Improvement of cardiovascular risk prediction: time to review current knowledge, debates, and fundamentals on how to assess test characteristics.

Cardiovascular risk assessment might be improved with the addition of emerging, new tests derived from atherosclerosis imaging, laboratory tests or functional tests. This article reviews relative risk, odds ratios, receiver-operating curves, posttest risk calculations based on likelihood ratios, the net reclassification improvement and integrated discrimination. This serves to determine whether a new test has an added clinical value on top of conventional risk testing and how this can be verified statistically. Two clinically meaningful examples serve to illustrate novel approaches. This work serves as a review and basic work for the development of new guidelines on cardiovascular risk prediction, taking into account emerging tests, to be proposed by members of the 'Taskforce on Vascular Risk Prediction' under the auspices of the Working Group 'Swiss Atherosclerosis' of the Swiss Society of Cardiology in the future.

Occupational exposure to solar ultraviolet radiation of outdoor workers in France

Question: Outdoor occupational exposure could be associated with important cumulative and intense exposure to ultraviolet (UV) solar radiation. Such exposure would increase risk of skin cancer. However, little information exists on jobs associated with intense UV exposure. The objective of this study was to characterise occupational UV exposure in a representative sample in France. Methods: A population-based survey was conducted in May-June 2012 through computer-assisted telephonic interviews in population 25 to 69 years of age. Individual UV irradiation was computed with declared time and place of residence matched to UV records from satellite measurement (Eurosun project). We analysed factors influencing exposure to UV (annual average and seasonal peak). Results: A total of 1442 individuals declared having an occupational exposure to UV which represents 18% of population aged 25 to 69 years. Outdoor workers were more frequently men (58%), aged 40-54 (43%), with a phototype III or IV (69%). Occupations associated with highest UV exposure were: construction workers (annual daily average 62.8 Joules/m2), gardeners (62.6), farmers (52.8), culture/art/social sciences workers (52.0) and transport workers/mail carriers (49.5). The maximum of UVA exposure was found for occupation with a strong seasonality of exposure: culture, art or social sciences works (98.1 Joules/m2), construction works (97.2), gardening (96.7) and farming (95.0). Significant factors associated with high occupational UV exposure were gender (men vs. women: 53.6 vs. 42.6), phototype (IV vs. I: 51.9 vs. 45.5) and taking lunch outdoors (always vs. never: 59.8 vs. 48.6). Conclusion: Our study showed that some occupations were associated with particularly intense UV exposure such as farmers, gardeners, construction workers. Other unexpected occupations were also associated with high UV exposure such as transport workers, mail carriers and culture/art/social sciences workers.

Risk factors of sunburns from occupational sun exposure in outdoor workers

Question: Outdoor workers can be exposed to intense ultraviolet (UV) solar radiation likely to results to sunburns. As sunburn is an important risk factor for skin cancer, in particular melanoma, we investigated the causes of occupational sunburns (OS) in French outdoor workers. Methods: A population-based survey was conducted in May-June 2012 through computer-assisted telephonic interviews in population 25 to 69 years of age. History of sunburn from occupational exposure within the year preceding interview was collected. We analysed the risk of OS in multivariate logistic regression. Results: Out of 1442 individuals who declared having an occupational exposure to solar UV radiation, 403 (27.9%) reported a sunburn from occupational exposure in the year preceding the interview. Sunburns were more frequent in women (30% vs. 26.4% in men although not significant p = 0.14), in younger workers (p = 0.0099), in sensitive phototype (40% in phototype I/II vs. 23% in phototype III/IV, p < 0.001) and in workers taking lunch outdoor (p = 0.0355). Some occupations were more associated with OS (more than 30%): health occupations, managing, research/engineering, construction workers and culture/art/social sciences workers. In multivariate analysis, risk factors for OS are phototype (I vs. IV, OR = 4.30 95% CI [2.65-6.98]), sunburn during leisure time (OR = 3.46 95% CI [2.62-4.59]), seasonality of exposure (seasonal vs. constant exposure OR = 1.36 95% CI [1.02-1.81] and annual UVA exposure (OR for 10J/m² daily average increment 1.08 95% CI [1.02-1.14]). In multivariate analysis the type of occupation was not associated with increased OS. Conclusion: Sunburns from occupation was also observed in non sensitive population, phototype IV, which shows that outdoor workers are potentially exposed to intense UV radiations. This study suggests that prevention should target UV sensitive outdoor workers as well as those cumulating intense UV exposure.

Subclinical Thyroid Dysfunction and the Risk of Heart Failure in Older Persons at High Cardiovascular Risk.

Context: Subclinical thyroid dysfunction is common in older people. However, its clinical importance is uncertain. Objective: Our objective was to determine the extent to which subclinical hyperthyroidism and hypothyroidism influence the risk of heart failure and cardiovascular diseases in older people. Setting and Design: The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) is an prospective cohort study. Patients: Patients included men and women aged 70-82 yr (n = 5316) with known cardiovascular risk factors or previous cardiovascular disease. Main Outcome Measures: Incidence rate of heart failure hospitalization, atrial fibrillation, and cardiovascular events and mortality according to baseline thyroid status were evaluated. Euthyroid participants (TSH =0.45-4.5 mIU/liter) were compared with those with subclinical hyperthyroidism (TSH <0.45 mIU/liter) and those with subclinical hypothyroidism (TSH ≥4.5 mIU/liter, both with normal free T(4)). Results: Subclinical hyperthyroidism was present in 71 participants and subclinical hypothyroidism in 199 participants. Over 3.2 yr follow-up, the rate of heart failure was higher for subclinical hyperthyroidism compared with euthyroidism [age- and sex-adjusted hazard ratio (HR) = 2.93, 95% confidence interval (CI) = 1.37-6.24, P = 0.005; multivariate-adjusted HR = 3.27, 95% CI = 1.52-7.02, P = 0.002). Subclinical hypothyroidism (only at threshold >10 mIU/liter) was associated with heart failure (age- and sex-adjusted HR = 3.01, 95% CI = 1.12-8.11, P = 0.029; multivariate HR = 2.28, 95% CI = 0.84-6.23). There were no strong evidence of an association between subclinical thyroid dysfunction and cardiovascular events or mortality, except in those with TSH below 0.1 or over 10 mIU/liter and not taking pravastatin. Conclusion: Older people at high cardiovascular risk with low or very high TSH along with normal free T(4) appear at increased risk of incident heart failure.

Brief alcohol intervention as pragmatic intervention: Who is voluntarily taking an offered intervention?

Brief alcohol interventions (BAI) have shown the potential to decrease problematic alcohol use among adolescents and young adults. Most of the BAI studies have been efficacy trials designed to achieve high internal validity but have raised questions regarding the feasibility of large-scale implementation. Providing interventions for those voluntarily wanting them might offer an alternative, and studies using this design would be more similar to effectiveness studies. The present research compares randomly selected 20-year-old men who took part in a scientific trial (efficacy) with those who voluntarily sought an intervention (effectiveness). Sampling took place during army recruitment procedures that are mandatory for all males in Switzerland. At-risk drinking (20+ drinks per week, or more than one risky drinking occasion of 6+ drinks per month) was determined a posteriori; there was no screening. There were a higher percentage of at-risk drinkers in the volunteer arm at baseline, but at-risk drinkers did not differ from those in the trial arm on any of the assessed alcohol measures. This suggests that offering BAI on a large-scale, voluntary basis may reach at-risk drinkers as effectively as do more scientifically oriented trials, without needing to adhere to screening and stringent research procedures. Nevertheless, BAI was more effective for at-risk drinkers who were invited for trial participation versus those who volunteered. This could be due to behavior that is already consolidated and is difficult to change. Lacking further modifications, real-world implementations of BAI for young men may be less effective than randomized controlled trials designed to test the efficacy of BAI.

Regulation of sodium transport in the cortical collecting duct : physiological role of GILZ in vitro and in vivo : characterisation of Na+ transport in the mCCDcl1 cell line

SUMMARY Regulation of sodium excretion by the kidney is a key mechanism in the long term regulation of blood pressure, and when altered it constitutes a risk factor for the appearance of arterial hypertension. Aldosterone, which secretion depends upon salt intake in the diet, is a steroid hormone that regulates sodium reabsorption in the distal part of the nephron (functional unit of the kidney) by modulating gene transcription. It has been shown that it can act synergistically with the peptidic hormone insulin through the interaction of their signalisation pathways. Our work consisted of two distinct parts: 1) the in vitro and in vivo characterisation of Glucocorticoid-Induced Leucine Zipper (GILZ) (an aldosterone-induced gene) mechanism of action; 2) the in vitro characterisation of insulin mechanism of action and its interaction with aldosterone. GILZ mRNA, coded by the TSC22D3 gene, is strongly induced by aldosterone in the cell line of principal cells of the cortical collecting duct (CCD) mpkCCDc14, suggesting that GILZ is a mediator of aldosterone response. Co-expression of GILZ and the amiloride-sensitive epithelial sodium channel ENaC in vitro in the Xenopus oocyte expression system showed that GILZ has no direct effect on the ENaC-mediated Na+ current in basal conditions. To define the role of GILZ in the kidney and in other organs (colon, heart, skin, etc.), a conditional knock-out mouse is being produced and will allow the in vivo study of its role. Previous data showed that insulin induced a transepithelial sodium transport at supraphysiological concentrations. Insulin and the insulin-like growth factor 1 (IGF-1) are able to bind to each other receptor with an affinity 50 to 100 times lower than to their cognate receptor. Our starting hypothesis was that the insulin effect observed at these supraphysiological concentrations is actually mediated by the IGF receptor type 1 (IGF-1R). In a new cell line that presents all the characteristics of the principal cells of the CCD (mCCDc11) we have shown that both insulin and IGF-1 induce a physiologically significant increase of Na+ transport through the activation of IGF-1R. Aldosterone and insulin/IGF-1 have an additive effect on Na+ transport, through the activation of the PI3-kinase (PI3-K) pathway and the phosphorylation of the serum- and glucocorticoid-induced kinase 1 (Sgk1) by the IGF-1R, and the induction of Sgk1 expression by aldosterone. Thus, Sgk1 integrates IGF-1/insulin and aldosterone effects. We suggest that IGF-1 is physiologically relevant in the modulation of sodium balance, while insulin can only regulate Na+ transport at supraphysiological conditions. Both hormones would bind to the IGF-1R and induce Na+ transport by activating the PI3-K PDK1/2 - Sgk1 pathway. We have shown for the first time that Sgk1 is expressed and phosphorylated in principal cells of the CCD in basal conditions, although the mechanism that maintains Sgk1 phosphorylation is not known. This new role for IGF-1 suggests that it could be a salt susceptibility gene. In effect, IGF-1 stimulates Na+ and water transport in the kidney in vivo. Moreover, 35 % of the acromegalic patients (overproduction of growth hormone and IGF-1) are hypertensives (higher proportion than in normal population), and genetic analysis suggest a link between the IGF-1 gene locus and blood pressure. RÉSUMÉ La régulation de l'excrétion rénale de sodium (Na+) joue un rôle principal dans le contrôle à long terme de la pression sanguine, et ses altérations constituent un facteur de risque de l'apparition d'une hypertension artérielle. L'aldosterone, dont la sécrétion dépend de l'apport en sel dans la diète, est une hormone stéroïdienne qui régule la réabsorption de Na+ dans la partie distale du nephron (unité fonctionnelle du rein) en contrôlant la transcription de gènes. Elle peut agir de façon synergistique avec l'hormone peptidique insuline, probablement via l'interaction de leurs voies de signalisation cellulaire. Le but de notre travail comportait deux volets: 1) caractériser in vitro et in vivo le mécanisme d'action du Glucocorticoid Induced Leucine Zipper (GILZ) (un gène induit par l'aldosterone); 2) caractériser in vitro le mécanisme d'action de l'insuline et son interaction avec l'aldosterone. L'ARNm de GILZ, codé par le gène TSC22D3, est induit par l'aldosterone dans la lignée cellulaire de cellules principales du tubule collecteur cortical (CCD) mpkCCDc14, suggérant que GILZ est un médiateur potentiel de la réponse à l'aldosterone. La co-expression in vitro de GILZ et du canal à Na+ sensible à l'amiloride ENaC dans le système d'expression de l'oocyte de Xénope a montré que GILZ n'a pas d'effet sur les courants sodiques véhiculées par ENaC en conditions basales. Une souris knock-out conditionnelle de GILZ est en train d'être produite et permettra l'étude in vivo de son rôle dans le rein et d'autres organes. Des expériences préliminaires ont montré que l'insuline induit un transport transépithelial de Na+ à des concentrations supraphysiologiques. L'insuline et l'insulin-like growth factor 1 (IGF-1) peuvent se lier à leurs récepteurs réciproques avec une affinité 50 à 100 fois moindre qu'à leur propre récepteur. Nous avons donc proposé que l'effet de l'insuline soit médié par le récepteur à l'IGF type 1 (IGF-1R). Dans une nouvelle lignée cellulaire qui présente toutes les caractéristiques des cellules principales du CCD (mCCDc11) nous avons montré que les deux hormones induisent une augmentation physiologiquement significative du transport du Na+ par l'activation des IGF-1 R. Aldosterone et insuline/IGF-1 ont un effet additif sur le transport de Na+, via l'activation de la voie de la PI3-kinase et la phosphorylation de la serum- and glucocorticoid-induced kinase 1 (Sgk1) par l'IGF-1R, dont l'expression est induite par l'aldosterone. Sgk1 intègre les effets de l'insuline et l'aldosterone. Nous proposons que l'IGF-1 joue un rôle dans la modulation physiologique de la balance sodique, tandis que l'insuline régule le transport de Na+ à des concentrations supraphysiologiques. Les deux hormones agissent en se liant à l'IGF-1R et induisent le transport de Na+ en activant la cascade de signalisation PI3-K - PDK1/2 - Sgk1. Nous avons montré pour la première fois que Sgk1 est exprimée et phosphorylée dans des conditions basales dans les cellules principales du CCD, mais le mécanisme qui maintient sa phosphorylation n'est pas connu. Ce nouveau rôle pour l'IGF-1 suggère qu'il pourrait être un gène impliqué de susceptibilité au sel. Aussi, l'IGF-1 stimule le transport rénal de Na+ in vivo. De plus, 35 % des patients atteints d'acromégalie (surproduction d'hormone de croissance et d'IGF-1) sont hypertensifs (prévalence plus élevée que la population normale), et des analyses génétiques suggèrent un lien entre le locus du gène de l'IGF-1 et la pression sanguine. RÉSUMÉ GRAND PUBLIC Nos ancêtres se sont génétiquement adaptés pendant des centaines de millénaires à un environnement pauvre en sel (chlorure de sodium) dans la savane équatoriale, où ils consommaient moins de 0,1 gramme de sel par jour. On a commencé à ajouter du sel aux aliments avec l'apparition de l'agriculture (il y a 5000 à 10000 années), et aujourd'hui une diète omnivore, qui inclut des plats préparés, contient plusieurs fois la quantité de sodium nécessaire pour notre fonction physiologique normale (environ 10 grammes par jour). Le corps garde sa concentration constante dans le sang en s'adaptant à une consommation très variable de sel. Pour ceci, il module son excrétion soit directement, soit en sécrétant des hormones régulatrices. Le rein joue un rôle principal dans cette régulation puisque l'excrétion urinaire de sel change selon la diète et peut aller d'une quantité dérisoire à plus de 36 grammes par jour. L'attention qu'on prête au sel est liée à sa relation avec l'hypertension essentielle. Ainsi, le contrôle rénal de l'excrétion de sodium et d'eau est le principal mécanisme dans la régulation de la pression sanguine, et une ingestion excessive de sel pourrait être l'un des facteurs-clé déclenchant l'apparition d'un phénotype hypertensif. L'hormone aldosterone diminue l'excrétion de sodium par le rein en modulant l'expression de gènes qui pourraient être impliqués dans la sensibilité au sel. Dans une lignée cellulaire de rein l'expression du gène TSC22D3, qui se traduit en la protéine Glucocorticoid Induced Leucine Zipper (GILZ), est fortement induite par l'aldosterone. Ceci suggère que GILZ est un médiateur potentiel de l'effet de l'aldosterone, et pourrait être impliqué dans la sensibilité au sel. Pour analyser la fonction de GILZ dans le rein plusieurs approches ont été utilisées. Par exemple, une souris dans laquelle GILZ est spécifiquement inactivé dans le rein est en train d'être produite et permettra l'étude du rôle de GILZ dans l'organisme. De plus, on a montré que GILZ, en conditions basales, n'a pas d'effet direct sur la protéine transportant le sodium à travers la membrane des cellules, le canal sodique épithélial ENaC. On a aussi essayé de trouver des protéines qui interagissent directement avec GILZ utilisant une technique appelée du « double-hybride dans la levure », mais aucun candidat n'a émergé. Des études ont montré que, à de hautes concentrations, l'insuline peut aussi diminuer l'excrétion de sodium. A ces concentrations, elle peut activer son récepteur spécifique, mais aussi le récepteur d'une autre hormone, l'Insulin-Like Growth Factor 1 (IGF-1). En plus, l'infusion d'IGF-1 augmente la rétention rénale de sodium et d'eau, et des mutations du gène codant pour l'IGF-1 sont liées aux différents niveaux de pression sanguine. On a utilisé une nouvelle lignée cellulaire de rein développée dans notre laboratoire, appelée mCCDc11, pour analyser l'importance relative des deux hormones dans l'induction du transport de sodium. On a montré que les deux hormones induisent une augmentation significative du transport de sodium par l'activation de récepteurs à l'IGF-1 et non du récepteur à l'insuline. On a montré qu'à l'intérieur de la cellule leur activation induit une augmentation du transport sodique par le biais du canal ENaC en modifiant la quantité de phosphates fixés sur la protéine Serumand Glucocorticoid-induced Kinase 1 (Sgk1). On a finalement montré que l'IGF-1 et l'aldosterone ont un effet additif sur le transport de sodium en agissant toutes les deux sur Sgk1, qui intègre leurs effets dans le contrôle du transport de sodium dans le rein.

Taking the fungal highway: mobilization of pollutant-degrading bacteria by fungi.

The capacity of fungi to serve as vectors for the dispersion of pollutant-degrading bacteria was analyzed in laboratory model systems mimicking water-saturated (agar surfaces) and unsaturated soil environments (glass-bead-filled columns). Two common soil fungi (Fusarium oxysporum and Rhexocercosporidium sp.) forming hydrophilic and hydrophobic mycelia, respectively, and three polycyclic aromatic hydrocarbon degrading bacteria (Achromobacter sp. SK1, Mycobacterium frederiksbergense LB501TG, and Sphingomonas sp. L138) were selected based on the absence of mutual antagonistic effects. It was shown that fungal hyphae act as vectors for bacterial transport with mobilization strongly depending on the specific microorganisms chosen: The motile strain Achromobacter sp. SK1 was most efficiently spread along hyphae of hydrophilic F. oxysporum in both model systems with transport velocities of up to 1 cm d(-1), whereas no dispersion of the two nonmotile strains was observed in the presence of F. oxysporum. By contrast, none of the bacteria was mobilized along the hydrophobic mycelia of Rhexocercosporidium sp. growing on agar surfaces. In column experiments however, strain SK1 was mobilized by Rhexocercosporidium sp. It is hypothesized that bacteria may move by their intrinsic motilitythrough continuous (physiological) liquid films forming around fungal hyphae. The results of this study suggest that the specific stimulation of indigenous fungi may be a strategy to mobilize pollutant-degrading bacteria leading to their homogenization in polluted soil thereby improving bioremediation.

Corrigendum : Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Absorption, transport and storage of iron are tightly regulated, as expected for an element, which is both essential and potentially toxic. Iron deficiency is the leading cause of anaemia, and it also compromises immune function and cognitive development. Iron overload damages the liver and other organs in hereditary hemochromatosis, and in thalassaemia patients with both transfusion and non-transfusionrelated iron accumulation. Excess iron has harmful effects in chronic liver diseases caused by excessive alcohol, obesity or viruses. There is evidence for involvement of iron in neurodegenerative diseases and in Type 2 diabetes. Variation in transferrin saturation, a biomarker of iron status, has been associated with mortality in patients with diabetes and in the general population13. All these associations between iron and either clinical disease or pathological processes make it important to understand the causes of variation in iron status. Importantly, information on genetic causes of variation can be used in Mendelian randomization studies to test whether variation in iron status is a cause or consequence of disease. We have used biomarkers of iron status (serum iron, transferrin, transferrin saturation and ferritin), which are commonly used clinically and readily measurable in thousands of individuals, and carried out a meta-analysis of human genomewide association study (GWAS) data from 11 discovery and eight replication cohorts. Our aims were to identify additional loci affecting markers of iron status in the general population and to relate the significant loci to information on gene expression to identify relevant genes. We also made an initial assessment of whether any such loci affect iron status in HFE C282Y homozygotes, who are at genetic risk of HFE-related iron overload (hereditary hemochromatosis type 1, OMIM #235200)

Quality of Disease Management and Risk of Mortality in English Primary Care Practices

OBJECTIVE: To investigate whether better management of chronic conditions by family practices reduces mortality risk. DATA: Two random samples of 5 million patients registered with over 8,000 English family practices followed up for 4 years (2004/5-2007/8). Measures of the quality of disease management for 10 conditions were constructed for each family practice for each year. The outcome measure was an indicator taking the value 1 if the patient died during a specified year, 0 otherwise. STUDY DESIGN: Cross-section and multilevel panel data multiple logistic regressions were estimated. Covariates included age, gender, morbidity, hospitalizations, attributed socio-economic characteristics, and local health care supply measures. PRINCIPAL FINDINGS: Although a composite measure of the quality of disease management for all 10 conditions was significantly associated with lower mortality, only the quality of stroke care was significant when all 10 quality measures were entered in the regression. CONCLUSIONS: The panel data results suggest that a 1 percent improvement in the quality of stroke care could reduce the annual number of deaths in England by 782 [95 percent CI: 423, 1140]. A longer study period may be necessary to detect any mortality impact of better management of other conditions.