Toward a conceptual framework of health and its operational definition: an application in the 1958 British birth cohort.

BACKGROUND: Defining and measuring Health presents a challenge, partly due to its conceptual pluralism. To measure Health as an ability to adapt and self-manage, we developed an approach within the theoretical framework of resources and reserves over the life course, recently proposed in the literature. We aimed to (i) use the conceptual framework developed to identify indicators of deteriorating health reserves, (ii) construct an overall health measure from these indicators, (iii) evaluate the association between the overall health measure and subsequent health outcomes and (iv) assess the robustness of our method. METHODS: We used data from 7,043 individuals born in 1958 in Great Britain included in the National Child Development Study. An overall health measure was constructed via the sum of three selected indicators of deteriorating health reserves in mid-life: chronic widespread pain (CWP), Clinical Interview Schedule - revised (CIS-r), and allostatic load (AL). A three-category variable was defined: impaired/medium/optimal overall health. We explored criterion validity by modelling the relationships between the overall health measure, or each reserve taken separately at 44-45 years, and self-rated health at 46 years and mortality up to 58 years, corresponding to 14 years of follow up, using Cox and logistic regressions respectively. We performed comparative analyses to assess the robustness of the method. RESULTS: Having an impaired overall health measure was significantly associated with all-cause premature mortality (HRimpaired = 2.74 [1.86; 4.05]) and an increased risk of later fair/poor/very poor self-rated health (ORimpaired = 7.50 [6.29; 8.95]). The overall health measure had a greater effect on the self-rated health estimates than each indicator of deteriorating health reserves considered separately (ORAL medium = 1.82 [1.59; 2.09]; ORAL high = 2.74 [2.37; 3.16]; ORCIS-r = 5.20 [4.45; 6.08]; ORCWP = 2.85 [2.53; 3.21]). CIS-r and allostatic load were also associated with premature mortality contrary to chronic widespread pain (HRAL medium1.82 [1.27; 2.61]; HRAL high = 3.10 [2.19; 4.40]; HRCIS-r = 1.77 [1.22; 2.56]; HRCWP = 1.32 [0.98; 1.76]). The multiple comparative analyses conducted allowed us to assess the robustness of our method within this cohort. CONCLUSIONS: We proposed a method for measuring Health in mid-life in line with the concept of Health as the ability to adapt and self-manage and the concept of health reserves. This method may be applied and further developed within the field of social and positive epidemiology.

The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression.

The human genome contains many thousands of long noncoding RNAs (lncRNAs). While several studies have demonstrated compelling biological and disease roles for individual examples, analytical and experimental approaches to investigate these genes have been hampered by the lack of comprehensive lncRNA annotation. Here, we present and analyze the most complete human lncRNA annotation to date, produced by the GENCODE consortium within the framework of the ENCODE project and comprising 9277 manually annotated genes producing 14,880 transcripts. Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths. In contrast to protein-coding genes, however, lncRNAs display a striking bias toward two-exon transcripts, they are predominantly localized in the chromatin and nucleus, and a fraction appear to be preferentially processed into small RNAs. They are under stronger selective pressure than neutrally evolving sequences-particularly in their promoter regions, which display levels of selection comparable to protein-coding genes. Importantly, about one-third seem to have arisen within the primate lineage. Comprehensive analysis of their expression in multiple human organs and brain regions shows that lncRNAs are generally lower expressed than protein-coding genes, and display more tissue-specific expression patterns, with a large fraction of tissue-specific lncRNAs expressed in the brain. Expression correlation analysis indicates that lncRNAs show particularly striking positive correlation with the expression of antisense coding genes. This GENCODE annotation represents a valuable resource for future studies of lncRNAs.

A comprehensive evaluation of normalization methods for Illumina high-throughput RNA sequencing data analysis.

During the last 3 years, a number of approaches for the normalization of RNA sequencing data have emerged in the literature, differing both in the type of bias adjustment and in the statistical strategy adopted. However, as data continue to accumulate, there has been no clear consensus on the appropriate normalization method to be used or the impact of a chosen method on the downstream analysis. In this work, we focus on a comprehensive comparison of seven recently proposed normalization methods for the differential analysis of RNA-seq data, with an emphasis on the use of varied real and simulated datasets involving different species and experimental designs to represent data characteristics commonly observed in practice. Based on this comparison study, we propose practical recommendations on the appropriate normalization method to be used and its impact on the differential analysis of RNA-seq data.

Aiming for SDAI remission versus low disease activity at 1†year after inclusion in ESPOIR cohort is associated with better 3-year structural outcomes.

OBJECTIVES: Using data for patients with early rheumatoid arthritis (RA) from the ESPOIR cohort, we aimed to evaluate the impact of remission versus low disease activity (LDA) by the Simple Disease Activity Index (SDAI) at 1 year on 3-year structural damage assessed by the modified Sharp-van der Heijde total score (mTSS) and functional impairment assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI). METHODS: We included 625 patients from the ESPOIR cohort who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA at baseline and had an SDAI score at 1 year. mTSS and HAQ-DI scores were compared at 3 years for patients with SDAI remission or LDA status at 1 year. A linear mixed model was used to assess the independent effect of SDAI status at 1 year on mTSS and HAQ-DI at 3 years. RESULTS: Of the 625 patients included (mean (SD) age 48.5 (12.1) years; 491 (78.6%) were women), 121 (19.4%) were in SDAI remission and 223 (35.7%) in LDA at 1 year. The mean (SD) mTSS and HAQ-DI score at 3 years was 9.6 (9.2) and 0.23 (0.42), respectively, for patients in remission at 1 year and 15.8 (16.1) and 0.43 (0.52), respectively, for patients with LDA (both p<0.05). Multivariate analysis revealed an association of remission rather than LDA status at 1 year and reduced mTSS score (p=0.005) but not HAQ-DI score (p=0.4) at 3 years. CONCLUSIONS: Aiming for SDAI remission rather than LDA at 1 year leads to better radiographic outcomes at 3 years in early RA patients.

A unique in vivo experimental approach reveals metabolic adaptation of the probiotic Propionibacterium freudenreichii to the colon environment.

BACKGROUND: Propionibacterium freudenreichii is a food grade bacterium consumed both in cheeses and in probiotic preparations. Its promising probiotic potential, relying largely on the active release of beneficial metabolites within the gut as well as the expression of key surface proteins involved in immunomodulation, deserves to be explored more deeply. Adaptation to the colon environment is requisite for the active release of propionibacterial beneficial metabolites and constitutes a bottleneck for metabolic activity in vivo. Mechanisms allowing P. freudenreichii to adapt to digestive stresses have been only studied in vitro so far. Our aim was therefore to study P. freudenreichii metabolic adaptation to intra-colonic conditions in situ. RESULTS: We maintained a pure culture of the type strain P. freudenreichii CIRM BIA 1, contained in a dialysis bag, within the colon of vigilant piglets during 24 hours. A transcriptomic analysis compared gene expression to identify the metabolic pathways induced by this environment, versus control cultures maintained in spent culture medium.We observed drastic changes in the catabolism of sugars and amino-acids. Glycolysis, the Wood-Werkman cycle and the oxidative phosphorylation pathways were down-regulated but induction of specific carbohydrate catabolisms and alternative pathways were induced to produce NADH, NADPH, ATP and precursors (utilizing of propanediol, gluconate, lactate, purine and pyrimidine and amino-acids). Genes involved in stress response were down-regulated and genes specifically expressed during cell division were induced, suggesting that P. freudenreichii adapted its metabolism to the conditions encountered in the colon. CONCLUSIONS: This study constitutes the first molecular demonstration of P. freudenreichii activity and physiological adaptation in vivo within the colon. Our data are likely specific to our pig microbiota composition but opens an avenue towards understanding probiotic action within the gut in further studies comparing bacterial adaptation to different microbiota.

Ten-year radiographic and functional outcomes in rheumatoid arthritis patients in remission compared to patients in low disease activity.

BACKGROUND: To compare the 10-year structural and functional prognosis between patients in sustained remission versus patients in sustained low disease activity (LDA) in early rheumatoid arthritis (RA). METHODS: We included 256 patients from the ESPOIR cohort who fulfilled the 2010 ACR/EULAR criteria for RA and who were in sustained remission using the Simple Disease Activity Index (SDAI) score (n = 48), in sustained LDA (n = 139) or in sustained moderate to high disease activity (MDA or HDA, n = 69) over 10 years. The mTSSs progression over 10 years and the 10-year HAQ-DI scores were compared between the 3 groups. A longitudinal latent process mixed model was used to assess the independent effect of SDAI status over time on 10-year mTSS progression and HAQ-DI at 10 years. RESULTS: Patients in sustained remission group were younger, had lower baseline HAQ-DI and mTSS scores and were less exposed to glucocorticoids, methotrexate or biologic disease-modifying anti-rheumatic drugs over 10 years. Patients in sustained remission had lower 10-year structural progression (variation of mTSS in the remission group: 4.06 (± 4.75) versus 14.59 (± 19.76) in the LDA group and 21.04 (± 24.08), p < 0.001 in the MDA or HDA groups) and lower 10-year HAQ-DI scores (10-year HAQ-DI in the remission group: 0.14 (± 0.33) versus 0.53 (± 0.49) in the LDA group and 1.20 (± 0.62) in the MDA or HDA groups, p < 0.001). The incidence of serious adverse events over 10 years was low, about 3.34/100 patient years, without any difference between the three groups. CONCLUSION: RA patients in sustained SDAI remission have better long-term structural and functional outcomes in comparison to patients in sustained LDA.

Transcriptomic analysis of intestinal genes following acquisition of pea enation mosaic virus by the pea aphid Acyrthosiphon pisum.

Viruses in the family Luteoviridae are strictly transmitted by aphids in a non-propagative, circulative and persistent mode. Virions ingested by aphids successively cross the gut and the accessory salivary gland epithelia before being released, together with saliva, into the plant vasculature. Virion transport through aphid cells occurs by a transcytosis mechanism. This study conducted a transcriptomic analysis of intestinal genes of the pea aphid Acyrthosiphon pisum following uptake of pea enation mosaic virus. Among the 7166 transcripts analysed, 128 were significantly regulated (105 genes downregulated and 23 upregulated). Of these genes, 5 % were involved in intracellular trafficking, endocytosis and signal transduction, three important steps in the internalization and transport of virions. The limited levels of downregulation (maximum of 3.45-fold) and upregulation (maximum of 1.37-fold) suggest that the virus hijacks a constitutive endocytosis-exocytosis mechanism without heavily perturbing cell metabolism. Although limited to about 20 % of the pea aphid genes, this work represents the first large-scale analysis of aphid gene regulation following virus acquisition. A better knowledge of this virus-vector interaction will be possible only when tools representing the complete genomic capacity of the aphid become available.

Effect of wheat roots infected with the pathogenic fungus Gaeumannomyces graminis var. tritici on gene expression of the biocontrol bacterium Pseudomonas fluorescens Pf29Arp.

Traits contributing to the competence of biocontrol bacteria to colonize plant roots are often induced in the rhizosphere in response to plant components. These interactions have been studied using the two partners in gnotobiotic systems. However, in nature, beneficial or pathogenic fungi often colonize roots. Influence of these plant-fungus interactions on bacterial behavior remains to be investigated. Here, we have examined the influence of colonization of wheat roots by the take-all fungus Gaeumannomyces graminis var. tritici on gene expression of the biocontrol bacterium Pseudomonas fluorescens Pf29Arp. Bacteria were inoculated onto healthy, early G. graminis var. tritici-colonized and necrotic roots and transcriptomes were compared by shotgun DNA microarray. Pf29Arp decreased disease severity when inoculated before the onset of necrosis. Necrotic roots exerted a broader effect on gene expression compared with early G. graminis var. tritici-colonized and healthy roots. A gene encoding a putative type VI secretion system effector was only induced in necrotic conditions. A common pool of Pf29Arp genes differentially expressed on G. graminis var. tritici-colonized roots was related to carbon metabolism and oxidative stress, with a highest fold-change with necrosis. Overall, the data showed that the association of the pathogenic fungus with the roots strongly altered Pf29Arp adaptation with differences between early and late G. graminis var. tritici infection steps.

Using transcriptome profiling to characterize QTL regions on chicken chromosome 5.

BACKGROUND: Although many QTL for various traits have been mapped in livestock, location confidence intervals remain wide that makes difficult the identification of causative mutations. The aim of this study was to test the contribution of microarray data to QTL detection in livestock species. Three different but complementary approaches are proposed to improve characterization of a chicken QTL region for abdominal fatness (AF) previously detected on chromosome 5 (GGA5). RESULTS: Hepatic transcriptome profiles for 45 offspring of a sire known to be heterozygous for the distal GGA5 AF QTL were obtained using a 20 K chicken oligochip. mRNA levels of 660 genes were correlated with the AF trait. The first approach was to dissect the AF phenotype by identifying animal subgroups according to their 660 transcript profiles. Linkage analysis using some of these subgroups revealed another QTL in the middle of GGA5 and increased the significance of the distal GGA5 AF QTL, thereby refining its localization. The second approach targeted the genes correlated with the AF trait and regulated by the GGA5 AF QTL region. Five of the 660 genes were considered as being controlled either by the AF QTL mutation itself or by a mutation close to it; one having a function related to lipid metabolism (HMGCS1). In addition, a QTL analysis with a multiple trait model combining this 5 gene-set and AF allowed us to refine the QTL region. The third approach was to use these 5 transcriptome profiles to predict the paternal Q versus q AF QTL mutation for each recombinant offspring and then refine the localization of the QTL from 31 cM (100 genes) at a most probable location confidence interval of 7 cM (12 genes) after determining the recombination breakpoints, an interval consistent with the reductions obtained by the two other approaches. CONCLUSION: The results showed the feasibility and efficacy of the three strategies used, the first revealing a QTL undetected using the whole population, the second providing functional information about a QTL region through genes related to the trait and controlled by this region (HMGCS1), the third could drastically refine a QTL region.

On the Use of Optimal Transportation Theory to Recode Variables and Application to Database Merging.

Merging databases is a strategy of paramount interest especially in medical research. A common problem in this context comes from a variable which is not coded on the same scale in both databases we aim to merge. This paper considers the problem of finding a relevant way to recode the variable in order to merge these two databases. To address this issue, an algorithm, based on optimal transportation theory, is proposed. Optimal transportation theory gives us an application to map the measure associated with the variable in database A to the measure associated with the same variable in database B. To do so, a cost function has to be introduced and an allocation rule has to be defined. Such a function and such a rule is proposed involving the information contained in the covariates. In this paper, the method is compared to multiple imputation by chained equations and a statistical learning method and has demonstrated a better average accuracy in many situations. Applications on both simulated and real datasets show that the efficiency of the proposed merging algorithm depends on how the covariates are linked with the variable of interest.

Medical prescriptions falsified by the patients: a 12-year national monitoring to assess prescription drug diversion.

Diversion of prescription drugs is difficult to assess in quality and quantity. This study aimed to characterize diversion of prescription drugs in France through a comparative analysis of falsified prescriptions collected during three periods from 2001 to 2012. The data recorded in a national program which records all falsified prescriptions presented to community pharmacies were studied. Included data regarded: subjects, prescription forms, and drugs. Description of the dataset in three periods (2001-2004, 2005-2008, and 2009-2012) was completed with clustering analyses to characterize profiles of prescriptions and subjects associated with the most reported drugs. The 4469 falsified prescriptions concerned most often females (51.6%). Average age was 46.5 years. Zolpidem, bromazepam, and buprenorphine were the most frequent drugs. Alone, 13 drugs (1.7%, 13/772) represented more than 40% of the total reports (3055/7272). They were associated with three diversion profiles: (i) buprenorphine, flunitrazepam, and morphine were mentioned on overlapping secure prescription forms presented by young men; (ii) alprazolam, bromazepam, zolpidem, codeine/acetaminophen were mentioned on simple prescription forms presented by experienced women; and (iii) acetaminophen and lorazepam were mentioned on modified prescription forms presented by elderly subjects. Clonazepam, clorazepate, dextropropoxyphene, zopiclone moved between those profiles. The patterns of falsified prescriptions provided in this study contribute to enhance the scientific knowledge on the most diverted prescription drugs. The latter follow distinct trajectories across time depending on their pharmacology (including their abuse/addiction potential) and on their regulation's history. The close and continuous analysis of falsified prescriptions is an excellent way to monitor prescription drug diversion.

Diagnostic accuracy in field conditions of the sickle SCAN® rapid test for sickle cell disease among children and adults in two West African settings: the DREPATEST study.

BACKGROUND: Sickle cell disease (SCD) accounts for 5% of mortality in African children aged < 5 years. Improving the care management and quality of life of patients with SCD requires a reliable diagnosis in resource-limited settings. We assessed the diagnostic accuracy of the rapid Sickle SCAN® point-of-care (POC) test for SCD used in field conditions in two West-African countries. METHODS: We conducted a case-control study in Bamako (Mali) and Lomé (Togo). Known cases of sickle cell disease (HbSS, HbSC), trait (HbAS), HbC heterozygotes (HbAC) and homozygous (HbCC), aged ≥6 months were compared to Controls (HbAA), recruited by convenience. All subjects received both an index rapid POC test and a gold standard (high-performance liquid chromatography in Bamako; capillary electrophoresis in Lomé). Personnel conducting tests were blinded from subjects' SCD status. Sensitivity and specificity were calculated for each phenotype. Practicality was assessed by local healthcare professionals familiar with national diagnostic methods and their associated constraints. RESULTS: In Togo, 209 Cases (45 HbAS, 39 HbAC, 41 HbSS, 44 HbSC and 40 HbCC phenotypes) were compared to 86 Controls (HbAA). 100% sensitivity and specificity were observed for AA Controls and HbCC cases. Estimated sensitivity was 97.7% [95% confidence interval: 88.0-99.9], 97.6% [87.1-99.9%], 95.6% [84.8-99.5%], and 94.9% [82.7-99.4], for HbSC, HbSS, HbAS, and HbAC, respectively. Specificity exceeded 99.2% for all phenotypes. Among 160 cases and 80 controls in Mali, rapid testing was 100% sensitive and specific. Rapid testing was well accepted by local healthcare professionals. CONCLUSION: Rapid POC testing is 100% accurate for homozygote healthy people and excellent (Togo) or perfect (Mali) for sickle cell trait and disease patients. In addition to its comparable diagnostic performance, this test is cheaper, easier to implement, and logistically more convenient than the current standard diagnostic methods in use. Its predictive value indicators and diagnostic accuracy in newborns should be further evaluated prior to implementation in large-scale screening programs in resource-limited settings where SCD is prevalent.

Transcriptomic profiling of the reproductive mode switch in the pea aphid in response to natural autumnal photoperiod.

Aphids are among the rare organisms that can change their reproductive mode across their life cycle. During spring and summer they reproduce clonally and efficiently by parthenogenesis. At the end of summer aphids perceive the shortening of day length which triggers the production of sexual individuals - males and oviparous females - that will mate and lay overwintering cold-resistant eggs. Recent large scale transcriptomic studies allowed the discovery of transcripts and functions such as nervous and hormonal signaling involved in the early steps of detection and transduction of the photoperiodic signal. Nevertheless these experiments were performed under controlled conditions when the photoperiod was the only varying parameter. To characterize the response of aphids under natural conditions, aphids were reared outdoor both in summer and autumn and material was collected to compare their transcriptomic profile using a cDNA microarray containing around 7000 transcripts. Statistical analyses revealed that close to 5% of these transcripts (367) were differentially expressed at two developmental stages of the process in response to the autumnal environmental conditions. Functional classification of regulated transcripts confirmed the putative contribution of the neuro-endocrine system in the process. Furthermore, these experiments revealed the regulation of transcripts involved in juvenile hormone synthesis and signaling pathway, confirming the key role played by these molecules in the reproductive mode switch. Aphids placed under outdoor conditions were confronted to a range of abiotic factors such as temperature fluctuations which was confirmed by the differential expression of an important proportion of heat shock protein transcripts between the two seasons. Finally, this original approach completed the understanding of genetic programs involved in aphid phenotypic plasticity.

Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC).

BACKGROUND: Body weight and body mass index (BMI) are positively related to risk of colon cancer in men, whereas weak or no associations exist in women. This discrepancy may be related to differences in fat distribution between sexes or to the use of hormone replacement therapy (HRT) in women. METHODS: We used multivariable adjusted Cox proportional hazards models to examine the association between anthropometric measures and risks of colon and rectal cancer among 368 277 men and women who were free of cancer at baseline from nine countries of the European Prospective Investigation Into Cancer and Nutrition. All statistical tests were two-sided. RESULTS: During 6.1 years of follow-up, we identified 984 and 586 patients with colon and rectal cancer, respectively. Body weight and BMI were statistically significantly associated with colon cancer risk in men (highest versus lowest quintile of BMI, relative risk [RR] = 1.55, 95% confidence interval [CI] = 1.12 to 2.15; P(trend) = .006) but not in women. In contrast, comparisons of the highest to the lowest quintile showed that several anthropometric measures, including waist circumference (men, RR = 1.39, 95% CI = 1.01 to 1.93; P(trend) = .001; women, RR = 1.48, 95% CI = 1.08 to 2.03; P(trend) = .008), waist-to-hip ratio (WHR; men, RR = 1.51, 95% CI = 1.06 to 2.15; P(trend) = .006; women, RR = 1.52, 95% CI = 1.12 to 2.05; P(trend) = .002), and height (men, RR = 1.40, 95% CI = 0.99 to 1.98; P(trend) = .04; women, RR = 1.79, 95% CI = 1.30 to 2.46; P(trend)<.001) were related to colon cancer risk in both sexes. The estimated absolute risk of developing colon cancer within 5 years was 203 and 131 cases per 100,000 men and 129 and 86 cases per 100,000 women in the highest and lowest quintiles of WHR, respectively. Upon further stratification, no association of waist circumference and WHR with risk of colon cancer was observed among postmenopausal women who used HRT. None of the anthropometric measures was statistically significantly related to rectal cancer. CONCLUSIONS: Waist circumference and WHR, indicators of abdominal obesity, were strongly associated with colon cancer risk in men and women in this population. The association of abdominal obesity with colon cancer risk may vary depending on HRT use in postmenopausal women; however, these findings require confirmation in future studies.