Preclinical Assessment of HIV Vaccines and Microbicides by Repeated Low-Dose Virus Challenges

BACKGROUND: Trials in macaque models play an essential role in the evaluation of biomedical interventions that aim to prevent HIV infection, such as vaccines, microbicides, and systemic chemoprophylaxis. These trials are usually conducted with very high virus challenge doses that result in infection with certainty. However, these high challenge doses do not realistically reflect the low probability of HIV transmission in humans, and thus may rule out preventive interventions that could protect against “real life” exposures. The belief that experiments involving realistically low challenge doses require large numbers of animals has so far prevented the development of alternatives to using high challenge doses. METHODS AND FINDINGS: Using statistical power analysis, we investigate how many animals would be needed to conduct preclinical trials using low virus challenge doses. We show that experimental designs in which animals are repeatedly challenged with low doses do not require unfeasibly large numbers of animals to assess vaccine or microbicide success. CONCLUSION: Preclinical trials using repeated low-dose challenges represent a promising alternative approach to identify potential preventive interventions

Dendritic Cells are preferentially targeted among hematolymphocytes by Modified Vaccinia Virus Ankara and play a key role in the induction of virus-specific T cell responses in vivo

<p>Abstract</p> <p>Background</p> <p>Modified Vaccinia Ankara (MVA) is a highly attenuated strain of vaccinia virus (VV) that has lost approximately 15% of the VV genome, along with the ability to replicate in most mammalian cells. It has demonstrated impressive safety and immunogenicity profile in both preclinical and clinical studies, and is being actively explored as a promising vaccine vector for a number of infectious diseases and malignancies. However, little is known about how MVA interacts with the host immune system constituents, especially dendritic cells (DCs), to induce strong immune responses despite its inability to replicate in vivo. Using <it>in vitro </it>and <it>in vivo </it>murine models, we systematically investigated the susceptibility of murine DCs to MVA infection, and the immunological consequences of the infection.</p> <p>Results</p> <p>Our data demonstrate that MVA preferentially infects professional antigen presenting cells, especially DCs, among all the subsets of hematolymphoid cells. In contrast to the reported blockage of DC maturation and function upon VV infection, DCs infected by MVA undergo phenotypic maturation and produce innate cytokine IFN-α within 18 h of infection. Substantial apoptosis of MVA-infected DCs occurs after 12 h following infection and the apoptotic DCs are readily phagocytosed by uninfected DCs. Using MHC class I – deficient mice, we showed that both direct and cross-presentation of viral Ags are likely to be involved in generating viral-specific CD8⁺T cell responses. Finally, DC depletion abrogated the T cell activation <it>in vivo</it>.</p> <p>Conclusion</p> <p>We present the first <it>in vivo </it>evidence that among hematolymphoid cells, DCs are the most susceptible targets for MVA infection, and DC-mediated Ag presentation is required for the induction of MVA-specific immune responses. These results provide important information concerning the mechanisms by which strong immune responses are elicited to MVA-encoded antigens and may inform efforts to further improve the immunogenicity of this already promising vaccine vector.</p

The Coparenting Relationship Scale—Father’s Prenatal Version

"Published online: 27 June 2018"This study aimed to examine the psychometric characteristics of the Coparenting Relationship Scale when administered in fathers during pregnancy. During the first trimester of a partner’s pregnancy, 91 primiparous fathers completed the Coparenting Relationship Scale—Father’s Prenatal Version (CRS-FPV), and self-report measures of depressive and anxious symptoms, adult attachment, and partner’s relationship quality. The CRS-FPV revealed good internal consistency. Exploratory factor analysis revealed four factors: lack of coparenting support, coparenting conflict, coparenting disagreement, and coparenting undermining. Confirmatory factor analysis revealed a good model fit. Significant associations between the CRSFPV and the original CRS subscales were found. Hypothesized associations between the CRS-FPV subscales and individual (depressive and anxious symptoms and adult attachment) and dyadic (partner’s relationship quality) constructs were also significant. The present study suggested that the CRS-FPV is a reliable multidimensional measure to assess coparenting in fathers during pregnancy.This study was conducted at Psychology Research Centre (UID/PSI/01662/2013), University of Minho, and supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Education and Science through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007653). This study was also supported by FEDER Funds through the Programa Operacional Factores de Competitividade - COMPETE and by National Funds through FCT – Fundação para a Ciência e a Tecnologia under the project PTDC/SAU/SAP/116738/2010.info:eu-repo/semantics/publishedVersio

Reality Check: Combining Survey and Market Data to Estimate the Importance of Product Attributes

Discrete choice models estimated using hypothetical choices made in a survey setting (i.e., choice experiments) are widely used to estimate the importance of product attributes in order to make product design and marketing mix decisions. Choice experiments allow the researcher to estimate preferences for product features that do not yet exist in the market. However, parameters estimated from experimental data often show marked inconsistencies with those inferred from the market, reducing their usefulness in forecasting and decision making. We propose an approach for combining choice-based conjoint data with individual-level purchase data to produce estimates that are more consistent with the market. Unlike prior approaches for calibrating conjoint models so that they correctly predict aggregate market shares for a “baseline” market, the proposed approach is designed to produce parameters that are more consistent with those that can be inferred from individual-level market data. The proposed method relies on a new general framework for combining two or more sources of individual-level choice data to estimate a hierarchical discrete choice model. Past approaches to combining choice data assume that the population mean for the parameters is the same across both data sets and require that data sets are sampled from the same population. In contrast, we incorporate in the model individual characteristic variables, and assert only that the mapping between individuals\u27 characteristics and their preferences is the same across the data sets. This allows the model to be applied even if the sample of individuals observed in each data set is not representative of the population as a whole, so long as appropriate product-use variables are collected that can explain the systematic deviations between them. The framework also explicitly incorporates a model for the individual characteristics, which allows us to use Bayesian missing-data techniques to handle the situation where each data set contains different demographic variables. This makes the method useful in practice for a wide range of existing market and conjoint data sets. We apply the method to a set of conjoint and market data for minivan choice and find that the proposed method predicts holdout market choices better than a model estimated from conjoint data alone or a model that does not include demographic variables

Knowledge Lability: Within-Person Changes in Parental Knowledge and Their Associations with Adolescent Problem Behavior

Higher levels of parental knowledge about youth activities has been associated with lower levels of youth risky behavior. Yet little is known about how parental knowledge fluctuates during early adolescence and how those fluctuations are associated with the development of problem behavior. We use the term lability to describe within-person fluctuations in knowledge over time with higher lability indicating greater fluctuations in knowledge from year-to-year. This longitudinal study of rural adolescents (N = 840) investigated if change in parental knowledge across four waves of data from Grades 6 to 8 is characterized by lability, and if greater lability is associated with higher youth substance use, delinquency, and internalizing problems in Grade 9. Our models indicated that only some of the variance in parental knowledge was accounted for by developmental trends. The remaining residual variance reflects within-person fluctuations around these trends, lability, plus measurement and occasion-specific error. Even controlling for level and developmental trends in knowledge, higher knowledge lability (i.e., more fluctuation) was associated with increased risk for later alcohol and tobacco use, and for girls, higher delinquency and internalizing problems. Our findings suggest that lability in parental knowledge has unique implications for adolescent outcomes. The discussion focuses on mechanisms that may link knowledge lability to substance use. Interventions may be most effective if they teach parents to consistently and predictably decrease knowledge across early adolescence

Bidirectional Associations Between Coparenting Relations and Family Member Anxiety: A Review and Conceptual Model

Research into anxiety has largely ignored the dynamics of family systems in anxiety development. Coparenting refers to the quality of coordination between individuals responsible for the upbringing of children and links different subsystems within the family, such as the child, the marital relationship, and the parents. This review discusses the potential mechanisms and empirical findings regarding the bidirectional relations of parent and child anxiety with coparenting. The majority of studies point to bidirectional associations between greater coparenting difficulties and higher levels of anxiety. For example, the few available studies suggest that paternal and perhaps maternal anxiety is linked to lower coparental support. Also, research supports the existence of inverse links between coparenting quality and child anxiety. A child’s reactive temperament appears to have adverse effects on particularly coparenting of fathers. A conceptual model is proposed that integrates the role of parental and child anxiety, parenting, and coparenting, to guide future research and the development of clinical interventions. Future research should distinguish between fathers’ and mothers’ coparenting behaviors, include parental anxiety, and investigate the coparental relationship longitudinally. Clinicians should be aware of the reciprocal relations between child anxiety and coparenting quality, and families presenting for treatment who report child (or parent) anxiety should be assessed for difficulties in coparenting. Clinical approaches to bolster coparenting quality are called for.FSW – Publicaties zonder aanstelling Universiteit Leide

Hostile Interactions in the Family: Patterns and Links to Youth Externalizing Problems

In line with family systems theory, we examined patterns of hostile interactions within families and their associations with externalizing problems among early-adolescent children. Using hostility scores based on observational data of six dyadic interactions during a triadic interaction (n = 462; i.e., child-to-mother, mother-to-child, child-to-father, father-to-child, mother-to-father, father-to-mother)—latent profile analysis supported three distinct profiles of hostility. The low/moderate hostile profile included families with the lowest levels of hostility across dyads; families in the mutual parent-child hostile profile scored higher on parent-child hostility, but lower on interparental hostility; the hostile parent profile showed higher levels of parent-to-child and interparental hostility, but lower child-to-parent hostility. Concerning links to youth outcomes, youth in the mutual parent-child hostile profile reported the highest level of externalizing problems, both concurrently and longitudinally. These results point to the importance of examining larger family patterns of hostility to fully understand the association between family hostility and youth adjustment