Modeling screening, prevention, and delaying of Alzheimer's disease: an early-stage decision analytic model

<p>Abstract</p> <p>Background</p> <p>Alzheimer's Disease (AD) affects a growing proportion of the population each year. Novel therapies on the horizon may slow the progress of AD symptoms and avoid cases altogether. Initiating treatment for the underlying pathology of AD would ideally be based on biomarker screening tools identifying pre-symptomatic individuals. Early-stage modeling provides estimates of potential outcomes and informs policy development.</p> <p>Methods</p> <p>A time-to-event (TTE) simulation provided estimates of screening asymptomatic patients in the general population age ≥55 and treatment impact on the number of patients reaching AD. Patients were followed from AD screen until all-cause death. Baseline sensitivity and specificity were 0.87 and 0.78, with treatment on positive screen. Treatment slowed progression by 50%. Events were scheduled using literature-based age-dependent incidences of AD and death.</p> <p>Results</p> <p>The base case results indicated increased AD free years (AD-FYs) through delays in onset and a reduction of 20 AD cases per 1000 screened individuals. Patients completely avoiding AD accounted for 61% of the incremental AD-FYs gained. Total years of treatment per 1000 screened patients was 2,611. The number-needed-to-screen was 51 and the number-needed-to-treat was 12 to avoid one case of AD. One-way sensitivity analysis indicated that duration of screening sensitivity and rescreen interval impact AD-FYs the most. A two-way sensitivity analysis found that for a test with an extended duration of sensitivity (15 years) the number of AD cases avoided was 6,000-7,000 cases for a test with higher sensitivity and specificity (0.90,0.90).</p> <p>Conclusions</p> <p>This study yielded valuable parameter range estimates at an early stage in the study of screening for AD. Analysis identified duration of screening sensitivity as a key variable that may be unavailable from clinical trials.</p

Lithic technological responses to Late Pleistocene glacial cycling at Pinnacle Point Site 5-6, South Africa

There are multiple hypotheses for human responses to glacial cycling in the Late Pleistocene, including changes in population size, interconnectedness, and mobility. Lithic technological analysis informs us of human responses to environmental change because lithic assemblage characteristics are a reflection of raw material transport, reduction, and discard behaviors that depend on hunter-gatherer social and economic decisions. Pinnacle Point Site 5-6 (PP5-6), Western Cape, South Africa is an ideal locality for examining the influence of glacial cycling on early modern human behaviors because it preserves a long sequence spanning marine isotope stages (MIS) 5, 4, and 3 and is associated with robust records of paleoenvironmental change. The analysis presented here addresses the question, what, if any, lithic assemblage traits at PP5-6 represent changing behavioral responses to the MIS 5-4-3 interglacial-glacial cycle? It statistically evaluates changes in 93 traits with no a priori assumptions about which traits may significantly associate with MIS. In contrast to other studies that claim that there is little relationship between broad-scale patterns of climate change and lithic technology, we identified the following characteristics that are associated with MIS 4: increased use of quartz, increased evidence for outcrop sources of quartzite and silcrete, increased evidence for earlier stages of reduction in silcrete, evidence for increased flaking efficiency in all raw material types, and changes in tool types and function for silcrete. Based on these results, we suggest that foragers responded to MIS 4 glacial environmental conditions at PP5-6 with increased population or group sizes, 'place provisioning', longer and/or more intense site occupations, and decreased residential mobility. Several other traits, including silcrete frequency, do not exhibit an association with MIS. Backed pieces, once they appear in the PP5-6 record during MIS 4, persist through MIS 3. Changing paleoenvironments explain some, but not all temporal technological variability at PP5-6.Social Science and Humanities Research Council of Canada; NORAM; American-Scandinavian Foundation; Fundacao para a Ciencia e Tecnologia [SFRH/BPD/73598/2010]; IGERT [DGE 0801634]; Hyde Family Foundations; Institute of Human Origins; National Science Foundation [BCS-9912465, BCS-0130713, BCS-0524087, BCS-1138073]; John Templeton Foundation to the Institute of Human Origins at Arizona State Universit

Indigenous identity, natural resources, and contentious politics in Bolivia: a disaggregated conflict analysis; 2000-2011

How do natural resources and ethnic identity interact to incite or to mitigate social conflict? This article argues that high-value natural resources can act as an important catalyst for the politicization of ethnic, specifically indigenous identity, and contribute to social conflict as they limit the malleability of identity frames and raise the stakes of confrontations. We test this argument using unique subnational data from Bolivian provinces. Drawing on Bolivian newspaper reports, we code conflict events for all of the 112 provinces from 2000 to 2011. We join this conflict data with information on local ethnic composition from the census, the political representation of ethnic groups at the national level, as well as geo-spatial information on gas deposits. Using time-series cross-sectional count models, we show a significant conflict-promoting effect of the share of indigenous people in provinces with gas reserves, but not without

Genetic parameters for body weight, carcass chemical composition and yield in a broiler-layer cross developed for QTL mapping

The objective of this study was to estimate genetic and phenotypic correlations of body weight at 6 weeks of age (BW6), as well as final carcass yield, and moisture, protein, fat and ash contents, using data from 3,422 F2 chickens originated from reciprocal cross between a broiler and a layer line. Variance components were estimated by the REML method, using animal models for evaluating random additive genetic and fixed contemporary group (sex, hatch and genetic group) effects. The heritability estimates (h2) for BW6, carcass yield and percentage of carcass moisture were 0.31 ± 0.07, 0.20 ± 0.05 and 0.33 ± 0.07, respectively. The h2 for the percentages of protein, fat and ash on a dry matter basis were 0.48 ± 0.09, 0.55 ± 0.10 and 0.36 ± 0.08, respectively. BW6 had a positive genetic correlation with fat percentage in the carcass, but a negative one with protein and ash contents. Carcass yield, thus, appears to have only low genetic association with carcass composition traits. The genetic correlations observed between traits, measured on a dry matter basis, indicated that selection for carcass protein content may favor higher ash content and a lower percentage of carcass fat

Hippurate as a metabolomic marker of gut microbiome diversity: Modulation by diet and relationship to metabolic syndrome

Reduced gut microbiome diversity is associated with multiple disorders including metabolic syndrome (MetS) features, though metabolomic markers have not been investigated. Our objective was to identify blood metabolite markers of gut microbiome diversity, and explore their relationship with dietary intake and MetS. We examined associations between Shannon diversity and 292 metabolites profiled by the untargeted metabolomics provider Metabolon Inc. in 1529 females from TwinsUK using linear regressions adjusting for confounders and multiple testing (Bonferroni: P < 1.71 × 10−4). We replicated the top results in an independent sample of 420 individuals as well as discordant identical twin pairs and explored associations with self-reported intakes of 20 food groups. Longitudinal changes in circulating levels of the top metabolite, were examined for their association with food intake at baseline and with MetS at endpoint. Five metabolites were associated with microbiome diversity and replicated in the independent sample. Higher intakes of fruit and whole grains were associated with higher levels of hippurate cross-sectionally and longitudinally. An increasing hippurate trend was associated with reduced odds of having MetS (OR: 0.795[0.082]; P = 0.026). These data add further weight to the key role of the microbiome as a potential mediator of the impact of dietary intake on metabolic status and health

Integrating climate adaptation, water governance and conflict management policies in lake riparian zones: insights from African drylands

As river basin authorities and national governments develop policies to achieve sustainable development outcomes, conflicting signals between existing policies are undermining cross-thematic integrative modes of policy planning. This raises fundamental questions over how coherent portfolios of policy interventions across vital themes can best be advanced and managed. Taking the Lake Chad Basin (LCB) as an empirical example, we analyse transboundary policies and intervention documents relating to climate adaptation, water governance and conflict management to ascertain the interdependencies at the adaptation-water-peace nexus. Using a Qualitative Document Analysis (QDA) approach and a set of subjective integration scoring criteria, we assess whether and how integration is planned, setting out ways forward for mutually beneficial integration actions.Despite recent progress in addressing lake drying and recognising cross-thematic challenges, most LCB intervention plans continue to adopt standalone basin-scale agendas and seldom consider action plan preparedness based on local-level assessments. Analysis of a few (existing) cross-thematic, well-integrated initiatives indicates that the timings of societal challenges and funding arrangements appear to play a key role in shaping policy strategies, the manner in which climate adaptation, water or security are treated and the level of integration attained. Based on the notion that integration is inherently desirable, we suggest a new ‘policy integration thinking’ that embraces a development landscape logic and balances short-term and long-term development priorities

“Trait EI in the relationship between needs fulfilment and symptoms and attitudes associated with EDs”

Eating disorders (EDs) are a set of pathologies, which have been increasing in prevalence in the recent years, suggesting the importance of studying symptoms and attitudes associated with EDs in depth. Several studies have showed that both psychological basic needs and trait emotion intelligence (trait EI) are relevant aspects of EDs, however these two aspects were never tested concurrently. Previous studies have shown that self-determined motivation could be a plausible antecedent that may account for individual variation in trait EI, and for this reason, it seems to be extremely relevant to integrate trait EI in a Self-Determination Theory (SDT) framework. The aim of this study is to test a mediation model of trait EI in the relationship between need fulfilment and eating disorders. In a sample of 159 females aged between 16 and 22 years old (M = 18.71; SD = 1.98) instruments were administered to measure the basic psychological needs, trait EI, and eating disorders. Results of this study showed that need fulfilment was negatively related to eating disorders and positively related to trait EI, whereas trait EI was negatively related to eating disorders. Furthermore, trait EI has shown a mediation role in the relation between basic psychological needs and eating disorders

“Trait EI in the relationship between needs fulfilment and symptoms and attitudes associated with EDs”

Eating disorders (EDs) are a set of pathologies, which have been increasing in prevalence in the recent years, suggesting the importance of studying symptoms and attitudes associated with EDs in depth. Several studies have showed that both psychological basic needs and trait emotion intelligence (trait EI) are relevant aspects of EDs, however these two aspects were never tested concurrently. Previous studies have shown that self-determined motivation could be a plausible antecedent that may account for individual variation in trait EI, and for this reason, it seems to be extremely relevant to integrate trait EI in a Self-Determination Theory (SDT) framework. The aim of this study is to test a mediation model of trait EI in the relationship between need fulfilment and eating disorders. In a sample of 159 females aged between 16 and 22 years old (M = 18.71; SD = 1.98) instruments were administered to measure the basic psychological needs, trait EI, and eating disorders. Results of this study showed that need fulfilment was negatively related to eating disorders and positively related to trait EI, whereas trait EI was negatively related to eating disorders. Furthermore, trait EI has shown a mediation role in the relation between basic psychological needs and eating disorders

Two Host Factors Regulate Persistence of H7a-Specific T Cells Injected in Tumor-Bearing Mice

BACKGROUND: Injection of CD8 T cells primed against immunodominant minor histocompatibility antigens (MiHA) such as H7(a) can eradicate leukemia and solid tumors. To understand why MiHA-targeted T cells have such a potent antitumor effect it is essential to evaluate their in vivo behavior. In the present work, we therefore addressed two specific questions: what is the proliferative dynamics of H7(a)-specifc T cells in tumors, and do H7(a)-specific T cells persist long-term after adoptive transfer? METHODOLOGY/PRINCIPAL FINDINGS: By day 3 after adoptive transfer, we observed a selective infiltration of melanomas by anti-H7(a) T cells. Over the next five days, anti-H7(a) T cells expanded massively in the tumor but not in the spleen. Thus, by day 8 after injection, anti-H7(a) T cells in the tumor had undergone more cell divisions than those in the spleen. These data strongly suggest that anti-H7(a) T cells proliferate preferentially and extensively in the tumors. We also found that two host factors regulated long-term persistence of anti-H7(a) memory T cells: thymic function and expression of H7(a) by host cells. On day 100, anti-H7(a) memory T cells were abundant in euthymic H7(a)-negative (B10.H7(b)) mice, present in low numbers in thymectomized H7(a)-positive (B10) hosts, and undetectable in euthymic H7(a)-positive recipients. CONCLUSIONS/SIGNIFICANCE: Although in general the tumor environment is not propitious to T-cell invasion and expansion, the present work shows that this limitation may be overcome by adoptive transfer of primed CD8 T cells targeted to an immunodominant MiHA (here H7(a)). At least in some cases, prolonged persistence of adoptively transferred T cells may be valuable for prevention of late cancer relapse in adoptive hosts. Our findings therefore suggest that it may be advantageous to target MiHAs with a restricted tissue distribution in order to promote persistence of memory T cells and thereby minimize the risk of cancer recurrence