The analysis of longitudinal studies of common diseases of childhood

Intensive, community-based, prospective studies have become increasingly popular for the study of the common diseases of childhood (diarrhoea, respiratory infections and malaria). The wealth of data collected in these studies permits the estimation of a range of outcome measures describing the incidence, prevalence and duration of disease. However, standard epidemiological and statistical techniques for the analysis of prospective studies were conceived with rare and non-recurrent diseases in mind, and their application to the case of common diseases is not always valid. This thesis provides a comprehensive approach to the analysis of longitudinal studies of common diseases of childhood. Starting with recommendations for successful data handling, it describes the definition, evaluation and calculation of a number of different epidemiological outcome measures, and then proceeds to investigate appropriate strategies for statistical modelling. At all stages, differences between studies of common diseases and the more familiar rare-disease studies are highlighted. The implications of these features of common disease studies for the validity of results obtained by using ‘standard’ analytic techniques are evaluated. A number of more ‘sophisticated’ analytic techniques are compared and contrasted, using criteria specifically proposed for the evaluation of statistical models in epidemiology. This evaluation is based to a large degree on illustrative analyses, using data used collected in a trial of the impact of vitamin A supplementation on the health of young children in Ghana, together with data from a rotavirus vaccine trial in Peru. Wide-ranging reviews are undertaken of the epidemiological literature on common diseases of childhood, permitting the characterisation of the range of analytic practices currently encountered. Recent advances in statistical theory are also critically described. These insights are combined to produce a series of pragmatic recommendations intended as guidance for those working on longitudinal studies of common diseases of childhood in the field

Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy

A paradigm shift has recently occurred in the field of cancer therapeutics. Traditional anticancer agents, such as chemotherapy, radiotherapy and small-molecule drugs targeting specific signalling pathways, have been joined by cellular immunotherapies based on T cell engineering. The rapid adoption of novel, patient-specific cellular therapies builds on scientific developments in tumour immunology, genetic engineering and cell manufacturing, best illustrated by the curative potential of chimeric antigen receptor (CAR) T cell therapy targeting CD19-expressing malignancies. However, the clinical benefit observed in many patients may come at a cost. In up to one-third of patients, significant toxicities occur that are directly associated with the induction of powerful immune effector responses. The most frequently observed immune-mediated toxicities are cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. This Review discusses our current understanding of their pathophysiology and clinical features, as well as the development of novel therapeutics for their prevention and/or management

Recreational Physical Activity as an Independent Predictor of Multivariable Cardiovascular Disease Risk

The role of physical activity in preventing CVD has been highlighted by Professor Jerry Morris in the 1950’s. We report outcome of a 15-year prospective study with the aim to identify whether physical activity showed cardiovascular benefit independent of common risk factors and of central obesity. Baseline data of 8662 subjects, with no previous history of heart disease, diabetes or stroke, were obtained from an age- and gender- stratified sample of adults in Australian capital cities and were linked with the National Death Index to determine the causes of death of 610 subjects who had died to 31 December 2004. The study consisted of 4175 males (age 42.3±13.1 years) and 4487 females (age 42.8±13.2 years). Fasting serum lipid levels, systolic and diastolic blood pressure and smoking habits at baseline were recorded. The Framingham Risk Scores of 15-year mortality due to CHD and CVD were calculated using established equations. Subjects were also asked if they engaged in vigorous exercise, less vigorous exercise or walk for recreation and exercise in the past 2 weeks. Subjects in the high recreational physical activity category were 0.16 (0.06–0.43; p<0.001) and 0.12 (0.03–0.48; p = 0.003) times as likely as subjects in the low category for CVD and CHD mortality respectively. After adjusting for both the Framingham Risk Score and central obesity (Waist circumference to Hip circumference Ratio), those in the high recreational physical activity group were 0.35 (0.13–0.98) times less likely compared to the low category for CVD mortality. Recreational physical activity independently predicted reduced cardiovascular mortality over fifteen years. A public health focus on increased physical activity and preventing obesity is required to reduce the risk of CVD and CHD

Global Health Estimates: Stronger Collaboration Needed with Low- and Middle-Income Countries

Osman Sankoh argues for much stronger collaboration between generators of global health estimates, and individuals and organizations working at the country level, as part of a PLoS Medicine cluster of articles on global health estimates

The global field of multi-family offices: An institutionalist perspective

We apply the notion of the organisational field to internationally operating multi-family offices. These organisations specialise on the preservation of enterprising and geographically dispersed families’ fortunes. They provide their services across generations and countries. Based on secondary data of Bloomberg’s Top 50 Family Offices, we show that they constitute a global organisational field that comprises two clusters of homogeneity. Clients may decide between two different configurations of activities, depending on their preferences regarding asset management, resource management, family management, and service architecture. The findings also reveal that multi-family offices make relatively similar value propositions all over the world. The distinctiveness of the clusters within the field is not driven by the embeddedness of the multi-family offices in different national environments or their various degrees of international experience. Rather, it is weakly affected by two out of four possible value propositions, namely the exclusiveness and the transparency of services

Association between the c.*229C>T polymorphism of the topoisomerase IIb binding protein 1 (TopBP1) gene and breast cancer

Topoisomerase IIb binding protein 1 (TopBP1) is involved in cell survival, DNA replication, DNA damage repair and cell cycle checkpoint control. The biological function of TopBP1 and its close relation with BRCA1 prompted us to investigate whether alterations in the TopBP1 gene can influence the risk of breast cancer. The aim of this study was to examine the association between five polymorphisms (rs185903567, rs116645643, rs115160714, rs116195487, and rs112843513) located in the 30UTR region of the TopBP1 gene and breast cancer risk as well as allele-specific gene expression. Five hundred thirty-four breast cancer patients and 556 population controls were genotyped for these SNPs. Allele-specific Top- BP1 mRNA and protein expressions were determined by using real time PCR and western blotting methods, respectively. Only one SNP (rs115160714) showed an association with breast cancer. Compared to homozygous common allele carriers, heterozygous and homozygous for the T variant had significantly increased risk of breast cancer (adjusted odds ratio = 3.81, 95 % confidence interval: 1.63–8.34, p = 0.001). Mean TopBP1 mRNA and protein expression were higher in the individuals with the CT or TT genotype. There was a significant association between the rs115160714 and tumor grade and stage. Most carriers of minor allele had a high grade (G3) tumors classified as T2-T4N1M0. Our study raises a possibility that a genetic variation of TopBP1 may be implicated in the etiology of breast cancer

Differences in the signaling pathways of α1A- and α1B-adrenoceptors are related to different endosomal targeting

Aims: To compare the constitutive and agonist-dependent endosomal trafficking of α1A- and α1B-adrenoceptors (ARs) and to establish if the internalization pattern determines the signaling pathways of each subtype. Methods: Using CypHer5 technology and VSV-G epitope tagged α1A- and α1B-ARs stably and transiently expressed in HEK 293 cells, we analyzed by confocal microscopy the constitutive and agonist-induced internalization of each subtype, and the temporal relationship between agonist induced internalization and the increase in intracellular calcium (determined by FLUO-3 flouorescence), or the phosphorylation of ERK1/2 and p38 MAP kinases (determined by Western blot). Results and Conclusions: Constitutive as well as agonist-induced trafficking of α1A and α1B ARs maintain two different endosomal pools of receptors: one located close to the plasma membrane and the other deeper into the cytosol. Each subtype exhibited specific characteristics of internalization and distribution between these pools that determines their signaling pathways: α1A-ARs, when located in the plasma membrane, signal through calcium and ERK1/2 pathways but, when translocated to deeper endosomes, through a mechanism sensitive to β-arrestin and concanavalin A, continue signaling through ERK1/2 and also activate the p38 pathway. α1B-ARs signal through calcium and ERK1/2 only when located in the membrane and the signals disappear after endocytosis and by disruption of the membrane lipid rafts by methyl-β-cyclodextrin

The role of asymmetric interactions on the effect of habitat destruction in mutualistic networks

Plant-pollinator mutualistic networks are asymmetric in their interactions: specialist plants are pollinated by generalist animals, while generalist plants are pollinated by a broad involving specialists and generalists. It has been suggested that this asymmetric ---or disassortative--- assemblage could play an important role in determining the equal susceptibility of specialist and generalist plants under habitat destruction. At the core of the argument lies the observation that specialist plants, otherwise candidates to extinction, could cope with the disruption thanks to their interaction with generalist pollinators. We present a theoretical framework that supports this thesis. We analyze a dynamical model of a system of mutualistic plants and pollinators, subject to the destruction of their habitat. We analyze and compare two families of interaction topologies, ranging from highly assortative to highly disassortative ones, as well as real pollination networks. We found that several features observed in natural systems are predicted by the mathematical model. First, there is a tendency to increase the asymmetry of the network as a result of the extinctions. Second, an entropy measure of the differential susceptibility to extinction of specialist and generalist species show that they tend to balance when the network is disassortative. Finally, the disappearance of links in the network, as a result of extinctions, shows that specialist plants preserve more connections than the corresponding plants in an assortative system, enabling them to resist the disruption.Comment: 14 pages, 7 figure

Economic factors influencing zoonotic disease dynamics: demand for poultry meat and seasonal transmission of avian influenza in Vietnam

While climate is often presented as a key factor influencing the seasonality of diseases, the importance of anthropogenic factors is less commonly evaluated. Using a combination of methods-wavelet analysis, economic analysis, statistical and disease transmission modelling-we aimed to explore the influence of climatic and economic factors on the seasonality of H5N1 Highly Pathogenic Avian Influenza in the domestic poultry population of Vietnam. We found that while climatic variables are associated with seasonal variation in the incidence of avian influenza outbreaks in the North of the country, this is not the case in the Centre and the South. In contrast, temporal patterns of H5N1 incidence are similar across these 3 regions: periods of high H5N1 incidence coincide with Lunar New Year festival, occurring in January-February, in the 3 climatic regions for 5 out of the 8 study years. Yet, daily poultry meat consumption drastically increases during Lunar New Year festival throughout the country. To meet this rise in demand, poultry production and trade are expected to peak around the festival period, promoting viral spread, which we demonstrated using a stochastic disease transmission model. This study illustrates the way in which economic factors may influence the dynamics of livestock pathogens