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BackgroundLeft ventricular ejection fraction (EF) is used to categorize heart failure (HF) into phenotypes but this information is often missing in electronic health records or non-HF registries.MethodsWe tested the applicability of a simplified version of a multivariable algorithm, that was developed on data of the Swedish Heart Failure Registry to predict EF in patients with HF. We used data from 4,868 patients with HF from the Cardiology Centers of the Netherlands database, an organization of 13 cardiac outpatient clinics that operate between the general practitioner and the hospital cardiologist. The algorithm included 17 demographical and clinical variables. We tested model discrimination, model performance and calculated model sensitivity, specificity, positive and negative predictive values for EF ≥ vs. ResultsMean age was 66 ±12 years, 44% of patients were women, 68% had HFpEF, 17% had HFrEF, and 15% had HFmrEF. The C-statistic was of 0.71 for EF ≥/< 50% (95% CI: 0.69-0.72) and of 0.74 (95% CI: 0.73-0.75) for EF ≥/< 40%. The model had the highest sensitivities for EF ≥50% (0.72, 95% CI: 0.63-0.75) and for EF ≥40% (0.70, 95% CI: 0.65-0.71). Similar results were achieved by the multinomial model, but the C-statistics for predicting HFpEF vs HFrEF was lower (0.61, 95% CI 0.58-0.63). The internal validation confirmed good discriminative ability.ConclusionsA simple algorithm based on routine clinical characteristics can help discern HF phenotypes in non-cardiology datasets and research settings such as research on primary care data, where measurements of EF is often not available.

Background: Left ventricular ejection fraction (EF) is used to categorize heart failure (HF) into phenotypes but this information is often missing in electronic health records or non-HF registries. Methods: We tested the applicability of a simplified version of a multivariable algorithm, that was developed on data of the Swedish Heart Failure Registry to predict EF in patients with HF. We used data from 4,868 patients with HF from the Cardiology Centers of the Netherlands database, an organization of 13 cardiac outpatient clinics that operate between the general practitioner and the hospital cardiologist. The algorithm included 17 demographical and clinical variables. We tested model discrimination, model performance and calculated model sensitivity, specificity, positive and negative predictive values for EF ≥ vs. <50% and EF ≥ vs. <40%. We additionally performed a multivariable multinomial analysis for all three separate HF phenotypes (with reduced, mildly reduced and preserved EF) HFrEF vs. HFmrEF vs. HFpEF. Finally, we internally validated the model by using temporal validation. Results: Mean age was 66 ±12 years, 44% of patients were women, 68% had HFpEF, 17% had HFrEF, and 15% had HFmrEF. The C-statistic was of 0.71 for EF ≥/< 50% (95% CI: 0.69–0.72) and of 0.74 (95% CI: 0.73–0.75) for EF ≥/< 40%. The model had the highest sensitivities for EF ≥50% (0.72, 95% CI: 0.63–0.75) and for EF ≥40% (0.70, 95% CI: 0.65–0.71). Similar results were achieved by the multinomial model, but the C-statistics for predicting HFpEF vs HFrEF was lower (0.61, 95% CI 0.58–0.63). The internal validation confirmed good discriminative ability. Conclusions: A simple algorithm based on routine clinical characteristics can help discern HF phenotypes in non-cardiology datasets and research settings such as research on primary care data, where measurements of EF is often not available. [ABSTRACT FROM AUTHOR]

One of the first steps in protein sequence analysis is comparing sequences to look for similarities. We propose an information theoretical distance to compare cellular automata representing protein sequences, and determine similarities. Our approach relies in a stationary Hamming distance for the evolution of the automata according to a properly chosen rule, and to build a pairwise similarity matrix and determine common ancestors among different species in a simpler and less computationally demanding computer codes when compared to other methods.

AimsDirect oral anticoagulants (DOAC) are progressively replacing vitamin K antagonists in the prevention of thromboembolism in patients with atrial fibrillation. However, their real-world clinical outcomes appear to be contradictory, with some studies reporting fewer and others reporting higher complications than the pivotal randomized controlled trials. We present the results of a clinical model for the management of DOACs in real clinical practice and provide a review of the literature.MethodsThe MACACOD project is an ongoing, observational, prospective, single-center study with unselected patients that focuses on rigorous DOAC selection, an educational visit, laboratory measurements, and strict follow-up.ResultsA total of 1,259 patients were included. The composite incidence of major complications was 4.93% py in the whole cohort vs 4.49% py in the edoxaban cohort. The rate of all-cause mortality was 6.11% py for all DOACs vs 5.12% py for edoxaban. There weren't differences across sex or between Edoxaban reduced or standard doses. However, there were differences across ages, with a higher incidence of major bleeding complications in patients >85 years (5.13% py vs 1.69% py in ConclusionsWe observed an incidence of serious complications of 4.93% py, in which severe bleeding predominated (3.65% py). Considering our results, more specialized attention seems necessary to reduce the incidence of severe complications and also a more critical view of the literature. Considering our results, and our indirect comparison with many real-world studies, more specialized attention seems necessary to reduce the incidence of severe complications in AF patients receiving DOACs.

Vulvovaginal candidiasis (VVC) is a common infection, and high-quality studies report that misdiagnosis is frequent, with diagnostic testing needed to distinguish it from other causes of vaginitis and avoid inappropriate empiric treatment. However, few recent studies have evaluated U.S. healthcare providers' testing practices for VVC in detail. We evaluated healthcare providers' self-reported testing practices for VVC and treatment outcomes as part of a nationwide online survey in order to identify potential opportunities for improving VVC testing and treatment in the United States. Among 1,503 providers surveyed, 21.3% reported "always" (7.4%) or "usually" (13.9%) ordering diagnostic testing for patients with suspected VVC; this proportion was higher among gynecologists (36.0%) compared with family practitioners (17.8%) and internists (15.8%). Most providers (91.2%) reported that patients' VVC "always" (6.4%) or "usually" (84.9%) responds to initial treatment. Whether the symptom resolution reported in this survey was truly related to VVC is unclear given high rates of misdiagnosis and known widespread empiric prescribing. With only about one-in-five providers reporting usually or always performing diagnostic testing for VVC despite guidelines recommending universal use, research is needed to address barriers to proper testing.

BackgroundFrench Nursing Homes (NHs) are in the early stages of implementing their Risk Management (RM) approach. A regional structure, which was mandated to provide independent support in RM, designed a training package.ObjectiveTo study the impact of the RM training package on safety culture (SC) in NHs and drivers for improvement in SC scores.Method and analysisThis randomised controlled study targeted French NHs. Inclusion criteria were voluntary participation, no external support provided on the topic of adverse incidents upstream of the project, and the commitment of top management to its implementation. The 61 NHs were randomly allocated to one of two groups: the first benefited from a training package; support was given to the second after the impact measurement. Seven dimensions of SC were measured, at an 18-month interval, using the validated Nursing Home Survey on Patient Safety Culture questionnaire (22 items), which was administered to all of the professionals working in NHs. Eleven variables were captured, relating to the structural profile of the NH, the choices of top management in terms of healthcare safety, and the implementation of the system. Further modelling identified predictive factors for changes in SC scores.Results95% of NHs completed both rounds of the questionnaire. The dimension Feedback and communication about incidents (SC = 85.4% before the intervention) significantly improved (+2.8%; p = 0.044). Improvement in the dimension Overall perceptions of resident safety-organizational learning was close to significant (+3.1%; p = 0.075). Drivers for improvement in scores were a pre-existing quality improvement approach, and a steering group that showed RM leadership.ConclusionsThe system appears to have improved several dimensions of SC. Our findings are all the more important given the current crisis in the healthcare sector.Trial registrationRetrospectively registered as NCT02908373 (September 21, 2016).

Background and purposeRenal excretion of direct oral anticoagulants (DOACs) varies depending on the drug. Hypothetically, an increased glomerular filtration rate (GFR) may lead to suboptimal dosing and a higher thromboembolic events incidence. However, real-world patient data do not support the theoretical risk. The aim is to analyse DOAC outcomes in patients with normal and high (≥90 mL/min) GFR, focusing on biological parameters and thrombotic/haemorrhagic events.MethodsObservational prospective single-centre study and registry of patients on DOACs. Follow-up was 1,343 patient-years. A bivariate analysis was performed of baseline variables according to GFR (Results1,135 patients anticoagulated with DOACs were included and 152 patients with GFR ≥90 mL/min. Of 18 serious thrombotic complications during follow-up, 17 occurred in patients with GFR 0.05). No statistically significant differences with clinical relevance were observed between the normal or supranormal groups in anti-Xa activity or in edoxaban plasma concentrations.ConclusionsThere was no increased incidence of thrombotic/haemorrhagic complications in our patients treated with DOACs, including 66% treated with edoxaban, and patients with GFR ≥90 mL/min. Likewise, drug anti-Xa activity and edoxaban plasma concentration did not seem to be influenced by GFR.

We report strong evidence of the importance of contact hubs (or superspreaders) in mitigating the current COVID-19 pandemic. Contact hubs have a much larger number of contacts than the average in the population, and play a key role on the effectiveness of vaccination strategies. By using an age-structures compartmental SEIAHRV (Susceptible, Exposed, Infected symptomatic, Asymptomatic, Hospitalized, Recovered, Vaccinated) model, calibrated from available demographic and COVID-19 incidence, and considering separately those individuals with a much greater number of contacts than the average in the population, we show that carefully choosing who will compose the first group to be vaccinated can impact positively the total death toll and the demand for health services. This is even more relevant in countries with a lack of basic resources for proper vaccination and a significant reduction in social isolation. In order to demonstrate our approach we show the effect of hypothetical vaccination scenarios in two countries of very different scales and mitigation policies, Brazil and Portugal.

In this paper we analyze the descriptive statistics of the Google search volume for the terms related to the National Reserve of Copper and Associates (RENCA), a Brazilian mineral reserve in the Amazon of 4.6 million hectares, before and after the government signed the decree releasing it for exploration. First, we analyze the volume of searches for expressions related to RENCA in Google Trends using descriptive statistics; second, we assess the cross-correlation coefficient ρDCCA, which measures the cross-correlation between two nonstationary time series across different time scales. After the government announced the release of the RENCA reserve, there was an increase in the average volume of Google searches for related terms, showing people's concern about the announcement. By using the cross-correlation coefficient ρDCCA, we identify strong cross-correlations between the different expressions related to RENCA in Google Trends. Our work shows the utility of Google Trends as an indicator of the perception of environmental policies. Additionally, we show that ρDCCA can be used as a tool to measure the cross-correlation between synonyms extracted from Google Trends for various time scales.

ObjectivesTo describe and analyse studies aiming at quantitatively assessing the impact of interventions on patient-reported burden of treatment as an outcome (primary or secondary).MethodsThe aim of the search strategy was to identify all publications describing a medical intervention intended to reduce patient-reported burden of treatment in adult patients with long-term conditions, from January 1, 2008 to July 15, 2019. Four databases (Medline, PsycINFO, the "Trials" section of the Cochrane-Library, and OpenGrey) were searched in English, French, Spanish, Italian and Portuguese. Each identified article was reviewed and the risk of bias was assessed using a tool adapted from the Cochrane Collaboration recommendations.ResultsOf 641 articles retrieved, 11 were included in this review. There were nine randomized controlled trials, one non-randomized controlled trial, and one before-and-after study. The sample sizes ranged from 55 to 1,546 patients. Eight out of the eleven studies reported significant positive outcomes of the studied interventions. Reducing dosing frequency, improving background therapy, offering home care or providing easier-to-use medical devices were associated with positive outcomes.ConclusionsOnly a few studies have specifically focused on decreasing the subjective burden of treatment. Small trials conducted in patients with a single specific disorder have reported positive outcomes. However, a large, high-quality study assessing the impact of a change in care process in patients with multiple morbidities did not show such results. Further studies are needed to implement this aspect of patient-centred care.

AimNoninvasive assessment of infraclinic coronary atherosclerosis by coronary artery calcium score (CAC) measurement leads to the identification of incidental findings. The aim of this study was to determine the prevalence of incidental findings following systematic CAC assessment in diabetic patients with high cardiovascular risk, to identify the determinants, and to assess the midterm consequences of these findings in patient care.Methods732 consecutive asymptomatic patients (187 type 1 diabetes (TD1), 482 type 2 diabetes (TD2) and 63 type 3 diabetes (TD3)) aged 60.6±0.7 years who had a CAC assessment by Multiple Detector Computed Tomography between 2015 and 2017 were systematically included. Clinical and biological data were collected from medical electronic files.Results117/732 diabetic patients (16.0%) had incidental findings of which 105 (14.3%) were unknown. Incidental findings were more frequent in TD3 (23.8%) and TD2 (17.0%) than in TD1 (10.7%) (p = 0.05). 76 diabetic patients (10.4%) had lung abnormalities, mainly pulmonary nodules (31 patients, 4.2%). The other incidental finding were pericardial (1.5%), vascular (1.2%), thymic (0.7%) and digestive diseases (0.5%). 42.6% of patients with incidental findings had an additional TDM and 56.8% a specialized medical advice. In 10 patients (9.3% of incidental findings), the identification of incidental finding led to a specific treatment of the underlying disease. In multivariate analysis, microalbuminuria, type of diabetes (TD2/TD3 vs TD1) and smoking were significantly associated with incidental findings (p = 0.003; p = 0.026; p = 0.050 respectively).ConclusionsIncidental findings are not rare in diabetic patients upon CAC assessment. A fraction of them are accessible to specific treatment. These findings raise the question if a systematic low dose chest TDM should be conducted in TD2 or TD3 patients and in any diabetic smokers by enlarging the window used for CAC assessment.

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.

Carotenoids are diverse lipophilic natural pigments which are stored in variable amounts by animals. Given the multiple biological functions of carotenoids, such variation may have strong implications in evolutionary biology. Crustaceans such as Gammarus amphipods store large amounts of these pigments and inter-population variation occurs. While differences in parasite selective pressure have been proposed to explain this variation, the contribution of other factors such as genetic differences in the gammarid ability to assimilate and/or store pigments, and the environmental availability of carotenoids cannot be dismissed. This study investigates the relative contributions of the gammarid genotype and of the environmental availability of carotenoids in the natural variability in carotenoid storage. It further explores the link of this natural variability in carotenoid storage with major crustacean immune parameters. We addressed these aspects using the cryptic diversity in the amphipod crustacean Gammarus fossarum and a diet supplementation protocol in the laboratory. Our results suggest that natural variation in G. fossarum storage of dietary carotenoids results from both the availability of the pigments in the environment and the genetically-based ability of the gammarids to assimilate and/or store them, which is associated to levels of stimulation of cellular immune defences. While our results may support the hypothesis that carotenoids storage in this crustacean may evolve in response to parasitic pressure, a better understanding of the specific roles of this large pigment storage in the crustacean physiology is needed.

The multimeric analysis (MA) of plasma von Willebrand factor (VWF) evaluates structural integrity and helps in the diagnosis of von Willebrand disease (VWD). This assay is a matter of controversy, being considered by some investigators cumbersome and only slightly informative. The centralised study 'Molecular and Clinical Profile of von Willebrand Disease in Spain (PCM-EVW-ES)' has been carried out by including the phenotypic assessment and the genetic analysis by next generation sequencing (NGS) of the VWF gene (VWF). The aim of the present study was to evaluate the role of MA to the diagnosis of these patients and their potential discrepancies. Two hundred and seventy out of 480 patients centrally diagnosed with VWD had normal multimers, 168 had abnormal multimers and 42 a total absence of multimers. VWF MA was of great significance in the diagnosis of 83 patients (17.3%), it was also of help in the diagnosis achieved in 365 additional patients (76%) and was not informative in 32 cases (6.7%). With regard to discrepancies, 110 out of 480 (23%) patients centrally diagnosed with VWD presented some kind of discordance between VWF:RCo/VWF:Ag and/or VWF:CB/VWF:Ag ratios, multimeric study and/or genetic results. The VWF MA was key in the presence of novel mutations as well as in cases with phenotypic discrepancies. A comparison between the contribution of MA and VWF:CB showed a clearly higher contribution of the former in the diagnostic process. These data seem to reinforce the relevance of the VWF MA in VWD diagnosis, despite all its limitations.

The objective of this study was to identify and describe levels of household economic vulnerability in HIV-affected communities in Côte d'Ivoire, defined as those with a high prevalence of HIV and large numbers of orphans and vulnerable children. We conducted a cross-sectional survey of 3,749 households in five health regions of Côte d'Ivoire. Using principal component analysis, we attempted to identify sets of correlated vulnerabilities and derive a small number of composite scores to create an index for targeting interventions to vulnerable populations. The 65 vulnerability measures examined did not cluster in ways that would allow for the creation of a small number of composite measures. Instead, we found that households face numerous unique pathways to vulnerability.

BACKGROUND:A healthy diet is important for normal growth and development. Exposure to undernutrition during important developmental periods such as childhood and adolescence can have effects later in life. Inhabitants of the west of the Netherlands were exposed to severe undernutrition during the famine in the last winter of the second World War (1944-1945). OBJECTIVE:We investigated if exposure of women to the Dutch famine during childhood and adolescence was associated with an unhealthy lifestyle later in life. DESIGN:We studied 7,525 women from the Prospect-EPIC cohort, recruited in 1993-97 and aged 0-18 years during the Dutch famine. An individual famine score was calculated based on self-reported information about experience of hunger and weight loss. We investigated the association between famine exposure in early life and four lifestyle factors in adulthood: smoking, alcohol consumption, physical activity level and a Mediterranean-style diet. RESULTS:Of the 7,525 included women, 46% were unexposed, 38% moderately exposed and 16% severely exposed to the Dutch famine. Moderately and severely exposed women were more often former or current smokers compared to women that did not suffer from the famine: adjusted prevalence ratio 1.10 (95% CI: 1.05; 1.14) and 1.18 (1.12; 1.25), respectively. They also smoked more pack years than unexposed women. Severely exposed women were more often physically inactive than unexposed women, adjusted prevalence ratio 1.32 (1.06; 1.64). Results did not differ between exposure age categories (0-9 and 10-17 years). We found no associations of famine exposure with alcohol consumption and no dose-dependent relations with diet. CONCLUSIONS:Exposure to famine early in female life may be associated with higher prevalence of smoking and physical inactivity later in life, but not with unhealthy diet and alcohol consumption.

In this article, the performance of a hybrid artificial neural network (i.e. scale-free and small-world) was analyzed and its learning curve compared to three other topologies: random, scale-free and small-world, as well as to the chemotaxis neural network of the nematode Caenorhabditis Elegans. One hundred equivalent networks (same number of vertices and average degree) for each topology were generated and each was trained for one thousand epochs. After comparing the mean learning curves of each network topology with the C. elegans neural network, we found that the networks that exhibited preferential attachment exhibited the best learning curves.

To evaluate the efficacy and safety of bevacizumab in the adjuvant cancer therapy setting within different subset of patients.PubMed, EMBASE, Cochrane and Clinical trials.gov databases were searched for English language studies of randomized controlled trials comparing bevacizumab and adjuvant therapy with adjuvant therapy alone published from January 1966 to 7th of May 2014. Progression free survival, overall survival, overall response rate, safety and quality of life were analyzed using random- or fixed-effects models according to the PRISMA guidelines. We obtained data from 44 randomized controlled trials (30,828 patients). Combining bevacizumab with different adjuvant therapies resulted in significant improvement of progression free survival (log hazard ratio, 0.87; 95% confidence interval (CI), 0.84-0.89), overall survival (log hazard ratio, 0.96; 95% CI, 0.94-0.98) and overall response rate (relative risk, 1.46; 95% CI: 1.33-1.59) compared to adjuvant therapy alone in all studied tumor types. In subgroup analyses, there were no interactions of bevacizumab with baseline characteristics on progression free survival and overall survival, while overall response rate was influenced by tumor type and bevacizumab dose (p-value: 0.02). Although bevacizumab use resulted in additional expected adverse drug reactions except anemia and fatigue, it was not associated with a significant decline in quality of life. There was a trend towards a higher risk of several side effects in patients treated by high-dose bevacizumab compared to the low-dose e.g. all grade proteinuria (9.24; 95% CI: 6.60-12.94 vs. 2.64; 95% CI: 1.29-5.40).Combining bevacizumab with different adjuvant therapies provides a survival benefit across all major subsets of patients, including by tumor type, type of adjuvant therapy, and duration and dose of bevacizumab therapy. Though bevacizumab was associated with increased risks of some adverse drug reactions such as hypertension and bleeding, anemia and fatigue were improved by the addition of bevacizumab.

Although metabolic profiles have been associated with chronic disease risk, lack of temporal stability of metabolite levels could limit their use in epidemiological investigations. The present study aims to evaluate the reliability over a two-year period of 158 metabolites and compare reliability over time in fasting and non-fasting serum samples.Metabolites were measured with the AbsolueIDQp180 kit (Biocrates, Innsbruck, Austria) by mass spectrometry and included acylcarnitines, amino acids, biogenic amines, hexoses, phosphatidylcholines and sphingomyelins. Measurements were performed on repeat serum samples collected two years apart in 27 fasting men from Turin, Italy, and 39 non-fasting women from Utrecht, The Netherlands, all participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Reproducibility was assessed by estimating intraclass correlation coefficients (ICCs) in multivariable mixed models.In fasting samples, a median ICC of 0.70 was observed. ICC values were 0.50 in fasting and non-fasting samples, respectively. ICCs were higher in fasting samples that are preferable to non-fasting.

The aim of our study was to relate four modifiable lifestyle factors (smoking status, body mass index, physical activity and diet) to health expectancy, using quality-adjusted life years (QALYs) in a prospective cohort study. Data of the prospective EPIC-NL study were used, including 33,066 healthy men and women aged 20-70 years at baseline (1993-7), followed until 31-12-2007 for occurrence of disease and death. Smoking status, body mass index, physical activity and adherence to a Mediterranean-style diet (excluding alcohol) were investigated separately and combined into a healthy lifestyle score, ranging from 0 to 4. QALYs were used as summary measure of healthy life expectancy, combining a person's life expectancy with a weight for quality of life when having a chronic disease. For lifestyle factors analyzed separately the number of years living longer in good health varied from 0.12 year to 0.84 year, after adjusting for covariates. A combination of the four lifestyle factors was positively associated with higher QALYs (P-trend

Protein α-helical coiled coil structures that elicit antibody responses, which block critical functions of medically important microorganisms, represent a means for vaccine development. By using bioinformatics algorithms, a total of 50 antigens with α-helical coiled coil motifs orthologous to Plasmodium falciparum were identified in the P. vivax genome. The peptides identified in silico were chemically synthesized; circular dichroism studies indicated partial or high α-helical content. Antigenicity was evaluated using human sera samples from malaria-endemic areas of Colombia and Papua New Guinea. Eight of these fragments were selected and used to assess immunogenicity in BALB/c mice. ELISA assays indicated strong reactivity of serum samples from individuals residing in malaria-endemic regions and sera of immunized mice, with the α-helical coiled coil structures. In addition, ex vivo production of IFN-γ by murine mononuclear cells confirmed the immunogenicity of these structures and the presence of T-cell epitopes in the peptide sequences. Moreover, sera of mice immunized with four of the eight antigens recognized native proteins on blood-stage P. vivax parasites, and antigenic cross-reactivity with three of the peptides was observed when reacted with both the P. falciparum orthologous fragments and whole parasites. Results here point to the α-helical coiled coil peptides as possible P. vivax malaria vaccine candidates as were observed for P. falciparum. Fragments selected here warrant further study in humans and non-human primate models to assess their protective efficacy as single components or assembled as hybrid linear epitopes.

To combat parasitism hosts often rely on their immune system, which is the last line of defense. However, the immune system may not always be effective, and other non-immunological defenses might be favored to reduce the cost of parasite infection. Here we report that larvae of the moth Lobesia botrana can rapidly accelerate their development and reach maturity earlier in response to cues perceived at a distance from parasitoids. Such a phenotypically plastic life history shift, induced by the perception of deadly enemies in the environment, is likely to be an adaptive defensive strategy to prevent parasitoid attack, and has important implications in host-parasite dynamics.

Reproductive factors have been linked to both breast cancer and DNA methylation, suggesting methylation as an important mechanism by which reproductive factors impact on disease risk. However, few studies have investigated the link between reproductive factors and DNA methylation in humans. Genome-wide methylation in peripheral blood lymphocytes of 376 healthy women from the prospective EPIC study was investigated using LUminometric Methylation Assay (LUMA). Also, methylation of 458877 CpG sites was additionally investigated in an independent group of 332 participants of the EPIC-Italy sub-cohort, using the Infinium HumanMethylation 450 BeadChip. Multivariate logistic regression and linear models were used to investigate the association between reproductive risk factors and genome wide and CpG-specific DNA methylation, respectively. Menarcheal age was inversely associated with global DNA methylation as measured with LUMA. For each yearly increase in age at menarche, the risk of having genome wide methylation below median level was increased by 32% (OR:1.32, 95%CI:1.14-1.53). When age at menarche was treated as a categorical variable, there was an inverse dose-response relationship with LUMA methylation levels (OR(12-14 vs. ≤11 yrs):1.78, 95%CI:1.01-3.17 and OR(≥15 vs. ≤11 yrs):4.59, 95%CI:2.04-10.33; P for trend

The onset of menopause has important implications on women's fertility and health. We previously identified genetic variants in genes involved in initial follicle recruitment as potential modifiers of age at natural menopause. The objective of this study was to extend our previous study, by searching for pairwise interactions between tagging single nucleotide polymorphisms (tSNPs) in the 5 genes previously selected (AMH, AMHR2, BMP15, FOXL2, GDF9). We performed a cross-sectional study among 3445 women with a natural menopause participating in the Prospect-EPIC study, a population-based prospective cohort study, initiated between 1993 and 1997. Based on the model-based multifactor dimensionality reduction (MB-MDR) test with a permutation-based maxT correction for multiple testing, we found a statistically significant interaction between rs10407022 in AMH and rs11170547 in AMHR2 (p = 0.019) associated with age at natural menopause. Rs10407022 did not have a statistically significant main effect. However, rs10407022 is an eQTL SNP that has been shown to influence mRNA expression levels in lymphoblastoid cell lines. This study provides additional insights into the genetic background of age at natural menopause and suggests a role of the AMH signaling pathway in the onset of natural menopause. However, these results remain suggestive and replication by independent studies is necessary.

The first step in biomarkers discovery is to identify the best protocols for their purification and analysis. This issue is critical when considering peripheral blood samples (plasma and serum) that are clinically interesting but meet several methodological problems, mainly complexity and low biomarker concentration. Analysis of small molecules, such as circulating microRNAs, should overcome these disadvantages. The present study describes an optimal RNA extraction method of microRNAs from human plasma samples. Different reagents and commercially available kits have been analyzed, identifying also the best pre-analytical conditions for plasma isolation. Between all of them, the column-based approaches were shown to be the most effective. In this context, miRNeasy Serum/Plasma Kit (from Qiagen) rendered more concentrated RNA, that was better suited for microarrays studies and did not require extra purification steps for sample concentration and purification than phenol based extraction methods. We also present evidences that the addition of low doses of an RNA carrier before starting the extraction process improves microRNA purification while an already published carrier dose can result in significant bias over microRNA profiles. Quality controls for best protocol selection were developed by spectrophotometry measurement of contaminants and microfluidics electrophoresis (Agilent 2100 Bioanalyzer) for RNA integrity. Selected donor and patient plasma samples and matched biopsies were tested by Affymetrix microarray technology to compare differentially expressed microRNAs. In summary, this study defines an optimized protocol for microRNA purification from human blood samples, increasing the performance of assays and shedding light over the best way to discover and use these biomarkers in clinical practice.

BACKGROUND: The fear of using topical corticosteroids, usually called topical corticophobia, is a frequent concern for atopic dermatitis patients and/or their parents. Assessing patients' atopic dermatitis and their parents' topical corticosteroid phobia is an essential step to improving adherence to treatment. Because topical corticophobia appears to be a complex phenomenon, its evaluation by binary responses (yes/no) is too simplistic. Thus, a scale is needed, which is capable of identifying the subtleties of topical corticosteroid phobia. OBJECTIVES: To develop and validate a scale, TOPICOP©, measuring worries and beliefs about topical corticosteroids among atopic dermatitis outpatients and their parents. METHODS: An initial statistical validation of TOPICOP was carried out, collecting qualitative data about patients' topical corticophobia behaviors and beliefs using focus-group methodology. Then, 208 outpatients or their parents from five French centers completed a self-administered questionnaire built from focus-group results. The scale-development process comprised an explanatory principal component analysis, Cronbach's α-coefficients and structural equation modeling. RESULTS: The validated questionnaire comprised 12 items, covering two important dimensions relative to "worries" (6 items) and "beliefs" (6 items). Psychometric properties showed that items had very good communality (>0.60) within their own dimension. The final two-factor solution accounted for 47.3% of the variance. Cronbach's α-coefficients were, respectively, 0.79 and 0.78. Structural equation modeling strongly supported the possibility of calculating a global score. CONCLUSIONS: TOPICOP© is the first scale aimed at assessing topical corticophobia in adult patients and parents of children with eczema. TOPICOP® has excellent psychometric properties and should be easy to use in everyday clinical practice for clinicians and researchers. Further studies are needed to confirm our results and validate TOPICOP© in other cultures.

BACKGROUND: Disability-Adjusted Life Years (DALYs) have the advantage that effects on total health instead of on a specific disease incidence or mortality can be estimated. Our aim was to address several methodological points related to the computation of DALYs at an individual level in a follow-up study. METHODS: DALYs were computed for 33,507 men and women aged 20-70 years when participating in the EPIC-NL study in 1993-7. DALYs are the sum of the Years Lost due to Disability (YLD) and the Years of Life Lost (YLL) due to premature mortality. Premature mortality was defined as death before the estimated date of individual Life Expectancy (LE). Different methods to compute LE were compared as well as the effect of different follow-up periods using a two-part model estimating the effect of smoking status on health as an example. RESULTS: During a mean follow-up of 12.4 years, there were 69,245 DALYs due to years lived with a disease or premature death. Current-smokers had lost 1.28 healthy years of their life (1.28 DALYs 95%CI 1.10; 1.46) compared to never-smokers. The outcome varied depending on the method used for estimating LE, completeness of disease and mortality ascertainment and notably the percentage of extinction (duration of follow-up) of the cohort. CONCLUSION: We conclude that the use of DALYs in a cohort study is an appropriate way to assess total disease burden in relation to a determinant. The outcome is sensitive to the LE calculation method and the follow-up duration of the cohort.

The advent of high-throughput technologies such as ChIP-seq has made possible the study of histone modifications. A problem of particular interest is the identification of regions of the genome where different cell types from the same organism exhibit different patterns of histone enrichment. This problem turns out to be surprisingly difficult, even in simple pairwise comparisons, because of the significant level of noise in ChIP-seq data. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods. We correlate the histone marks with gene expression data and confirm that histone modifications H3K27me3 and H3K4me3 act as respectively a repressor and an activator of genes. Compared to what was previously reported in the literature, we find that a substantially higher fraction of bivalent marks in ES cells for H3K27me3 and H3K4me3 move into a K27-only state. We find that most of the promoter regions in protein-coding genes have differential histone-modification sites. The software for this work can be downloaded from http://lcbb.epfl.ch/software.html.

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.

While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR(≥4vs.0): 1.74, 95% CI: 1.20-2.70; number of cases in this category: n = 23). This association was particularly evident for multiple miscarriages (HR(≥4vs.0): 1.99, 95% CI: 1.06-3.73; number of cases in this category: n = 10), with no significant association for multiple induced abortions (HR(≥4vs.0): 1.46, 95% CI: 0.68-3.14; number of cases in this category: n = 7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.

BACKGROUND:Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. METHODOLOGY:The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. PRINCIPAL FINDINGS:We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. CONCLUSIONS:Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism.

Investigating human cognitive faculties such as language, attention, and memory most often relies on testing small and homogeneous groups of volunteers coming to research facilities where they are asked to participate in behavioral experiments. We show that this limitation and sampling bias can be overcome by using smartphone technology to collect data in cognitive science experiments from thousands of subjects from all over the world. This mass coordinated use of smartphones creates a novel and powerful scientific "instrument" that yields the data necessary to test universal theories of cognition. This increase in power represents a potential revolution in cognitive science.

There is a large variation in caloric intake and macronutrient preference between individuals and between ethnic groups, and these food intake patterns show a strong heritability. The transition to new food sources during the agriculture revolution around 11,000 years ago probably created selective pressure and shaped the genome of modern humans. One major player in energy homeostasis is the appetite-stimulating hormone neuropeptide Y, in which the stimulatory capacity may be mediated by the neuropeptide Y receptors 1, 2 and 5 (NPY1R, NPY2R and NPY5R). We assess association between variants in the NPY1R, NPY2R and NPY5R genes and nutrient intake in a cross-sectional, single-center study of 400 men aged 40 to 80 years, and we examine whether genomic regions containing these genes show signatures of recent selection in 270 HapMap individuals (90 Africans, 90 Asians, and 90 Caucasians) and in 846 Dutch bloodbank controls. Our results show that derived alleles in NPY1R and NPY5R are associated with lower carbohydrate intake, mainly because of a lower consumption of mono- and disaccharides. We also show that carriers of these derived alleles, on average, consume meals with a lower glycemic index and glycemic load and have higher alcohol consumption. One of these variants shows the hallmark of recent selection in Europe. Our data suggest that lower carbohydrate intake, consuming meals with a low glycemic index and glycemic load, and/or higher alcohol consumption, gave a survival advantage in Europeans since the agricultural revolution. This advantage could lie in overall health benefits, because lower carbohydrate intake, consuming meals with a low GI and GL, and/or higher alcohol consumption, are known to be associated with a lower risk of chronic diseases.

BACKGROUND:The lactase enzyme allows lactose digestion in fresh milk. Its activity strongly decreases after the weaning phase in most humans, but persists at a high frequency in Europe and some nomadic populations. Two hypotheses are usually proposed to explain the particular distribution of the lactase persistence phenotype. The gene-culture coevolution hypothesis supposes a nutritional advantage of lactose digestion in pastoral populations. The calcium assimilation hypothesis suggests that carriers of the lactase persistence allele(s) (LCT*P) are favoured in high-latitude regions, where sunshine is insufficient to allow accurate vitamin-D synthesis. In this work, we test the validity of these two hypotheses on a large worldwide dataset of lactase persistence frequencies by using several complementary approaches. METHODOLOGY:We first analyse the distribution of lactase persistence in various continents in relation to geographic variation, pastoralism levels, and the genetic patterns observed for other independent polymorphisms. Then we use computer simulations and a large database of archaeological dates for the introduction of domestication to explore the evolution of these frequencies in Europe according to different demographic scenarios and selection intensities. CONCLUSIONS:Our results show that gene-culture coevolution is a likely hypothesis in Africa as high LCT*P frequencies are preferentially found in pastoral populations. In Europe, we show that population history played an important role in the diffusion of lactase persistence over the continent. Moreover, selection pressure on lactase persistence has been very high in the North-western part of the continent, by contrast to the South-eastern part where genetic drift alone can explain the observed frequencies. This selection pressure increasing with latitude is highly compatible with the calcium assimilation hypothesis while the gene-culture coevolution hypothesis cannot be ruled out if a positively selected lactase gene was carried at the front of the expansion wave during the Neolithic transition in Europe.

BACKGROUND: The TUB gene, encoding an evolutionary conserved protein, is highly expressed in the hypothalamus and might act as a transcription factor. Mutations in TUB cause late-onset obesity, insulin-resistance and neurosensory deficits in mice. An association of common variants in the TUB gene with body weight in humans has been reported. METHODS/FINDINGS: The aim was to investigate the relationship of single nucleotide polymorphisms (SNPs) of the TUB gene (rs2272382, rs2272383 and rs1528133) with both anthropometry and self-reported macronutrient intake from a validated food frequency questionnaire. These associations were studied in a population-based, cross-sectional study of 1680 middle-aged Dutch women, using linear regression analysis. The minor allele C of the rs1528133 SNP was significantly associated with increased weight (+1.88 kg, P = 0.022) and BMI (+0.56 units, P = 0.05). Compared with non-carriers, both AG heterozygotes and AA homozygotes of the rs2272382 SNP derived less energy from fat (AG: -0.55+/-0.28%, P = 0.05, AA: -0.95+/-0.48%, P = 0.047). However, both genotypes were associated with an increased energy intake from carbohydrates (0.69+/-0.33%, P = 0.04 and 1.68+/-0.56%, P = 0.003, respectively), mainly because of a higher consumption of mono- and disaccharides. Both these SNPs, rs2272382 and rs1528133, were also associated with a higher glycemic load in the diet. The glycemic load was higher among those with AG and AA genotypes for the variant rs2272382 than among the wild types (+1.49 (95% CI: -0.27-3.24) and +3.89 (95% CI: 0.94-6.85) units, respectively). Carriers of the minor allele C of rs1528133 were associated with an increased glycemic load of 1.85 units compared with non-carriers. CONCLUSIONS: Genetic variation of the TUB gene was associated with both body composition and macronutrient intake, suggesting that TUB might influence eating behavior.