Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection.

BackgroundWe reported previously on the emergence and clinical implications of simian immunodeficiency virus (SIVmac251) mutants with a K65R mutation in reverse transcriptase (RT), and the role of CD8+ cell-mediated immune responses in suppressing viremia during tenofovir therapy. Because of significant sequence differences between SIV and HIV-1 RT that affect drug susceptibilities and mutational patterns, it is unclear to what extent findings with SIV can be extrapolated to HIV-1 RT. Accordingly, to model HIV-1 RT responses, 12 macaques were inoculated with RT-SHIV, a chimeric SIV containing HIV-1 RT, and started on prolonged tenofovir therapy 5 months later.ResultsThe early virologic response to tenofovir correlated with baseline viral RNA levels and expression of the MHC class I allele Mamu-A*01. For all animals, sensitive real-time PCR assays detected the transient emergence of K70E RT mutants within 4 weeks of therapy, which were then replaced by K65R mutants within 12 weeks of therapy. For most animals, the occurrence of these mutations preceded a partial rebound of plasma viremia to levels that remained on average 10-fold below baseline values. One animal eventually suppressed K65R viremia to undetectable levels for more than 4 years; sequential experiments using CD8+ cell depletion and tenofovir interruption demonstrated that both CD8+ cells and continued tenofovir therapy were required for sustained suppression of viremia.ConclusionThis is the first evidence that tenofovir therapy can select directly for K70E viral mutants in vivo. The observations on the clinical implications of the K65R RT-SHIV mutants were consistent with those of SIVmac251, and suggest that for persons infected with K65R HIV-1 both immune-mediated and drug-dependent antiviral activities play a role in controlling viremia. These findings suggest also that even in the presence of K65R virus, continuation of tenofovir treatment as part of HAART may be beneficial, particularly when assisted by antiviral immune responses

Binge-drinking and non-binge-drinking student-athletes: The Role of Proximal Norms, Negative Expectancies, and Selected Socio-Demographic Variables

Researchers have identified college student-athletes as a subgroup at risk for heavy drinking and associated consequences. Yet, few studies have examined multiple variables simultaneously to determine which stand out as most robust to explain drinking behavior among student-athletes. Student-athletes from 54 National Collegiate Athletic Association (NCAA) member institutions (N = 2,659) completed an online questionnaire as part of an online alcohol education program. Logistic regression analyses demonstrated a unique profile based on descriptive and injunctive norms and alcohol outcome expectancies among binge-drinking student-athletes compared to non-binge-drinking athletes. Gender differences also emerged within the sample. Implications for campus mental health, university, and athletic personnel are discussed

Sport-related Concussion Reporting and Coach-Athlete Attachment Among Collegiate Student-Athletes

Between 2001 and 2015, 3.4 million traumatic brain injury (TBI) occurrences in the U.S. were accounted for by sport participation. It is estimated between 12% and 60% of athletes delay seeking care after sustaining a concussion. Differences in sport-related concussion (SRC) reporting have been attributed to several different factors. Whereas prior research related to SRC reporting behavior focus on normative and competitive pressures to continue play, less attention is given to the interpersonal context in which reporting takes place. Grounded in attachment theory, this study investigated relationships between coach-athlete attachment and help-seeking behavior. Findings suggest that as coach-athlete anxiousness increases, not reporting increases. and as coach-athlete secureness increases, not reporting decreases. Logistic regression analyses indicate that secure coach attachment significantly predicts greater likelihood of SRC reporting. These findings underscore the important role coach-athlete relationships may have on care-seeking behaviors of student-athletes and can inform individual and group interventions promoting SRC reporting

Family-level factors affecting social and academic competence of African American children: An examination of promotive and protective factors

Background: Research shows children’s life trajectories and outcomes are strongly influenced by factors affecting development of social and academic competence that also interact with racial disparities in academic settings. Given the importance of social and academic competencies, identifying factors that promote these competencies among African American children is critical to their success over the life course. Objective: This study examines a socioeconomically diverse sample of African American children to determine whether family-level factors promote and protect social and academic competence. Method: We analyze longitudinal data from a convenience sample of 97 African American children (54 girls, 43 boys) and their families who participated in a larger study of social and academic development. We analyze 2 waves of data collected when children were 7 and 10 years old. Results: A series of 2-level, random-intercept, fixed-effects models show social competence is positively affected by quality of parent–child relationships, positive parenting practices, low parental stress, and routine family home environment. Similarly, academic competence is positively affected by low parental stress and family social support. Conclusions: Study findings fill a critical knowledge gap regarding predictors of social and academic competence of African American children from various socioeconomic strata. Potential avenues for intervention are discussed

Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses

ABSTRACT Background: Human Polyomavirus 6 (HPyV6) and Human Polyomavirus 7 (HPyV7) are shed chronically from human skin. HPyV7, but not HPyV6, has been linked to a pruritic skin eruption of immunosuppression. Objective: We determined whether biopsies showing a characteristic pattern of dyskeratosis and parakeratosis might be associated with polyomavirus infection. Methods: We screened biopsies showing "peacock plumage" histology by PCR for human polyomaviruses. Cases positive for HPyV 6 or 7 were then analyzed by immunohistochemistry, electron microscopy (EM), immunofluorescence, quantitative PCR, and complete sequencing, including unbiased, next generation sequencing (NGS). Results: We identified three additional cases of HPyV6 or 7 skin infections. Expression of T antigen and viral capsid was abundant in lesional skin. Dual immunofluorescence staining experiments confirmed that HPyV7 primarily infects keratinocytes. High viral loads in lesional skin compared to normal skin and the identification of intact virions by both EM and NGS support a role for active viral infections in these skin diseases. Limitation: This was a small case-series of archived materials. Conclusion: We have found that HPyV6 and HPyV7 are associated with rare, pruritic skin eruptions with a unique histologic pattern and describe this entity as "HPyV6- and HPyV7-associated pruritic and dyskeratotic dermatosis (H6PD and H7PD).

Sex-influenced association of nonalcoholic fatty liver disease with coronary heart disease

This study investigated whether nonalcoholic fatty liver disease (NAFLD) predicts prevalent coronary heart disease (CHD)

Different paths to the modern state in Europe: the interaction between domestic political economy and interstate competition

Theoretical work on state formation and capacity has focused mostly on early modern Europe and on the experience of western European states during this period. While a number of European states monopolized domestic tax collection and achieved gains in state capacity during the early modern era, for others revenues stagnated or even declined, and these variations motivated alternative hypotheses for determinants of fiscal and state capacity. In this study we test the basic hypotheses in the existing literature making use of the large date set we have compiled for all of the leading states across the continent. We find strong empirical support for two prevailing threads in the literature, arguing respectively that interstate wars and changes in economic structure towards an urbanized economy had positive fiscal impact. Regarding the main point of contention in the theoretical literature, whether it was representative or authoritarian political regimes that facilitated the gains in fiscal capacity, we do not find conclusive evidence that one performed better than the other. Instead, the empirical evidence we have gathered lends supports to the hypothesis that when under pressure of war, the fiscal performance of representative regimes was better in the more urbanized-commercial economies and the fiscal performance of authoritarian regimes was better in rural-agrarian economie

Defining Patient-Level Molecular Heterogeneity in Psoriasis Vulgaris Based on Single-Cell Transcriptomics

Identifying genetic variation underlying human diseases establishes targets for therapeutic development and helps tailor treatments to individual patients. Large-scale transcriptomic profiling has extended the study of such molecular heterogeneity between patients to somatic tissues. However, the lower resolution of bulk RNA profiling, especially in a complex, composite tissue such as the skin, has limited its success. Here we demonstrate approaches to interrogate patient-level molecular variance in a chronic skin inflammatory disease, psoriasis vulgaris, leveraging single-cell RNA-sequencing of CD45+ cells isolated from active lesions. Highly psoriasis-specific transcriptional abnormalities display greater than average inter-individual variance, nominating them as potential sources of clinical heterogeneity. We find that one of these chemokines, CXCL13, demonstrates significant correlation with severity of lesions within our patient series. Our analyses also establish that genes elevated in psoriatic skin-resident memory T cells are enriched for programs orchestrating chromatin and CDC42-dependent cytoskeleton remodeling, specific components of which are distinctly correlated with and against Th17 identity on a single-cell level. Collectively, these analyses describe systematic means to dissect cell type- and patient-level differences in cutaneous psoriasis using high-resolution transcriptional profiles of human inflammatory disease

Sex and race differences in the prevalence of fatty liver disease as measured by computed tomography liver attenuation in European American and African American participants of the NHLBI family heart study

Liver attenuation (LA) (Hounsfield Units, HU) by computed tomography (CT) is a validated quantitative measure inversely related to liver fat burden. We examined race-and sex- differences on the distribution of LA (one of the first stages of fatty liver disease) and the predictors of these mean differences in European American (EA) and African American (AA) participants of the Family Heart Study. A total of 1242 (1064 EA, 178 AA) and 1477 (1150 EA, 327 AA) men and women, respectively, underwent CT examination from which LA and abdominal adipose volume were measured. LA (adjusted for phantom and field center) was the dependent variable in linear mixed models (to control for family relatedness) that tested for mean differences by race and by sex. Independent explanatory variables included age, body mass index, visceral adipose tissue volume, subcutaneous adipose tissue volume, alcohol consumption, TG, HDL-C, and insulin resistance. Mean LA varied significantly by sex, [(men) 57.76 ±10.03 HU and (women) 60.03 ±10.91 HU, p=0.0002], but not by race. Higher LA was associated with older age, while higher values of VAT, triglycerides, and insulin resistance were associated with lower LA in men and women. In contrast, alcohol consumption and BMI were associated with lower LA only among men. In analyses stratified by race LA was associated with alcohol consumption, VAT, and insulin resistance in both EA and AA and with age, BMI, and HDL-C in EA participants only. Our study findings confirm that there are important sex differences and race by sex interaction effects on the distribution of liver attenuation, the prevalence of FLD, and on the influence of metabolic risk factors on LA and FLD

International Coercion, Emulation and Policy Diffusion: Market-Oriented Infrastructure Reforms, 1977-1999

Why do some countries adopt market-oriented reforms such as deregulation, privatization and liberalization of competition in their infrastructure industries while others do not? Why did the pace of adoption accelerate in the 1990s? Building on neo-institutional theory in sociology, we argue that the domestic adoption of market-oriented reforms is strongly influenced by international pressures of coercion and emulation. We find robust support for these arguments with an event-history analysis of the determinants of reform in the telecommunications and electricity sectors of as many as 205 countries and territories between 1977 and 1999. Our results also suggest that the coercive effect of multilateral lending from the IMF, the World Bank or Regional Development Banks is increasing over time, a finding that is consistent with anecdotal evidence that multilateral organizations have broadened the scope of the “conditionality” terms specifying market-oriented reforms imposed on borrowing countries. We discuss the possibility that, by pressuring countries into policy reform, cross-national coercion and emulation may not produce ideal outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/40099/3/wp713.pd