Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population

The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome--a subset of the metabolome--and, using targeted proteomics, quantified a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein, and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, Dhtkd1 was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans. These integrated molecular profiles also allowed further characterization of complex pathways, particularly the mitochondrial unfolded protein response (UPR(mt)). UPR(mt) shows strikingly variant responses at the transcript and protein level that are remarkably conserved among C. elegans, mice, and humans. Overall, these examples demonstrate the value of an integrated multilayered omics approach to characterize complex metabolic phenotypes.

A Single High Dose of Oral Vitamin D3 Is Not Enough to Correct Insufficiency and Deficiency in a Rheumatologic Population

Introduction: Vitamin D plays a major role in bone metabolism and neuromuscular function. Supplementation with vitamin D is effective to reduce the risk of fall and of fracture. However adherence to oral daily vitamin D supplementation is low. Screening and correcting vitamin D insufficiency in a general rheumatologic population could improve both morbidity and quality of life in these patients with chronic painful disorders and at high risk of osteoporosis. After determining the prevalence of vitamin D deficiency in this population, we evaluated if supplementation with a single high dose of oral 25-OH vitamin D3 was sufficient to correct this abnormality. Methods: During one month (November 2009), levels of 25-OH vitamin D were systematically determined in our rheumatology outpatient clinic and classified into three groups: vitamin D deficiency (<10 μg/l), vitamin D insufficiency (10 to 30 μg/l) or normal vitamin D (>30 μg/l). Patients with insufficiency or deficiency received respectively a single high dose of 300000 IU or 600000 IU oral vitamin D3. In addition, all patients with osteoporosis were prescribed daily supplement of calcium (1 g) and vitamin D (800 IU). 25-OH vitamin D levels were reevaluated after 3 months. Results: Vitamin D levels were initially determined in 292 patients (mean age 53, 211 women, 87% Caucasian). 77% had inflammatory rheumatologic disease (IRD), 20% osteoporosis (OP) and 12% degenerative disease (DD). Vitamin D deficiency was present in 20 (6.8%), while 225 (77.1%) had insufficiency. Of the 245 patients with levels <30 μg/l, a new determination of vitamin D level was available in 173 (71%) at 3 months. Conclusion: Vitamin D insufficiency is highly prevalent in our rheumatologic population (84%), and is not adequately corrected by a single high dose of oral vitamin D3 in more than half of the patients with IRD and DD. In patients with OP, despite association of a single high dose with daily oral vitamin D supplementation, 40% of patients are still deficient when reevaluated at 3 months.

Sex allocation and sex-dependent selection for body size in Trypoxylon rogenhoferi Kohl (Hymenoptera, Sphecidae)

Two populations of the wasp Trypoxylon rogenhoferi Kohl, 1884 from São Carlos and Luís Antônio, State of São Paulo, Brazil, were observed and sampled from May 1999 to February 2001 using trap-nests. This mass-provisioning wasp was used to test some aspects of optimal sex allocation theory. Both populations fit all the predictions of the models of Green and Brockmann and Grafen. Maternal provisions determined the size of each offspring, and females allocated well-stocked brood cells to daughters, the sex that benefits most being large. This strategy resulted in a difference in size between the sexes. In São Carlos, female weight at emergence was 1.18 times that of males, in Luís Antônio this value was 1.13. The brood cell volume was correlated with both wing length and weight at emergence in both sexes, and the chance that a given brood cell contained a male offspring decreased with increased brood cell volume. In T. rogenhoferi female body size was related to fitness. Larger females were able to collect more mass of spiders per day, the spiders they captured were heavier, and they provisioned more brood cells per day. They also produced larger daughters. For males, no relationship between body size and fitness was found, but the data were scarce. Since the patterns of provisioning were variable among different females in both study sites, it is possible that the females not follow a unique strategy for sex allocation. The sex ratio and/or investment ratio in the São Carlos population was female-biased and in Luís Antônio, male-biased. In spite of the influence of trap-nests diameters on male production in Luís Antônio, there is some evidence that in São Carlos population the local availability of prey and/or lower rate of parasitism may be major forces in determining the observed sex ratio, but further studies are necessary to verify such hypothesis.

Prediction of myocardial infarction size using the SYNTAX score in patients treated with primary percutaneous coronary intervention for acute ST- segment elevation myocardial infarction

Objectives The relevance of the SYNTAX score for the particular case of patients with acute ST- segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI)  has previously only been studied in the setting of post hoc analysis of large prospective randomized clinical trials. A "real-life" population approach has never been explored before. The aim of this study was to evaluate the impact of the SYNTAX score for the prediction of the myocardial infarction size, estimated by the creatin-kinase (CK) peak value, using the SYNTAX score in patients treated with primary coronary intervention for acute ST-segment elevation myocardial infarction. Methods The primary endpoint of the study was myocardial infarction size as measured by the CK peak value. The SYNTAX score was calculated retrospectively in 253 consecutive patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) in a large tertiary referral center in Switzerland, between January 2009 and June 2010. Linear regression analysis was performed to compare myocardial infarction size with the SYNTAX score. This same endpoint was then stratified according to SYNTAX score tertiles: low <22 (n=178), intermediate [22-32] (n=60), and high >=33 (n=15). Results There were no significant differences in terms of clinical characteristics between the three groups. When stratified according to the SYNTAX score tertiles, average CK peak values of 1985 (low<22), 3336 (intermediate [22-32]) and 3684 (high>=33) were obtained with a p-value <0.0001. Bartlett's test for equal variances between the three groups was 9.999 (p-value <0.0067). A moderate Pearson product-moment correlation coefficient (r=0.4074) with a high statistical significance level (p-value <0.0001) was found. The coefficient of determination (R^2=0.1660) showed that approximately 17% of the variation of CK peak value (myocardial infarction size) could be explained by the SYNTAX score, i.e. by the coronary disease complexity. Conclusion In an all-comers population, the SYNTAX score is an additional tool in predicting myocardial infarction size in patients treated with primary percutaneous coronary intervention (PPCI). The stratification of patients in different risk groups according to SYNTAX enables to identify a high-risk population that may warrant particular patient care.

Spanning tests in return and stochastic discount factor mean-variance frontiers: A unifying approach

We propose new spanning tests that assess if the initial and additional assets share theeconomically meaningful cost and mean representing portfolios. We prove their asymptoticequivalence to existing tests under local alternatives. We also show that unlike two-step oriterated procedures, single-step methods such as continuously updated GMM yield numericallyidentical overidentifyng restrictions tests, so there is arguably a single spanning test.To prove these results, we extend optimal GMM inference to deal with singularities in thelong run second moment matrix of the influence functions. Finally, we test for spanningusing size and book-to-market sorted US stock portfolios.

Does direct democracy reduce the size of government? New evidence from historical data, 1890-2000

Using historical data for all Swiss cantons from 1890 to 2000, we estimate the causal effect of direct democracy on government spending. The main innovation in this paper is that we use fixed effects to control for unobserved heterogeneity and instrumental variables to address the potential endogeneity of institutions. We find that the budget referendum and lower costs to launch a voter initiative are effective tools in reducing canton level spending. However, we find no evidence that the budget referendum results in more decentralized government or a larger local government. Our instrumental variable estimates suggest that a mandatory budget referendum reduces the size of canton spending between 13 and 19 percent. A 1 percent lower signature requirement for the initiative reduces canton spending by up to 2 percent.

Demographic and behavioral factors associated with adolescent pregnancy in Switzerland.

Switzerland has the lowest adolescent fertility rate in Western Europe. According to data collected in 1993 as part of the Swiss Multicentre Adolescent Survey on Health, 5% of 1,726 sexually active adolescents in a group of 3,993 15-20-year-old women enrolled in academic or vocational classes had ever been pregnant; most of these women (80%) had terminated their pregnancy. Adolescents who had ever been pregnant did not differ significantly from those who had not by demographic characteristics. Multiple logistic regression analysis identified seven factors associated with pregnancy: having had four or more sexual partners; not having used contraceptives at first intercourse; ever use of less-effective contraceptive methods; having used illicit drugs during the last 30 days; living apart from one's parents; recently experiencing stress; and perceiving a lack of future prospects.

Communication, coordination and efficiency in evolutionary one-population models

We analyze the role of commitment in pre-play communication for ensuringefficient evolutionarily stable outcomes in coordination games. All players are a priori identical as they are drawn from the same population. In games where efficient outcomes can be reached by players coordinating on the same action we find commitment to be necessary to enforce efficiency. In games where efficienct outcomes only result from play of different actions, communication without commitment is most effective although efficiency can no longer be guaranteed. Only when there are many messages then inefficient outcomes are negligible as their basins of attraction become very small.

The size and burden of mental disorders and other disorders of the brain in Europe 2010.

Aims: To provide 12-month prevalence and disability burden estimates of a broad range of mental and neurological disorders in the European Union (EU) and to compare these findings to previous estimates. Referring to our previous 2005 review, improved up-to-date data for the enlarged EU on a broader range of disorders than previously covered are needed for basic, clinical and public health research and policy decisions and to inform about the estimated number of persons affected in the EU. Method: Stepwise multi-method approach, consisting of systematic literature reviews, reanalyses of existing data sets, national surveys and expert consultations. Studies and data from all member states of the European Union (EU-27) plus Switzerland, Iceland and Norway were included. Supplementary information about neurological disorders is provided, although methodological constraints prohibited the derivation of overall prevalence estimates for mental and neurological disorders. Disease burden was measured by disability adjusted life years (DALY). Results: Prevalence: It is estimated that each year 38.2% of the EU population suffers from a mental disorder. Adjusted for age and comorbidity, this corresponds to 164.8 million persons affected. Compared to 2005 (27.4%) this higher estimate is entirely due to the inclusion of 14 new disorders also covering childhood/adolescence as well as the elderly. The estimated higher number of persons affected (2011: 165 m vs. 2005: 82 m) is due to coverage of childhood and old age populations, new disorders and of new EU membership states. The most frequent disorders are anxiety disorders (14.0%), insomnia (7.0%), major depression (6.9%), somatoform (6.3%), alcohol and drug dependence (>4%), ADHD (5%) in the young, and dementia (1-30%, depending on age). Except for substance use disorders and mental retardation, there were no substantial cultural or country variations. Although many sources, including national health insurance programs, reveal increases in sick leave, early retirement and treatment rates due to mental disorders, rates in the community have not increased with a few exceptions (i.e. dementia). There were also no consistent indications of improvements with regard to low treatment rates, delayed treatment provision and grossly inadequate treatment. Disability: Disorders of the brain and mental disorders in particular, contribute 26.6% of the total all cause burden, thus a greater proportion as compared to other regions of the world. The rank order of the most disabling diseases differs markedly by gender and age group; overall, the four most disabling single conditions were: depression, dementias, alcohol use disorders and stroke. Conclusion: In every year over a third of the total EU population suffers from mental disorders. The true size of "disorders of the brain" including neurological disorders is even considerably larger. Disorders of the brain are the largest contributor to the all cause morbidity burden as measured by DALY in the EU. No indications for increasing overall rates of mental disorders were found nor of improved care and treatment since 2005; less than one third of all cases receive any treatment, suggesting a considerable level of unmet needs. We conclude that the true size and burden of disorders of the brain in the EU was significantly underestimated in the past.Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research in order to identify better strategies for improved prevention and treatment for isorders of the brain as the core health challenge of the 21st century. (C) 2011 Published by Elsevier B.V.

World population growth and fertility patterns, 1960-2000. A simple model explaining the evolution of world's fertility during the second half of the 20th Century

In this paper we attempt to describe the general reasons behind the world populationexplosion in the 20th century. The size of the population at the end of the century inquestion, deemed excessive by some, was a consequence of a dramatic improvementin life expectancies, attributable, in turn, to scientific innovation, the circulation ofinformation and economic growth. Nevertheless, fertility is a variable that plays acrucial role in differences in demographic growth. We identify infant mortality, femaleeducation levels and racial identity as important exogenous variables affecting fertility.It is estimated that in poor countries one additional year of primary schooling forwomen leads to 0.614 child less per couple on average (worldwide). While it may bepossible to identify a global tendency towards convergence in demographic trends,particular attention should be paid to the case of Africa, not only due to its differentdemographic patterns, but also because much of the continent's population has yet toexperience improvement in quality of life generally enjoyed across the rest of theplanet.

A single high dose of oral Vitamin D3 is not enough to correct insufficiency and deficiency in a rheumatologic population

Introduction: Vitamin D plays a major role in bone metabolism and neuromuscular function. Supplementation with vitamin D is effective to reduce the risk of fall and of fracture. However adherence to oral daily vitamin D supplementation is low. Screening and correcting vitamin D insufficiency in a general rheumatologic population could improve both morbidity and quality of life in these patients with chronic painful disorders and at high risk of osteoporosis. After determining the prevalence of vitamin D deficiency in this population, we evaluated if supplementation with a single high dose of oral 25-OH vitamin D3 was sufficient to correct this abnormality. Methods: During one month (November 2009), levels of 25-OH vitamin D were systematically determined in our rheumatology outpatient clinic and classified into three groups: vitamin D deficiency (<10 µg/l), vitamin D insufficiency (10 to 30µg/l) or normal vitamin D (>30 µg/l). Patients with insufficiency or deficiency received respectively a single high dose of 300'000 IU or 600'000 IU oral vitamin D3. In addition, all patients with osteoporosis were prescribed daily supplement of calcium (1g) and vitamin D (800 IU). 25-OH vitamin D levels were reevaluated after 3 months. Results: Vitamin D levels were initially determined in 292 patients (mean age 53, 211 women, 87% Caucasian). 77% had inflammatory rheumatologic disease (IRD), 20% osteoporosis (OP) and 12% degenerative disease (DD). Vitamin D deficiency was present in 20 (6.8%), while 225 (77.1%) had insufficiency. Of the 245 patients with levels <30µg/l, a new determination of vitamin D level was available in 173 (71%) at 3 months (table 1). Conclusion: Vitamin D insufficiency is highly prevalent in our rheumatologic population (84%), and is not adequately corrected by a single high dose of oral vitamin D3 in more than half of the patients with IRD and DD. In patients with OP, despite association of a single high dose with daily oral vitamin D supplementation, 40% of patients are still deficient when reevaluated at 3 months.

Estimates of patient costs related with population morbidity: Can indirect costs affect the results?

A number of health economics works require patient cost estimates as a basic information input.However the accuracy of cost estimates remains in general unspecified. We propose to investigate howthe allocation of indirect costs or overheads can affect the estimation of patient costs in order to allow forimprovements in the analysis of patient costs estimates. Instead of focusing on the costing method, thispaper proposes to highlight changes in variance explained observed when a methodology is chosen. Wecompare three overhead allocation methods for a specific Spanish population adjusted using the ClinicalRisk Groups (CRG), and we obtain different series of full-cost group estimates. As a result, there aresignificant gains in the proportion of the variance explained, depending upon the methodology used.Furthermore, we find that the global amount of variation explained by risk adjustment models dependsmainly on direct costs and is independent of the level of aggregation used in the classification system.

Serum calcium levels are associated with novel cardiometabolic risk factors in the population-based CoLaus study.

BACKGROUND: Associations of serum calcium levels with the metabolic syndrome and other novel cardio-metabolic risk factors not classically included in the metabolic syndrome, such as those involved in oxidative stress, are largely unexplored. We analyzed the association of albumin-corrected serum calcium levels with conventional and non-conventional cardio-metabolic risk factors in a general adult population. METHODOLOGY/PRINCIPAL FINDINGS: The CoLaus study is a population-based study including Caucasians from Lausanne, Switzerland. The metabolic syndrome was defined using the Adult Treatment Panel III criteria. Non-conventional cardio-metabolic risk factors considered included: fat mass, leptin, LDL particle size, apolipoprotein B, fasting insulin, adiponectin, ultrasensitive CRP, serum uric acid, homocysteine, and gamma-glutamyltransferase. We used adjusted standardized multivariable regression to compare the association of each cardio-metabolic risk factor with albumin-corrected serum calcium. We assessed associations of albumin-corrected serum calcium with the cumulative number of non-conventional cardio-metabolic risk factors. We analyzed 4,231 subjects aged 35 to 75 years. Corrected serum calcium increased with both the number of the metabolic syndrome components and the number of non-conventional cardio-metabolic risk factors, independently of the metabolic syndrome and BMI. Among conventional and non-conventional cardio-metabolic risk factors, the strongest positive associations were found for factors related to oxidative stress (uric acid, homocysteine and gamma-glutamyltransferase). Adiponectin had the strongest negative association with corrected serum calcium. CONCLUSIONS/SIGNIFICANCE: Serum calcium was associated with the metabolic syndrome and with non-conventional cardio-metabolic risk factors independently of the metabolic syndrome. Associations with uric acid, homocysteine and gamma-glutamyltransferase were the strongest. These novel findings suggest that serum calcium levels may be associated with cardiovascular risk via oxidative stress.

The stationary distribution of a continuously varying strategy in a class-structured population under mutation-selection-drift balance.

Many traits and/or strategies expressed by organisms are quantitative phenotypes. Because populations are of finite size and genomes are subject to mutations, these continuously varying phenotypes are under the joint pressure of mutation, natural selection and random genetic drift. This article derives the stationary distribution for such a phenotype under a mutation-selection-drift balance in a class-structured population allowing for demographically varying class sizes and/or changing environmental conditions. The salient feature of the stationary distribution is that it can be entirely characterized in terms of the average size of the gene pool and Hamilton's inclusive fitness effect. The exploration of the phenotypic space varies exponentially with the cumulative inclusive fitness effect over state space, which determines an adaptive landscape. The peaks of the landscapes are those phenotypes that are candidate evolutionary stable strategies and can be determined by standard phenotypic selection gradient methods (e.g. evolutionary game theory, kin selection theory, adaptive dynamics). The curvature of the stationary distribution provides a measure of the stability by convergence of candidate evolutionary stable strategies, and it is evaluated explicitly for two biological scenarios: first, a coordination game, which illustrates that, for a multipeaked adaptive landscape, stochastically stable strategies can be singled out by letting the size of the gene pool grow large; second, a sex-allocation game for diploids and haplo-diploids, which suggests that the equilibrium sex ratio follows a Beta distribution with parameters depending on the features of the genetic system.

Exposure of the Swiss population to computed tomography.

BACKGROUND: The frequency of CT procedures has registered a significant increase over the last decade, which led at the international level to an increasing concern on the radiological risk associated with the use of CT especially in paediatrics. This work aimed at investigating the use of computed tomography in Switzerland, following the evolution of CT frequency and dose data over a decade and comparing it to data reported in other countries. METHODS: The frequency and dose data related to CT are obtained by means of a nationwide survey. National frequencies were established by projecting the collected data, using the ratio of the number of CT units belonging to the respondents to the total number of CT units in the country. The effective doses per examination were collected during an auditing campaign. RESULTS: In 2008 about 0.8 Million CT procedures (~ 100 CT examinations / 1000 population) were performed in the country, leading to a collective effective dose of more than 6000 man.Sv (0.8 mSv/caput). In a decade the frequency of CT examinations averaged over the population and the associated average effective dose per caput increased by a factor of 2.2 and 2.9 respectively. CONCLUSIONS: Although the contribution of CT to the total medical X-rays is 6% in terms of the frequency, it represents 68% in terms of the collective effective dose. These results are comparable to those reported in a number of countries in Europe and America with similar health level.