Risk-hedging using options for an upgrading investment in a data network

In this paper, we illustrate how a mobile data network operator can plan an upgrading investment to anticipate explosions of the demand, taking into account the expected generated profit and the customers satisfaction. The former parameter grows with the demand, whereas the latter sinks if the demand is too high as throughput may collapse. As the equipment price decreases with time, it may be interesting to wait rather than to invest at once. We then propose a real option strategy to hedge against the risk that the investment has to take place earlier than expected. At last, we price this option with a backward dynamic programming approach, using recent improvements based on least-squares estimations.

Modelling trace metal background to evaluate anthropogenic contamination in arable soils of south-western France

The trace metal (TM) content in arable soils has been monitored across a region of France characterised by a large proportion of calcareous soils. Within this particular geological context, the objectives were to first determine the natural levels of trace metals in the soils and secondly, to assess which sites were significantly contaminated. Because no universal contamination assessment method is currently available, four different methods were applied and compared in order to facilitate the best diagnosis of contamination. First, the TM geochemical background was determined by using basic descriptive statistics and linear regression models calculated with semi-conservative major elements as predictors. The natural concentrations of trace metals varied greatly due to the high soil heterogeneity encountered on the regional scale and were more-or-less accurately modelled according to the considered TM. Second, the basic descriptive statistics and the linear regression methods were then compared with the enrichment factor (EF) method and multivariate analysis (PCA), in order to evaluate whether the concentrations measured in soils were abnormally high or not. The advantages and disadvantages of each method were discussed and their results used to identify the most probable contamination cases, the influence of the soils characteristics, as well as the agricultural land cover. The basic descriptive method was good as a first and easy approach to describe the TM ambient concentrations, but may misinterpret the natural anomalies as contaminations. Based on geochemical associations, the linear regression method provided more realistic results even if the relationships between major and trace metals were not significant for the most mobile TM. The EF method was useful to identify high point source contaminations, but it was not suitable when considering a large dataset of low TM concentrations. Finally, the PCA method was a good preliminary tool for the description of the global TM concentrations in a studied area, but it could only give indication on the highest contaminated points. By comparing the results of the different methods in the studied region, we estimated that 24% of the arable soils were contaminated by at least one trace metal, mainly Cu in vineyards/orchards and Cd, Pb and/or Zn in grazing lands. In addition, the calcareous soils exhibited globally higher natural and anthropogenic TM concentrations than non-calcareous soils, probably because of the lower TM mobility at alkaline pH

Longitudinal study of DNA methylation during the first 5 years of life.

Background: Early life epigenetic programming influences adult health outcomes. Moreover, DNA methylation levels have been found to change more rapidly during the first years of life. Our aim was the identification and characterization of the CpG sites that are modified with time during the first years of life. We hypothesize that these DNA methylation changes would lead to the detection of genes that might be epigenetically modulated by environmental factors during early childhood and which, if disturbed, might contribute to susceptibility to diseases later in life. Methods: The study of the DNA methylation pattern of 485577 CpG sites was performed on 30 blood samples from 15 subjects, collected both at birth and at 5 years old, using Illumina® Infinium 450 k array. To identify differentially methylated CpG (dmCpG) sites, the methylation status of each probe was examined using linear models and the Empirical Bayes Moderated t test implemented in the limma package of R/Bioconductor. Surogate variable analysis was used to account for batch effects. Results: DNA methylation levels significantly changed from birth to 5 years of age in 6641 CpG sites. Of these, 36.79 % were hypermethylated and were associated with genes related mainly to developmental ontology terms, while 63.21 % were hypomethylated probes and associated with genes related to immune function. Conclusions: Our results suggest that DNA methylation alterations with age during the first years of life might play a significant role in development and the regulation of leukocyte-specific functions. This supports the idea that blood leukocytes experience genome remodeling related to their interaction with environmental factors, underlining the importance of environmental exposures during the first years of life and suggesting that new strategies should be take into consideration for disease prevention

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment

Background High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods We used data for exposure to risk factors by country, age group, and sex from pooled analyses of populationbased health surveys. We obtained relative risks for the eff ects of risk factors on cause-specifi c mortality from metaanalyses of large prospective studies. We calculated the population attributable fractions for- each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the eff ects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specifi c population attributable fractions by the number of disease-specifi c deaths. We obtained cause-specifi c mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the fi nal estimates. Findings In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10\ub78 million deaths, 95% CI 10\ub71\u201311\ub75) of deaths from these diseases in 2010 were attributable to the combined eff ect of these four metabolic risk factors, compared with 67% (7\ub71 million deaths, 6\ub76\u20137\ub76) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined eff ects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing eff ect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the globalresponse to non-communicable diseases

Cardiovascular risk of metabolically healthy obesity in two european populations: Prevention potential from a metabolomic study

Background: A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern. Methods: This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure < 130 mmHg, no antihypertensive drugs, waist-to-hip ratio < 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI < 25, 25-30, ≥ 30 kg/m2). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events. Results: Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7-13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73-6.28] for normal weight, 2.50 [95% CI: 1.34-4.66] for overweight, and 3.42 [95% CI: 1.81-6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36-3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10-1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91). Conclusions: Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention.The work was supported by Internal Funds KU Leuven (STG-18-00379), the European Research Area Net for Cardiovascular Diseases (JTC2017-046-PROACT), the Ministerio de Ciencia e Innovación of Spain (PID2019-108973RB-C21 and C22 and PCIN2017-117), the Generalitat Valenciana of Spain (GV/2020/048), and GUTMOM (INTIMIC-085) from the EU Joint Programming Initiative Healthy Diet Healthy Life (HDHL).S

Impact of renal impairment on beta-blocker efficacy in patients with heart failure

14 p.The Beta-Blockers in Heart Failure Collaborative Group (Collaborative Systematic Overview of Randomised Controlled Trials of Beta-Blockers in the Treatment of Heart Failure [BB-meta-HF])Background: Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. Objectives: This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR). Methods: Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm. Results: Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m 2 ; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m 2 , and 2,286 (13.7%) 30 to 44 ml/min/1.73 m 2 . Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m 2 lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m 2 (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m 2 (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m 2 ) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR. Conclusions: Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction.AstraZenecaGlaxoSmithKlineMerck SeronoMenarin

Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome

22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with congenital and late-onset features. Testing for the genomic content of copy number variations (CNVs) may help elucidate the 22q11.2 deletion mechanism and the variable clinical expression of the syndrome including the high (25%) risk for schizophrenia. We used genome-wide microarrays to assess CNV content and the parental origin of 22q11.2 deletions in a cohort of 100 adults with 22q11.2DS (44 with schizophrenia) and controls. 22q11.2DS subjects with schizophrenia failed to exhibit de novo CNVs or any excess of novel inherited CNVs outside the 22q11.2 region. There were no significant effects of parental origin of the 22q11.2 deletion, deletion length, parental age or family history on expression of schizophrenia. There was no evidence for a general increase of de novo CNVs in 22q11.2DS. A novel finding was the relative paucity of males with de novo 22q11.2 deletions of paternal origin (P = 0.019). The Y chromosome may play a mediating role in the mechanism of 22q11.2 deletion events during spermatogenesis, resulting in the previously observed excess of maternal de novo 22q11.2 deletions. Hemizygosity of the 22q11.2 region appears to be the major CNV-related risk factor for schizophrenia in 22q11.2DS. The results reinforce the need for further efforts to identify specific molecular mechanisms underlying this expression and to identify the 1% of patients with schizophrenia who carry 22q11.2 deletions