Association of adiposity genetic variants with menarche timing in 92,105 women of European descent.

Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)(2)), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.

The average crossing number of equilateral random polygons.

In this paper, we study the average crossing number of equilateral random walks and polygons. We show that the mean average crossing number ACN of all equilateral random walks of length n is of the form . A similar result holds for equilateral random polygons. These results are confirmed by our numerical studies. Furthermore, our numerical studies indicate that when random polygons of length n are divided into individual knot types, the for each knot type can be described by a function of the form where a, b and c are constants depending on and n0 is the minimal number of segments required to form . The profiles diverge from each other, with more complex knots showing higher than less complex knots. Moreover, the profiles intersect with the ACN profile of all closed walks. These points of intersection define the equilibrium length of , i.e., the chain length at which a statistical ensemble of configurations with given knot type -upon cutting, equilibration and reclosure to a new knot type -does not show a tendency to increase or decrease . This concept of equilibrium length seems to be universal, and applies also to other length-dependent observables for random knots, such as the mean radius of gyration Rg.

Comparative analysis of ten assesment grids of quality criteria in qualitative research

The authors present 10 grids which are widely used in Health Sciences for the assessment of quality in research. They proceed through a comparative thematic analysis of these grids and show which points of view are preferred. They insist on the issues that differentiate these grids from each other and suggest the analysis of their differences by distinguishing the theoretical perspectives that underpin each one of these grids. Whilst the authors of the assessment grids rarely refer to the implicit theoretical backgrounds that guide their work, findings show that these grids convey varied epistemologies and research models. This gap renders the comparison of quality assessment in qualitative research a very difficult task, unless we shift our focus on the relationship between the grids, their theoretical backgrounds and their specific research subjects.

Assessment of left coronary artery beat-to-beat repositioning in order to propose an optimal acquisition window for coronary MRA

Introduction: Coronary magnetic resonance angiography (MRA) is a medical imaging technique that involves collecting data from consecutive heartbeats, always at the same time in the cardiac cycle, in order to minimize heart motion artifacts. This technique relies on the assumption that coronary arteries always follow the same trajectory from heartbeat to heartbeat. Until now, choosing the acquisition window in the cardiac cycle was based exclusively on the position of minimal coronary motion. The goal of this study was to test the hypothesis that there are time intervals during the cardiac cycle when coronary beat-to-beat repositioning is optimal. The repositioning uncertainty values in these time intervals were then compared with the intervals of low coronary motion in order to propose an optimal acquisition window for coronary MRA. Methods: Cine breath-hold x-ray angiograms with synchronous ECG were collected from 11 patients who underwent elective routine diagnostic coronarography. Twenty-three bifurcations of the left coronary artery were selected as markers to evaluate repositioning uncertainty and velocity during cardiac cycle. Each bifurcation was tracked by two observers, with the help of a user-assisted algorithm implemented in Matlab (The Mathworks, Natick, MA, USA) that compared the trajectories of the markers coming from consecutive heartbeats and computed the coronary repositioning uncertainty with steps of 50ms until 650ms after the R-wave. Repositioning uncertainty was defined as the diameter of the smallest circle encompassing the points to be compared at the same time after the R-wave. Student's t-tests with a false discovery rate (FDR, q=0.1) correction for multiple comparison were applied to see whether coronary repositioning and velocity vary statistically during cardiac cycle. Bland-Altman plots and linear regression were used to assess intra- and inter-observer agreement. Results: The analysis of left coronary artery beat-to-beat repositioning uncertainty shows a tendency to have better repositioning in mid systole (less than 0.84±0.58mm) and mid diastole (less than 0.89±0.6mm) than in the rest of the cardiac cycle (highest value at 50ms=1.35±0.64mm). According to Student's t-tests with FDR correction for multiple comparison (q=0.1), two intervals, in mid systole (150-200ms) and mid diastole (550-600ms), provide statistically better repositioning in comparison with the early systole and the early diastole. Coronary velocity analysis reveals that left coronary artery moves more slowly in end systole (14.35±11.35mm/s at 225ms) and mid diastole (11.78±11.62mm/s at 625ms) than in the rest of the cardiac cycle (highest value at 25ms: 55.96±22.34mm/s). This was confirmed by Student's t-tests with FDR correction for multiple comparison (q=0.1, FDR-corrected p-value=0.054): coronary velocity values at 225, 575 and 625ms are not much different between them but they are statistically inferior to all others. Bland-Altman plots and linear regression show that intra-observer agreement (y=0.97x+0.02 with R²=0.93 at 150ms) is better than inter-observer (y=0.8x+0.11 with R²=0.67 at 150ms). Discussion: The present study has demonstrated that there are two time intervals in the cardiac cycle, one in mid systole and one in mid diastole, where left coronary artery repositioning uncertainty reaches points of local minima. It has also been calculated that the velocity is the lowest in end systole and mid diastole. Since systole is less influenced by heart rate variability than diastole, it was finally proposed to test an acquisition window between 150 and 200ms after the R-wave.

Parts, places, and perspectives : a theory of spatial relations based an mereotopology and convexity

This thesis suggests to carry on the philosophical work begun in Casati's and Varzi's seminal book Parts and Places, by extending their general reflections on the basic formal structure of spatial representation beyond mereotopology and absolute location to the question of perspectives and perspective-dependent spatial relations. We show how, on the basis of a conceptual analysis of such notions as perspective and direction, a mereotopological theory with convexity can express perspectival spatial relations in a strictly qualitative framework. We start by introducing a particular mereotopological theory, AKGEMT, and argue that it constitutes an adequate core for a theory of spatial relations. Two features of AKGEMT are of particular importance: AKGEMT is an extensional mereotopology, implying that sameness of proper parts is a sufficient and necessary condition for identity, and it allows for (lower- dimensional) boundary elements in its domain of quantification. We then discuss an extension of AKGEMT, AKGEMTS, which results from the addition of a binary segment operator whose interpretation is that of a straight line segment between mereotopological points. Based on existing axiom systems in standard point-set topology, we propose an axiomatic characterisation of the segment operator and show that it is strong enough to sustain complex properties of a convexity predicate and a convex hull operator. We compare our segment-based characterisation of the convex hull to Cohn et al.'s axioms for the convex hull operator, arguing that our notion of convexity is significantly stronger. The discussion of AKGEMTS defines the background theory of spatial representation on which the developments in the second part of this thesis are built. The second part deals with perspectival spatial relations in two-dimensional space, i.e., such relations as those expressed by 'in front of, 'behind', 'to the left/right of, etc., and develops a qualitative formalism for perspectival relations within the framework of AKGEMTS. Two main claims are defended in part 2: That perspectival relations in two-dimensional space are four- place relations of the kind R(x, y, z, w), to be read as x is i?-related to y as z looks at w; and that these four-place structures can be satisfactorily expressed within the qualitative theory AKGEMTS. To defend these two claims, we start by arguing for a unified account of perspectival relations, thus rejecting the traditional distinction between 'relative' and 'intrinsic' perspectival relations. We present a formal theory of perspectival relations in the framework of AKGEMTS, deploying the idea that perspectival relations in two-dimensional space are four-place relations, having a locational and a perspectival part and show how this four-place structure leads to a unified framework of perspectival relations. Finally, we present a philosophical motivation to the idea that perspectival relations are four-place, cashing out the thesis that perspectives are vectorial properties and argue that vectorial properties are relations between spatial entities. Using Fine's notion of "qua objects" for an analysis of points of view, we show at last how our four-place approach to perspectival relations compares to more traditional understandings.

Manufacturing and characterization of a recombinant adeno-associated virus type 8 reference standard material.

Gene therapy approaches using recombinant adeno-associated virus serotype 2 (rAAV2) and serotype 8 (rAAV8) have achieved significant clinical benefits. The generation of rAAV Reference Standard Materials (RSM) is key to providing points of reference for particle titer, vector genome titer, and infectious titer for gene transfer vectors. Following the example of the rAAV2RSM, here we have generated and characterized a novel RSM based on rAAV serotype 8. The rAAV8RSM was produced using transient transfection, and the purification was based on density gradient ultracentrifugation. The rAAV8RSM was distributed for characterization along with standard assay protocols to 16 laboratories worldwide. Mean titers and 95% confidence intervals were determined for capsid particles (mean, 5.50×10(11) pt/ml; CI, 4.26×10(11) to 6.75×10(11) pt/ml), vector genomes (mean, 5.75×10(11) vg/ml; CI, 3.05×10(11) to 1.09×10(12) vg/ml), and infectious units (mean, 1.26×10(9) IU/ml; CI, 6.46×10(8) to 2.51×10(9) IU/ml). Notably, there was a significant degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This outcome emphasizes the need to use RSMs to calibrate the titers of rAAV vectors in preclinical and clinical studies at a time when the field is maturing rapidly. The rAAV8RSM has been deposited at the American Type Culture Collection (VR-1816) and is available to the scientific community.

Predicting spatial patterns of plant species richness: a comparison of direct macroecological and species stacking approaches

Aim This study compares the direct, macroecological approach (MEM) for modelling species richness (SR) with the more recent approach of stacking predictions from individual species distributions (S-SDM). We implemented both approaches on the same dataset and discuss their respective theoretical assumptions, strengths and drawbacks. We also tested how both approaches performed in reproducing observed patterns of SR along an elevational gradient.Location Two study areas in the Alps of Switzerland.Methods We implemented MEM by relating the species counts to environmental predictors with statistical models, assuming a Poisson distribution. S-SDM was implemented by modelling each species distribution individually and then stacking the obtained prediction maps in three different ways - summing binary predictions, summing random draws of binomial trials and summing predicted probabilities - to obtain a final species count.Results The direct MEM approach yields nearly unbiased predictions centred around the observed mean values, but with a lower correlation between predictions and observations, than that achieved by the S-SDM approaches. This method also cannot provide any information on species identity and, thus, community composition. It does, however, accurately reproduce the hump-shaped pattern of SR observed along the elevational gradient. The S-SDM approach summing binary maps can predict individual species and thus communities, but tends to overpredict SR. The two other S-SDM approaches the summed binomial trials based on predicted probabilities and summed predicted probabilities - do not overpredict richness, but they predict many competing end points of assembly or they lose the individual species predictions, respectively. Furthermore, all S-SDM approaches fail to appropriately reproduce the observed hump-shaped patterns of SR along the elevational gradient.Main conclusions Macroecological approach and S-SDM have complementary strengths. We suggest that both could be used in combination to obtain better SR predictions by following the suggestion of constraining S-SDM by MEM predictions.

Properties of ideal composite knots.

The shortest tube of constant diameter that can form a given knot represents the 'ideal' form of the knot. Ideal knots provide an irreducible representation of the knot, and they have some intriguing mathematical and physical features, including a direct correspondence with the time-averaged shapes of knotted DNA molecules in solution. Here we describe the properties of ideal forms of composite knots-knots obtained by the sequential tying of two or more independent knots (called factor knots) on the same string. We find that the writhe (related to the handedness of crossing points) of composite knots is the sum of that of the ideal forms of the factor knots. By comparing ideal composite knots with simulated configurations of knotted, thermally fluctuating DNA, we conclude that the additivity of writhe applies also to randomly distorted configurations of composite knots and their corresponding factor knots. We show that composite knots with several factor knots may possess distinct structural isomers that can be interconverted only by loosening the knot.

Surgery for Hirschsprung's disease: comparison between the Duhamel method and the transanal endorectal pull-through based on 59 patients and a review of the literature

Background:¦Hirschsprung's disease (HSCR) is a congenital malformation of the enteric nervous system due to the¦arrest of migration of neural crest cells to form the myenteric and submucosal plexuses. It leads to an anganglionic intestinal segment, which is permanently contracted causing intestinal obstruction. Its incidence is approximately 1/5000 birth, and males are more frequently affected with a male/female ratio of 4/1. The diagnosis is in most cases made within the first year of life. The rectal biopsy of the mucosa and sub-mucosa is the diagnostic gold standard.¦Purpose:¦The aim of this study was to compare two surgical approaches for HSCR, the Duhamel technique and the transanal endorectal pull-through (TEPT) in term of indications, duration of surgery, duration of hospital stay, postoperative treatment, complications, frequency of enterocolitis and functional outcomes.¦Methods:¦Fifty-nine patients were treated for HSCR by one of the two methods in our department of pediatric¦surgery between 1994 and 2010. These patients were separated into two groups (I: Duhamel, II: TEPT), which were compared on the basis of medical records. Statistics were made to compare the two groups (ANOVA test). The first group includes 43 patients and the second 16 patients. It is noteworthy that twenty-four patients (about 41% of all¦patients) were referred from abroad (Western Africa). Continence was evaluated with the Krickenbeck's score.¦Results:¦Statistically, this study showed that operation duration, hospital stay, postoperative fasting and duration of postoperative antibiotics were significantly shorter (p value < 0.05) in group II (TEPT). But age at operation and length of aganglionic segment showed no significant difference between the two groups. The continence follow-up showed generally good results (Krickenbeck's scores 1; 2.1; 3.1) in both groups with a slight tendency to constipation in group I and soiling in group II.¦Conclusion:¦We found two indications for the Duhamel method that are being referred from a country without¦careful postoperative surveillance and/or having a previous colostomy. Even if the Duhamel technique tends to be replaced by the TEPT, it remains the best operative approach for some selected patients. TEPT has also proved some advantages but must be followed carefully because, among other points, of the postoperative dilatations. Our postoperative standards, like digital rectal examination and anal dilatations seem to reduce the occurrence of complications like rectal spur and anal/anastomosis stenosis, respectively in the Duhamel method and the TEPT technique.

The average inter-crossing number of equilateral random walks and polygons

In this paper, we study the average inter-crossing number between two random walks and two random polygons in the three-dimensional space. The random walks and polygons in this paper are the so-called equilateral random walks and polygons in which each segment of the walk or polygon is of unit length. We show that the mean average inter-crossing number ICN between two equilateral random walks of the same length n is approximately linear in terms of n and we were able to determine the prefactor of the linear term, which is a = (3 In 2)/(8) approximate to 0.2599. In the case of two random polygons of length n, the mean average inter-crossing number ICN is also linear, but the prefactor of the linear term is different from that of the random walks. These approximations apply when the starting points of the random walks and polygons are of a distance p apart and p is small compared to n. We propose a fitting model that would capture the theoretical asymptotic behaviour of the mean average ICN for large values of p. Our simulation result shows that the model in fact works very well for the entire range of p. We also study the mean ICN between two equilateral random walks and polygons of different lengths. An interesting result is that even if one random walk (polygon) has a fixed length, the mean average ICN between the two random walks (polygons) would still approach infinity if the length of the other random walk (polygon) approached infinity. The data provided by our simulations match our theoretical predictions very well.

Dummy run and conformity indices in the ongoing EORTC low-grade glioma trial 22033-26033: First evaluation of quality of radiotherapy planning.

PURPOSE: Early assessment of radiotherapy (RT) quality in the ongoing EORTC trial comparing primary temozolomide versus RT in low-grade gliomas. MATERIALS AND METHODS: RT plans provided for dummy cases were evaluated and compared against expert plans. We analysed: (1) tumour and organs-at-risk delineation, (2) geometric and dosimetric characteristics, (3) planning parameters, compliance with dose prescription and Dmax for OAR (4) indices: RTOG conformity index (CI), coverage factor (CF), tissue protection factor (PF); conformity number (CN = PF x CF); dose homogeneity in PTV (U). RESULTS: Forty-one RT plans were evaluated. Only two (5%) centres were requested to repeat CTV-PTV delineations. Three (7%) plans had a significant under-dosage and dose homogeneity in one deviated > 10%. Dose distribution was good with mean values of 1.5, 1, 0.68, and 0.68 (ideal values = 1) for CI, CF, PF, and CN, respectively. CI and CN strongly correlated with PF and they correlated with PTV. Planning with more beams seems to increase PTV(Dmin), improving CF. U correlated with PTV(Dmax). CONCLUSION: Preliminary results of the dummy run procedure indicate that most centres conformed to protocol requirements. To quantify plan quality we recommend systematic calculation of U and either CI or CN, both of which measure the amount of irradiated normal brain tissue.

Validation of the Addiction Severity Index in French-speaking alcoholic patients.

OBJECTIVE: Evaluation of a French translation of the Addiction Severity Index (ASI) in 100 (78 male) alcoholic patients. METHOD: Validity of the instrument was assessed by measuring test-retest and interrater reliability, internal consistency and convergence and discrimination between items and scales. Concurrent validity was assessed by comparing the scores from the ASI with those obtained from three other clinimetric instruments. RESULTS: Test-retest reliability of ASI scores (after a 10-day interval) was good (r = 0.63 to r = 0.95). Interrater reliability was evaluated using six video recordings of patient interviews. Severity ratings assigned by six rates were significantly different (p < .05), but 72% of the ratings assigned by those who viewed the videos were within two points of the interviewer's severity ratings. Cronbach alpha coefficient of internal consistency varied from 0.58 to 0.81 across scales. The average item-to-scale convergent validity (r value) was 0.49 (range 0.0 to 0.84) for composite scores and 0.35 (range 0.00 to 0.68) for severity ratings, whereas discriminant validity was 0.11 on average (range-0.19 to 0.46) for composite scores and 0.12 (range-0.20 to 0.52) for severity ratings. Finally, concurrent validity with the following instruments was assessed: Severity of Alcoholism Dependence Questionnaire (40% shared variance with ASI alcohol scale), Michigan Alcoholism Screening Test (2% shared variance with ASI alcohol scale) and Hamilton Depression Rating Scale (31% shared variance with ASI psychiatric scale). CONCLUSIONS: The Addiction Severity Index covers a large scope of problems encountered among alcoholics and quantifies need for treatment. This French version presents acceptable criteria of reliability and validity.

PlGF-1 and VEGFR-1 pathway regulation of the external epithelial hemato-ocular barrier. A model for retinal edema.

VEGF is considered as an important factor in the pathogenesis of macular edema. VEGF induces the rupture of the blood retinal barrier and may also influence the retinal pigment epithelial (RPE) outer retinal barrier. The aim of this work was to analyze the influence of the VEGF receptor pathways in the modulation of the RPE barrier breakdown in vitro and in vivo. The ARPE19 human junctions in culture are modulated by VEGF through VEGFR-1 but not through VEGFR-2. PlGF-1, that is a pure agonist of VEGFR-1, is produced in ARPE-19 cells under hypoxic conditions and mimics VEGF effects on the external retinal barrier as measured by TER and inulin flux. In vivo, the intravitreous injection of PlGF-1 induces a rupture of the external retinal barrier together with a retinal edema. This effect is reversible within 4 days. VEGF-E, that is a pure agonist of VEGFR-2, does not induce any acute effect on the RPE barrier. These results demonstrate that PlGF-1 can reproduce alterations of the RPE barrier occurring during diabetic retinopathy.

Migrating concepts: Immigrant integration and the regulation of religious dress in France and Canada

Religion in general, and Islam in particular, has become one of the main focal points of policy-making and constitutional politics in many Western liberal states. This article proposes to examine the legal and political dynamics behind new regulations targeting individual religious practices of Muslims. Although one could presuppose that church-state relations or the understanding of secularism is the main factor accounting for either accommodation or prohibition of Muslim religious practices, I make the case that the policy frame used to conceptualize the integration of immigrants in each national context is a more significant influence on how a liberal state approaches the legal regulation of individual practices such as veiling. However, this influence must be assessed carefully since it may have different effects on the different institutional actors in charge of regulating religion, such as the Courts and the legislature. To assess these hypotheses I compare two countries, France and Canada, which are solid examples of two contrasting national policy frames for the integration of immigrants.

Multi-level modeling of aspects associated with poor mental health in a sample of prehospital emergency professionals.

BACKGROUND: The goal of this paper is to investigate the respective influence of work characteristics, the effort-reward ratio, and overcommitment on the poor mental health of out-of-hospital care providers. METHODS: 333 out-of-hospital care providers answered a questionnaire that included queries on mental health (GHQ-12), demographics, health-related information and work characteristics, questions from the Effort-Reward Imbalance Questionnaire, and items about overcommitment. A two-level multiple regression was performed between mental health (the dependent variable) and the effort-reward ratio, the overcommitment score, weekly number of interventions, percentage of non-prehospital transport of patients out of total missions, gender, and age. Participants were first-level units, and ambulance services were second-level units. We also shadowed ambulance personnel for a total of 416 hr. RESULTS: With cutoff points of 2/3 and 3/4 positive answers on the GHQ-12, the percentages of potential cases with poor mental health were 20% and 15%, respectively. The effort-reward ratio was associated with poor mental health (P < 0.001), irrespective of age or gender. Overcommitment was associated with poor mental health; this association was stronger in women (β = 0.054) than in men (β = 0.020). The percentage of prehospital missions out of total missions was only associated with poor mental health at the individual level. CONCLUSIONS: Emergency medical services should pay attention to the way employees perceive their efforts and the rewarding aspects of their work: an imbalance of those aspects is associated with poor mental health. Low perceived esteem appeared particularly associated with poor mental health. This suggests that supervisors of emergency medical services should enhance the value of their employees' work. Employees with overcommitment should also receive appropriate consideration. Preventive measures should target individual perceptions of effort and reward in order to improve mental health in prehospital care providers.