A model for measuring the health burden of classic congenital adrenal hyperplasia in adults

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Aim: Patients with classic Congenital Adrenal Hyperplasia (CAH) have poor health outcomes. In the absence of a comprehensive observational study, this manuscript provides a model to estimate the lifetime disease burden of adults with classic CAH. Methods: The model, built in Excel, comprises sub-domains addressing the health consequences of CAH, and synthesises evidence from clinical and epidemiological studies on health outcomes. Results: The model estimates that adults with classic CAH will implement “sick day rules” (doubling or tripling glucocorticoid and/or use of parenteral therapy) 171 times over their lifetime, and attend hospital for adrenal crisis on 11 occasions. In a population of 1,000, over 200 will die of a condition complicated by adrenal crisis resulting, on average, in a loss of 7 years of life. CAH patients may also suffer from excess CVD events. Treatment with glucocorticoids almost doubles the risk of bone fractures in CAH patients compared to the general population, leading on average to an additional 0.8 fractures per CAH patient over their lifetime. Conclusions: The disease burden model highlights gaps in evidence, particularly regarding intensity of care and adrenal crisis, and the relationship between control of CAH and risks of CVD, osteoporosis, diabetes and infertility. The model can be used for research on the impact of new clinical pathways and therapeutic interventions in terms of clinical events and cost.Funded by: European Commission under the Framework 7 programme. Grant Number: HEALTH-F5-2011-281654Diurnal Limited (UK

Selective progesterone receptor modulators (SPRMs): Progesterone receptor action, mode of action on the endometrium and treatment options in gynaecological therapies.

Introduction: The progesterone receptor plays an essential role in uterine physiology and reproduction. Selective progesterone receptor modulators (SPRMs) have emerged as a valuable treatment option for hormone dependent conditions like uterine fibroids, which have a major impact on women’s quality of life. SPRMs offer potential for longer term medical treatment and thereby patients may avoid surgical intervention. Areas covered: The authors have reviewed the functional role of the progesterone receptor and its isoforms and their molecular mechanisms of action via genomic and non-genomic pathways. The current knowledge of the interaction of the PR and different SPRMs tested in clinical trials has been reviewed. The authors focused on pharmacological effects of selected SPRMs on the endometrium, their anti-proliferative action, and their suppression of bleeding. Potential underlying molecular mechanisms and the specific histological changes in the endometrium induced by SPRMs (PAEC; Progesterone receptor modulator Associated Endometrial Changes) have been discussed. The clinical potential of this compound class including its impact on quality of life has been covered. Expert Opinion: Clinical studies indicate SPRMs hold promise for treatment of benign gynecological complaints (fibroids, heavy menstrual bleeding; HMB). There however remains a knowledge gap concerning mechanism of action

Apparatus for histological validation of in vivo and ex vivo magnetic resonance imaging of the human prostate

This article describes apparatus to aid histological validation of magnetic resonance imaging studies of the human prostate. The apparatus includes a 3D-printed patientspecific mold that facilitates aligned in vivo and ex vivo imaging, in situ tissue fixation, and tissue sectioning with minimal organ deformation. The mold and a dedicated container include MRI-visible landmarks to enable consistent tissue positioning and minimize image registration complexity. The inclusion of high spatial resolution ex vivo imaging aids in registration of in vivo MRI and histopathology data

Modelling stereotyping in cooperation systems

Cooperation is a sophisticated example of collective intelligence. This is particularly the case for indirect reciprocity, where benefit is provided to others without a guarantee of a future return. This is becoming increasingly relevant to future technology, where autonomous machines face cooperative dilemmas. This paper addresses the problem of stereotyping, where traits belonging to an individual are used as proxy when assessing their reputation. This is a cognitive heuristic that humans frequently use to avoid deliberation, but can lead to negative societal implications such as discrimination. It is feasible that machines could be equally susceptible. Our contribution concerns a new and general framework to examine how stereotyping affects the reputation of agents engaging in indirect reciprocity. The framework is flexible and focuses on how reputations are shared. This offers the opportunity to assess the interplay between the sharing of traits and the cost, in terms of reduced cooperation, through opportunities for shirkers to benefit. This is demonstrated using a number of key scenarios. In particular, the results show that cooperation is sensitive to the structure of reputation sharing between individuals

Children grow and horses race: is the adiposity rebound a critical period for later obesity?

BACKGROUND: The adiposity rebound is the second rise in body mass index that occurs between 3 and 7 years. An early age at adiposity rebound is known to be a risk factor for later obesity. The aim here is to clarify the connection between the age at rebound and the corresponding pattern of body mass index change, in centile terms, so as to better understand its ability to predict later fatness. DISCUSSION: Longitudinal changes in body mass index during adiposity rebound, measured both in original (kg/m(2)) and standard deviation (SD) score units, are studied in five hypothetical subjects. Two aspects of the body mass index curve, the body mass index centile and the rate of body mass index centile crossing, determine a child's age at rebound. A high centile and upward centile crossing are both associated separately with an early rebound, while a low centile and/or downward centile crossing correspond to a late rebound. Early adiposity rebound is a risk factor for later fatness because it identifies children whose body mass index centile is high and/or crossing upwards. Such children are likely to have a raised body mass index later in childhood and adulthood. This is an example of Peto's "horse racing effect". The association of centile crossing with later obesity is statistical not physiological, and it applies at all ages not just at rebound, so adiposity rebound cannot be considered a critical period for future obesity. Body mass index centile crossing is a more direct indicator of the underlying drive to fatness. SUMMARY: An early age at adiposity rebound predicts later fatness because it identifies children whose body mass index centile is high and/or crossing upwards. Such children are likely to have a raised body mass index later. Body mass index centile crossing is more direct than the timing of adiposity rebound for predicting later fatness

Vibro-Injection Pile Installation in Sand: Part I—Interpretation as Multi-material Flow

The installation of vibro-injection piles into saturated sand has a significant impact on the surrounding soil and neighboring buildings. It is generally characterized by a multi-material flow with large material deformations, non-stationary and new material interfaces, and by the interaction of the grain skeleton and the pore water. Part 1 in this series of papers is concerned with the mathematical and physical modeling of the multi-material flow associated with vibro-injection pile installation. This model is the backbone of a new multi-material arbitrary Lagrangian-Eulerian (MMALE) numerical method presented in Part 2.DFG, 76838227, Numerische Modellierung der Herstellung von Rüttelinjektionspfähle

Body mass index and height over three generations: evidence from the Lifeways cross-generational cohort study

Background: Obesity and its measure of body mass index are strongly determined by parental body size. Debate continues as to whether both parents contribute equally to offspring body mass which is key to understanding the aetiology of the disease. The aim of this study was to use cohort data from three generations of one family to examine the relative maternal and paternal associations with offspring body mass index and how these associations compare with family height to demonstrate evidence of genetic or environmental cross-generational transmission. Methods: 669 of 1082 families were followed up in 2007/8 as part of the Lifeways study, a prospective observational cross-generation linkage cohort. Height and weight were measured in 529 Irish children aged 5 to 7 years and were self-reported by parents and grandparents. All adults provided information on self-rated health, education status, and indicators of income, diet and physical activity. Associations between the weight, height, and body mass index of family members were examined with mixed models and heritability estimates computed using linear regression analysis. Results: Self-rated health was associated with lower BMI for all family members, as was age for children. When these effects were accounted for evidence of familial associations of BMI from one generation to the next was more apparent in the maternal line. Heritability estimates were higher (h2 = 0.40) for mother-offspring pairs compared to father-offspring pairs (h2 = 0.22). In the previous generation, estimates were higher between mothersparents (h2 = 0.54-0.60) but not between fathers-parents (h2 = -0.04-0.17). Correlations between mother and offspring across two generations remained significant when modelled with fixed variables of socioeconomic status, health, and lifestyle. A similar analysis of height showed strong familial associations from maternal and paternal lines across each generation. Conclusions: This is the first family cohort study to report an enduring association between mother and offspring BMI over three generations. The evidence of BMI transmission over three generations through the maternal line in an observational study corroborates the findings of animal studies. A more detailed analysis of geno and phenotypic data over three generations is warranted to understand the nature of this maternal-offspring relationship.TS 24.4.1

Genotype x environment interactions in eggplant for fruit phenolic acid content

Eggplant fruit are a rich source of phenolic acids that influence fruit culinary quality and antioxidant content. We evaluated the influence of production environments and stability of diverse genotypes across environments for eggplant fruit phenolic acid content. Ten Solanum melongena accessions consisting of five F-1 hybrid cultivars, three open-pollinated cultivars and two land race accessions, plus one S. macrocarpon and one S. aethiopicum accession, were grown at two locations under greenhouse and open field environments. Twenty phenolic acid conjugates were identified in fruit flesh and assigned to six classes that included hydroxycinnamic acid amides, caffeoylquinic acid esters, hydroxycinnamoylquinic acid esters, malonylcaffeoylquinic acid esters, di-hydroxycinnamoylquinic acid esters, and other hydroxycinnamic acid conjugates. There were significant differences among accessions for total phenolic acid conjugate content and for all six classes. There were no significant differences detected among the environments for any of the variables. However, the environment x accession interaction was highly significant for all phenolic acid classes. Broad-sense heritability estimates for all six phenolic acid classes were high, ranging from 0.64 to 0.96. Stability analysis demonstrated widespread instability for phenolic acid content across environments. Stability of the predominant caffeoylquinic acid esters class positively influenced stability of total phenolic acid content for some but not all genotypes. High heritability, coupled with highly significant genotype x environment interactions suggests that stability estimates may improve the efficiency of breeding new genotypes with predictable performance across environments.Stommel, JR.; Whitaker, B.; Haynes, K.; Prohens Tomás, J. (2015). Genotype x environment interactions in eggplant for fruit phenolic acid content. 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