor necrosis factor (TNF)-alpha inhibited miR-223-3p secretion while enhancing miR-223-3p intracellular accumulation in 3T3-L1 (pre)adipocytes. Overexpression studies showed that an intracellular increase of miR-223-3p impaired glucose and lipid metabolism in these cells. Our findings provide mechanistic insights into the alteration of circulating miRNAs preceding T2D, unveiling both preadipocytes and adipocytes as miR-223-3p-secreting cells and suggesting that inflammation promotes miR-223-3p intracellular accumulation, which might contribute to (pre)adipocyte dysfunction and body metabolic dysregulation

Long-term consumption of a Mediterranean diet improves postprandial lipemia in patients with type 2 diabetes: the Cordioprev randomized trial.

Patients with type 2 diabetes (T2D) have an elevated postprandial lipemia (PPL) that has been associated with increased cardiovascular risk. We aimed to analyze whether the long-term consumption of 2 healthy dietary patterns is associated with an improvement in PPL and remnant cholesterol (RC) concentrations in patients with T2D. We selected patients from the Cordioprev study who underwent oral fat load tests (FLTs) at baseline and the 3-y follow-up (241 patients with and 316 patients without T2D). Subjects were randomly assigned to receive either a Mediterranean diet rich in olive oil (MedDiet; 35% of calories from fat [22% monounsaturated fatty acids (MUFAs)] and 50% from carbohydrates) or a low-fat (LF) diet [ After 3 y of dietary intervention, patients with T2D showed an improvement in their PPL measured as postprandial triglycerides (TGs) (P  0.05) or in patients without T2D (P > 0.05) regardless of the dietary intervention. In addition, the MedDiet induced a significant improvement in the RC AUC in patients with T2D (P = 0.04). However, there was no significant improvement in those following the LF diet. Our findings show that the long-term consumption of a MedDiet rich in olive oil improves PPL and RC concentrations mainly in patients with T2D. This trial was registered at clinicaltrials.gov as NCT00924937