Diet diversity and the risk of laryngeal cancer: a case-control study from Italy and Switzerland.

Diet diversity (defined as the number of different foods consumed) has been considered an indicator of a healthy diet, and favorably related to the risk of several digestive tract cancers. We analyzed the relation between diet diversity and the risk of laryngeal cancer using data from a case-control study carried out between 1992 and 2000 in Italy and Switzerland. The subjects of the study were 527 patients with histologically confirmed incident cancers of the larynx and 1297 patients admitted for acute, non-neoplastic diseases, unrelated to tobacco or alcohol consumption. Total diversity was computed as the number of different foods (overall and within four food groups, i.e., vegetables, fruit, meat, and cereals) consumed at least once per week. A significant inverse association was observed for vegetable diversity (OR=0.41, 95% CI: 0.28-0.59, for the highest versus the lowest quartile) and fruit diversity (OR=0.40, 95% CI: 0.27-0.59). Conversely, a direct association was found for meat diversity (OR=1.67, 95% CI: 1.11-2.50), while no meaningful association was found for total diet and cereal diversity. The results were consistent across strata of age, alcohol drinking and tobacco smoking. This study suggests that a diet not only rich but also varied in fruit and vegetables is related to a decreased risk of laryngeal cancer risk.

Visualització dinàmica d'un procés metabòlic amb finalitats docents

La incorporació del Moodle com a eina de docència, i l’augment de hores no presencials a les diverses assignatures fa que calgui incorporar les noves tecnologies perquè els alumnes disposin de més material docent al seu abast. Però l’acumulació de material fa que només sigui útil aquell material que es guanyi a l’alumne. En aquest sentit, creiem que les animacions i les eines interactives poden ser materials atractius pels alumnes. En aquest projecte hem creat una eina d’animació interactiva perquè l’estudiant de Bioquímica practiqui i aprengui una de les rutes metabòliques principals: la glucòlisi. Aquesta eina consta d’una pantalla separada en 3 zones: 1) una zona lateral que inclou la ruta metabòlica completa, i en la que l’alumne pot prémer sobre cada un dels passos que estructuren la ruta (finestra del metabolisme); 2) una zona inferior que presenta la reacció individual de la ruta metabòlica, en la que s’observa l’estructura química de les molècules i informació de l’enzim implicat en la reacció (finestra de l’enzim); i 3) una zona central en la que a través d’una animació amb Macromedia Flash MX, l’alumne observa el mecanisme químic de la reacció (finestra del mecanisme químic). Les tres zones són interactives i en prémer sobre elles donen informació, respectivament sobre la ruta completa, l’enzim de cada pas en particular i el mecanisme d’acció. A més, la finestra del mecanisme químic permet aturar en qualsevol moment la animació, tornar enrere i veure els intermediaris. Durant el segon semestre del curs 2006-2007 hem avaluat l’eina amb alumnes de Bioquímica de la Llicenciatura de Química, incorporant-la als dossier electrònics. Creiem que hem assolit els objectius que es proposaven: aprendre una ruta metabòlica, de manera divertida; aprendre el mecanisme de cada un dels passos de la ruta i aprendre l’estructura química dels metabòlits intermediaris de la ruta.

Exhaled nitric oxide in high-altitude pulmonary edema: role in the regulation of pulmonary vascular tone and evidence for a role against inflammation.

High-altitude pulmonary edema (HAPE) is a life-threatening condition occurring in predisposed subjects at altitudes above 2,500 m. It is not clear whether, in addition to hemodynamic factors and defective alveolar fluid clearance, inflammation plays a pathogenic role in HAPE. We therefore made serial measurements of exhaled pulmonary nitric oxide (NO), a marker of airway inflammation, in 28 HAPE-prone and 24 control subjects during high-altitude exposure (4,559 m). To examine the relationship between pulmonary NO synthesis and pulmonary vascular tone, we also measured systolic pulmonary artery pressure (Ppa). In the 13 subjects who developed HAPE, exhaled NO did not show any tendency to increase during the development of lung edema. Throughout the entire sojourn at high altitude, pulmonary exhaled NO was roughly 30% lower in HAPE-prone than in control subjects, and there existed an inverse relationship between Ppa and exhaled NO (r = -0.51, p < 0.001). These findings suggest that HAPE is not preceded by airway inflammation. Reduced exhaled NO may be related to altered pulmonary NO synthesis and/or transport and clearance, and the data in our study could be consistent with the novel concept that in HAPE-prone subjects, a defect in pulmonary epithelial NO synthesis may contribute to exaggerated hypoxic pulmonary vasoconstriction and in turn to pulmonary edema.

ATiPAP : desenvolupament de materials docents amb suport multimedia pels continguts d'Atenció, Percepció Auditiva i de la Parla adaptats als crédits ECTS i a l'EEES dins l'ensenyament de Psicologia

El projecte ha permès finançar el suport tècnic necessari per a poder desenvolupar materials informatitzats corresponents a activitats teòrico-pràctiques de l’assignatura troncal de la llicenciatura de Psicologia (actualment també en el Grau) “Percepció i Atenció”. Els materials desenvolupats corresponen a diferents punts del programa de l’assignatura i són els següents: demostració de la tècnica d’ombrejat per l’anàlisi de l’atenció focalitzada; parpelleig atencional en sèries de presentacions ràpides d’informació visual (RSVP); canvis encoberts de l’atenció i el mecanisme d’inhibició de retorn; efectes dels filtrats sobre la percepció de la parla i la música; il·lusions auditives i els principis d’organització de la informació sonora complexa; la percepció categòrica dels sons de la parla i la naturalesa continua del processament lèxic (paradigma d’obertura successiva o gating). Per totes aquelles activitats amb continguts de llenguatge, s’han desenvolupat dues versions equivalents, catalana i castellana, per permetre que els estudiants fessin la pràctica en la seva llengua dominant. A la primera fase del projecte, al llarg del curs 2006-07, es van preparar els materials i la programació de les diferents pràctiques i es van poder identificar alguns problemes que es van solucionar posteriorment. En el curs 2007-08 totes les activitats de pràctiques ja es van fer accessibles als estudiants (Plataforma Moodle, Campus Virtual) i la valoració sobre el seu funcionament, feta pels estudiants mitjançant qüestionaris, va ser satisfactòria en més d’un 95% dels casos (els únics problemes detectats estaven relacionats amb les característiques dels ordinadors del usuaris i del navegador utilitzat per accedir als materials). La valoració de les activitats per part dels estudiants va ser globalment positiva i, en el seu ús continuat al llarg dels cursos 2008-09 i 2009-10, s’ha observat una participació creixent (accés voluntari a les activitats) i un aprofitament millor de la informació presentada, que es tradueix en millores en les puntuacions obtingudes en les avaluacions de l'assignatura.

Animació de les rutes glucolítica i gluconeogènica : una eina no presencial per a aprendre de manera amena

La incorporació del Moodle com a eina de docència, i l’augment de hores no presencials a les diverses assignatures fa que calgui incorporar les noves tecnologies perquè els alumnes disposin de més material docent al seu abast. Però l’acumulació de material fa que només sigui útil aquell material que es guanyi a l’alumne. En aquest sentit, creiem que les animacions i les eines interactives poden ser materials atractius pels alumnes. En aquest projecte hem creat una eina d’animació interactiva perquè l’estudiant de Bioquímica practiqui i aprengui dues rutes principals del metabolisme de hidrats de carboni: la glucòlisi i la gluconeogènesi. Aquesta eina consta d’una pantalla separada en 3 zones: 1) una zona lateral que inclou la ruta metabòlica completa, i en la que l’alumne pot prémer sobre cada un dels passos que estructuren la ruta (finestra del metabolisme); 2) una zona inferior que presenta la reacció individual de la ruta metabòlica, en la que s’observa l’estructura química de les molècules i informació de l’enzim implicat en la reacció (finestra de l’enzim); i 3) una zona central en la que a través d’una animació amb Macromedia Flash MX, l’alumne observa el mecanisme químic de la reacció (finestra del mecanisme químic). Les tres zones són interactives i en prémer sobre elles donen informació, respectivament sobre la ruta completa, l’enzim de cada pas en particular i el mecanisme d’acció. A més, la finestra del mecanisme químic permet aturar en qualsevol moment la animació, tornar enrere i veure els intermediaris. Durant el segon semestre del curs 2007-2008 hem avaluat l’eina amb alumnes de Bioquímica de la Llicenciatura de Química, incorporant-la als dossier electrònics i al Moodle. Creiem que hem assolit els objectius que es proposaven: que l’alumne aprengui les dues rutes metabòliques, de manera divertida; el mecanisme de cada un dels passos de les rutes i l’estructura química dels metabòlits intermediaris de les rutes.

Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: relation to alterations in endocannabinoids and adipocytokines.

AIMS: To investigate the effect of surgical gastric bypass-induced weight loss and related alterations in endocannabinoids (ECs) and adipocytokine plasma levels on coronary circulatory dysfunction in morbidly obese (MOB) individuals. METHODS AND RESULTS: Myocardial blood flow (MBF) responses to cold pressor test (CPT) from rest (ΔMBF) and during pharmacologically induced hyperaemia were measured with &supl;³N-ammonia PET/CT in 18 MOB individuals with a body mass index (BMI) > 40 kg/m² at baseline and after a median follow-up period of 22 months. Gastric bypass intervention decreased BMI from a median of 44.8 (inter-quartile range: 43.3, 48.2) to 30.8 (27.3, 34.7) kg/m² (P < 0.0001). This decrease in BMI was accompanied by a marked improvement in endothelium-related ΔMBF to CPT and hyperaemic MBFs, respectively [0.34 (0.18, 0.41) from 0.03 (-0.08, 0.15) mL/g/min, P = 0.002; and 2.51 (2.17, 2.64) from 1.53 (1.39, 2.18) mL/g/min, P < 0.001]. There was an inverse correlation between decreases in plasma concentrations of the EC anandamide and improvement in ΔMBF to CPT (r = -0.59, P = 0.009), while increases in adiponectin plasma levels correlated positively with hyperaemic MBFs (r = 0.60, P = 0.050). Conversely, decreases in leptin plasma concentrations were not observed to correlate with the improvement in coronary circulatory function (r = 0.22, P = 0.400, and r = -0.31, P = 0.250). CONCLUSIONS: Gastric bypass-related reduction of BMI in MOB individuals beneficially affects coronary circulatory dysfunction. The dysbalance between ECs and adipocytokines appears to be an important determinant of coronary circulatory function in obesity.

White matter maturation reshapes structural connectivity in the late developing human brain.

From toddler to late teenager, the macroscopic pattern of axonal projections in the human brain remains largely unchanged while undergoing dramatic functional modifications that lead to network refinement. These functional modifications are mediated by increasing myelination and changes in axonal diameter and synaptic density, as well as changes in neurochemical mediators. Here we explore the contribution of white matter maturation to the development of connectivity between ages 2 and 18 y using high b-value diffusion MRI tractography and connectivity analysis. We measured changes in connection efficacy as the inverse of the average diffusivity along a fiber tract. We observed significant refinement in specific metrics of network topology, including a significant increase in node strength and efficiency along with a decrease in clustering. Major structural modules and hubs were in place by 2 y of age, and they continued to strengthen their profile during subsequent development. Recording resting-state functional MRI from a subset of subjects, we confirmed a positive correlation between structural and functional connectivity, and in addition observed that this relationship strengthened with age. Continuously increasing integration and decreasing segregation of structural connectivity with age suggests that network refinement mediated by white matter maturation promotes increased global efficiency. In addition, the strengthening of the correlation between structural and functional connectivity with age suggests that white matter connectivity in combination with other factors, such as differential modulation of axonal diameter and myelin thickness, that are partially captured by inverse average diffusivity, play an increasingly important role in creating brain-wide coherence and synchrony.

Quantitative ultrasound of the heel and fracture risk assessment: an updated meta-analysis.

Meta-analysis of prospective studies shows that quantitative ultrasound of the heel using validated devices predicts risk of different types of fracture with similar performance across different devices and in elderly men and women. These predictions are independent of the risk estimates from hip DXA measures.Introduction Clinical utilisation of heel quantitative ultrasound (QUS) depends on its power to predict clinical fractures. This is particularly important in settings that have no access to DXA-derived bone density measurements. We aimed to assess the predictive power of heel QUS for fractures using a meta-analysis approach.Methods We conducted an inverse variance random effects meta-analysis of prospective studies with heel QUS measures at baseline and fracture outcomes in their follow-up. Relative risks (RR) per standard deviation (SD) of different QUS parameters (broadband ultrasound attenuation [BUA], speed of sound [SOS], stiffness index [SI], and quantitative ultrasound index [QUI]) for various fracture outcomes (hip, vertebral, any clinical, any osteoporotic and major osteoporotic fractures) were reported based on study questions.Results Twenty-one studies including 55,164 women and 13,742 men were included in the meta-analysis with a total follow-up of 279,124 person-years. All four QUS parameters were associated with risk of different fracture. For instance, RR of hip fracture for 1 SD decrease of BUA was 1.69 (95% CI 1.43-2.00), SOS was 1.96 (95% CI 1.64-2.34), SI was 2.26 (95%CI 1.71-2.99) and QUI was 1.99 (95% CI 1.49-2.67). There was marked heterogeneity among studies on hip and any clinical fractures but no evidence of publication bias amongst them. Validated devices from different manufacturers predicted fracture risks with similar performance (meta-regression p values > 0.05 for difference of devices). QUS measures predicted fracture with a similar performance in men and women. Meta-analysis of studies with QUS measures adjusted for hip BMD showed a significant and independent association with fracture risk (RR/SD for BUA = 1.34 [95%CI 1.22-1.49]).Conclusions This study confirms that heel QUS, using validated devices, predicts risk of different fracture outcomes in elderly men and women. Further research is needed for more widespread utilisation of the heel QUS in clinical settings across the world.

Prevalence of Helicobacter pylori Infection in a Rural Area of the State of Mato Grosso, Brazil

The prevalence of Helicobacter pylori infection was evaluated by ELISA in 40 children and teenagers and in 164 adults from a rural area of the State of Mato Grosso, Brazil. Antibodies to H. pylori were detected in the serum of 31 (77.5%) children and teenagers and in 139 (84.7%) adults. The prevalence of infection increased with age (c2 for trend, p < 0.01) even though no variations occurred in the region in the present century in terms of living conditions or sanitation, economical development and migratory influx supporting the hypothesis that the infection is also acquired during later life in developing countries. An inverse correlation was observed between the prevalence of infection and annual family income (c2 for trend, p < 0.013). There was no correlation between type of system for sewage disposal and prevalence of infection (p = 0.8). In conclusion, the prevalence of H. pylori infection in Nossa Senhora do Livramento, a rural area from Brazil, is very high and similar to that observed in other developing countries. Furthermore, the increase in the prevalence of infection with age observed in this population seems to be due to both, cohort effect and acquisition of the infection during later life

Insomnia in hospitalised patients with advanced disease: prevalence and related factors

Objectiu: Avaluar prevalença i factors associats a l’insomni en pacients ingressats a una unitat de cures pal•liatives. Mètode: Entrevista estructurada a pacients consecutivament ingressats avaluant l’insomni a través de l’escala Sleep Disturbance Scale, i els factors físics, psicològics i ambientals potencialment associats. Resultats principals: El 47% presentà insomni moderat a sever. Els factors potencialment associats més prevalents foren dolor, distrés psicològic, rumiacions nocturnes i factors ambientals. En l’anàlisi multivariada, rumiacions nocturnes i somnolència diürna (relació inversa) es relacionaren amb insomni moderat a sever. Conclusions: L’insomni és un símptoma prevalent relacionat amb rumiacions nocturnes i absència de somnolència diürna.

Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma.

BACKGROUND & AIMS: Recently, genetic variations in MICA (lead single nucleotide polymorphism [SNP] rs2596542) were identified by a genome-wide association study (GWAS) to be associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) in Japanese patients. In the present study, we sought to determine whether this SNP is predictive of HCC development in the Caucasian population as well. METHODS: An extended region around rs2596542 was genotyped in 1924 HCV-infected patients from the Swiss Hepatitis C Cohort Study (SCCS). Pair-wise correlation between key SNPs was calculated both in the Japanese and European populations (HapMap3: CEU and JPT). RESULTS: To our surprise, the minor allele A of rs2596542 in proximity of MICA appeared to have a protective impact on HCC development in Caucasians, which represents an inverse association as compared to the one observed in the Japanese population. Detailed fine-mapping analyses revealed a new SNP in HCP5 (rs2244546) upstream of MICA as strong predictor of HCV-related HCC in the SCCS (univariable p=0.027; multivariable p=0.0002, odds ratio=3.96, 95% confidence interval=1.90-8.27). This newly identified SNP had a similarly directed effect on HCC in both Caucasian and Japanese populations, suggesting that rs2244546 may better tag a putative true variant than the originally identified SNPs. CONCLUSIONS: Our data confirms the MICA/HCP5 region as susceptibility locus for HCV-related HCC and identifies rs2244546 in HCP5 as a novel tagging SNP. In addition, our data exemplify the need for conducting meta-analyses of cohorts of different ethnicities in order to fine map GWAS signals.

Monitoring the domiciliary and peridomiciliary invasion process of Triatoma rubrovaria in the State of Rio Grande do Sul, Brazil

The presence of Triatoma rubrovaria in Brazil has only been confirmed in the States of Paraná and Rio Grande do Sul (RS), where it is found naturally infected with Trypanosoma cruzi. In the wild environment it occurs in rocky habitats and has an eclectic diet, feeding from cockroaches, reptiles and mammals. Data from the Chagas Disease Control Program obtained by the Fundação Nacional de Saúde, between 1975 and 1997, indicate a growing domiciliary and peridomiciliary invasion of T. rubrovaria in RS, where it has become the most frequently Triatominae species captured in this state since the control of Triatoma infestans. In order to monitor this process, we analyzed collection data derived from 22 years of control campaigns against T. infestans. Collection data for triatomines from domestic habitats show an inverse relationship, with high numbers of T. infestans and low numbers of T. rubrovaria during 1976-1987, compared to the following ten years, 1986-1997, when the number of T. infestans dropped drastically and that of T. rubrovaria increased. There are no consistent indications of intradomiciliary colonization by T. rubrovaria, since only low numbers of nymphs have been captured in the intradomiciliary ecotopes. Nevertheless, this species appears to have preadaptive characteristics for anthropic ecotopes, and should be kept under constant epidemiological surveillance.

Heterogeneity of human monocytes: an optimized four-color flow cytometry protocol for analysis of monocyte subsets.

Monocytes are central mediators in the development of atherosclerotic plaques. They circulate in blood and eventually migrate into tissue including the vessel wall where they give rise to macrophages and dendritic cells. The existence of monocyte subsets with distinct roles in homeostasis and inflammation suggests specialization of function. These subsets are identified based on expression of the CD14 and CD16 markers. Routinely applicable protocols remain elusive, however. Here, we present an optimized four-color flow cytometry protocol for analysis of human blood monocyte subsets using a specific PE-Cy5-conjugated monoclonal antibody (mAb) to HLA-DR, a PE-Cy7-conjugated mAb to CD14, a FITC-conjugated mAb to CD16, and PE-conjugated mAbs to additional markers relevant to monocyte function. Classical CD14(+)CD16(-) monocytes (here termed "Mo1" subset) expressed high CCR2, CD36, CD64, and CD62L, but low CX(3)CR1, whereas "nonclassical" CD14(lo)CD16(+) monocytes (Mo3) essentially showed the inverse expression pattern. CD14(+)CD16(+) monocytes (Mo2) expressed high HLA-DR, CD36, and CD64. In patients with stable coronary artery disease (n = 13), classical monocytes were decreased, whereas "nonclassical" monocytes were increased 90% compared with healthy subjects with angiographically normal coronary arteries (n = 14). Classical monocytes from CAD patients expressed higher CX(3)CR1 and CCR2 than controls. Thus, stable CAD is associated with expansion of the nonclassical monocyte subset and increased expression of inflammatory markers on monocytes. Flow cytometric analysis of monocyte subsets and marker expression may provide valuable information on vascular inflammation. This may translate into the identification of monocyte subsets as selective therapeutic targets, thus avoiding adverse events associated with indiscriminate monocyte inhibition.

Quantitative integration of geophysical and hydraulic data : from the local towards the regional scale range

Des progrès significatifs ont été réalisés dans le domaine de l'intégration quantitative des données géophysique et hydrologique l'échelle locale. Cependant, l'extension à de plus grandes échelles des approches correspondantes constitue encore un défi majeur. Il est néanmoins extrêmement important de relever ce défi pour développer des modèles fiables de flux des eaux souterraines et de transport de contaminant. Pour résoudre ce problème, j'ai développé une technique d'intégration des données hydrogéophysiques basée sur une procédure bayésienne de simulation séquentielle en deux étapes. Cette procédure vise des problèmes à plus grande échelle. L'objectif est de simuler la distribution d'un paramètre hydraulique cible à partir, d'une part, de mesures d'un paramètre géophysique pertinent qui couvrent l'espace de manière exhaustive, mais avec une faible résolution (spatiale) et, d'autre part, de mesures locales de très haute résolution des mêmes paramètres géophysique et hydraulique. Pour cela, mon algorithme lie dans un premier temps les données géophysiques de faible et de haute résolution à travers une procédure de réduction déchelle. Les données géophysiques régionales réduites sont ensuite reliées au champ du paramètre hydraulique à haute résolution. J'illustre d'abord l'application de cette nouvelle approche dintégration des données à une base de données synthétiques réaliste. Celle-ci est constituée de mesures de conductivité hydraulique et électrique de haute résolution réalisées dans les mêmes forages ainsi que destimations des conductivités électriques obtenues à partir de mesures de tomographic de résistivité électrique (ERT) sur l'ensemble de l'espace. Ces dernières mesures ont une faible résolution spatiale. La viabilité globale de cette méthode est testée en effectuant les simulations de flux et de transport au travers du modèle original du champ de conductivité hydraulique ainsi que du modèle simulé. Les simulations sont alors comparées. Les résultats obtenus indiquent que la procédure dintégration des données proposée permet d'obtenir des estimations de la conductivité en adéquation avec la structure à grande échelle ainsi que des predictions fiables des caractéristiques de transports sur des distances de moyenne à grande échelle. Les résultats correspondant au scénario de terrain indiquent que l'approche d'intégration des données nouvellement mise au point est capable d'appréhender correctement les hétérogénéitées à petite échelle aussi bien que les tendances à gande échelle du champ hydraulique prévalent. Les résultats montrent également une flexibilté remarquable et une robustesse de cette nouvelle approche dintégration des données. De ce fait, elle est susceptible d'être appliquée à un large éventail de données géophysiques et hydrologiques, à toutes les gammes déchelles. Dans la deuxième partie de ma thèse, j'évalue en détail la viabilité du réechantillonnage geostatique séquentiel comme mécanisme de proposition pour les méthodes Markov Chain Monte Carlo (MCMC) appliquées à des probmes inverses géophysiques et hydrologiques de grande dimension . L'objectif est de permettre une quantification plus précise et plus réaliste des incertitudes associées aux modèles obtenus. En considérant une série dexemples de tomographic radar puits à puits, j'étudie deux classes de stratégies de rééchantillonnage spatial en considérant leur habilité à générer efficacement et précisément des réalisations de la distribution postérieure bayésienne. Les résultats obtenus montrent que, malgré sa popularité, le réechantillonnage séquentiel est plutôt inefficace à générer des échantillons postérieurs indépendants pour des études de cas synthétiques réalistes, notamment pour le cas assez communs et importants où il existe de fortes corrélations spatiales entre le modèle et les paramètres. Pour résoudre ce problème, j'ai développé un nouvelle approche de perturbation basée sur une déformation progressive. Cette approche est flexible en ce qui concerne le nombre de paramètres du modèle et lintensité de la perturbation. Par rapport au rééchantillonage séquentiel, cette nouvelle approche s'avère être très efficace pour diminuer le nombre requis d'itérations pour générer des échantillons indépendants à partir de la distribution postérieure bayésienne. - Significant progress has been made with regard to the quantitative integration of geophysical and hydrological data at the local scale. However, extending corresponding approaches beyond the local scale still represents a major challenge, yet is critically important for the development of reliable groundwater flow and contaminant transport models. To address this issue, I have developed a hydrogeophysical data integration technique based on a two-step Bayesian sequential simulation procedure that is specifically targeted towards larger-scale problems. The objective is to simulate the distribution of a target hydraulic parameter based on spatially exhaustive, but poorly resolved, measurements of a pertinent geophysical parameter and locally highly resolved, but spatially sparse, measurements of the considered geophysical and hydraulic parameters. To this end, my algorithm links the low- and high-resolution geophysical data via a downscaling procedure before relating the downscaled regional-scale geophysical data to the high-resolution hydraulic parameter field. I first illustrate the application of this novel data integration approach to a realistic synthetic database consisting of collocated high-resolution borehole measurements of the hydraulic and electrical conductivities and spatially exhaustive, low-resolution electrical conductivity estimates obtained from electrical resistivity tomography (ERT). The overall viability of this method is tested and verified by performing and comparing flow and transport simulations through the original and simulated hydraulic conductivity fields. The corresponding results indicate that the proposed data integration procedure does indeed allow for obtaining faithful estimates of the larger-scale hydraulic conductivity structure and reliable predictions of the transport characteristics over medium- to regional-scale distances. The approach is then applied to a corresponding field scenario consisting of collocated high- resolution measurements of the electrical conductivity, as measured using a cone penetrometer testing (CPT) system, and the hydraulic conductivity, as estimated from electromagnetic flowmeter and slug test measurements, in combination with spatially exhaustive low-resolution electrical conductivity estimates obtained from surface-based electrical resistivity tomography (ERT). The corresponding results indicate that the newly developed data integration approach is indeed capable of adequately capturing both the small-scale heterogeneity as well as the larger-scale trend of the prevailing hydraulic conductivity field. The results also indicate that this novel data integration approach is remarkably flexible and robust and hence can be expected to be applicable to a wide range of geophysical and hydrological data at all scale ranges. In the second part of my thesis, I evaluate in detail the viability of sequential geostatistical resampling as a proposal mechanism for Markov Chain Monte Carlo (MCMC) methods applied to high-dimensional geophysical and hydrological inverse problems in order to allow for a more accurate and realistic quantification of the uncertainty associated with the thus inferred models. Focusing on a series of pertinent crosshole georadar tomographic examples, I investigated two classes of geostatistical resampling strategies with regard to their ability to efficiently and accurately generate independent realizations from the Bayesian posterior distribution. The corresponding results indicate that, despite its popularity, sequential resampling is rather inefficient at drawing independent posterior samples for realistic synthetic case studies, notably for the practically common and important scenario of pronounced spatial correlation between model parameters. To address this issue, I have developed a new gradual-deformation-based perturbation approach, which is flexible with regard to the number of model parameters as well as the perturbation strength. Compared to sequential resampling, this newly proposed approach was proven to be highly effective in decreasing the number of iterations required for drawing independent samples from the Bayesian posterior distribution.

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.