MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background: Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. Objective: MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. Methods and Findings: We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Conclusions: Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. Trial Registration: ClinicalTrials.gov NCT00592124

Investigating the Relationship Between Statins and Bacterial Skin Infections

Statins are extensively prescribed medicines to reduce cholesterol for cardioprotection, but they also exhibit antimicrobial and pleiotropic effects, which plausibly reduces both skin infection risks and antimicrobial resistance. Adopting a bench-to-bedside framework, the results of laboratory experiments (identifying suitable statins as topical antibiotics and postulating a mechanism of antibacterial action) and clinical evidence (via prescription sequence symmetry analysis and a retrospective case-control study) were reconciled to determine if prior statin use translated into beneficial outcomes

Evaluation of financial liberalization : a general equilibrium model with constrained occupation choice

The objective of this paper is to assess both the aggregate growth effects and the distributional consequences of financial liberalization as observed in Thailand from 1976 to 1996. A general equilibrium occupational choice model with two sectors, one without intermediation, and the other with borrowing and lending, is taken to Thai data. Key parameters of the production technology and the distribution of entrepreneurial talent are estimated by maximizing the likelihood of transition into business given initial wealth as observed in two distinct datasets. Other parameters of the model are calibrated to try to match the two decades of growth as well as observed changes in inequality, labor share, savings, and the number of entrepreneurs. Without an expansion in the size of the intermediated sector, Thailand would have evolved very differently, namely, with a drastically lower growth rate, high residual subsistence sector, non-increasing wages, but lower inequality. The financial liberalization brings welfare gains and losses to different subsets of the population. Primary winners are talented would-be entrepreneurs who lack credit and cannot otherwise go into business (or invest little capital). Mean gains for these winners range from 17 to 34 percent of observed overall average household income. But liberalization also induces greater demand by entrepreneurs for workers resulting in increases in the wage and lower profits of relatively rich entrepreneurs of the same order of magnitude as the observed overall average income of firm owners. Foreign capital has no significant impact on growth or the distribution of observed income.Fiscal&Monetary Policy,Environmental Economics&Policies,Economic Conditions and Volatility,Economic Theory&Research,Banks&Banking Reform,Economic Theory&Research,Environmental Economics&Policies,Banks&Banking Reform,Economic Conditions and Volatility,International Terrorism&Counterterrorism

Cerebrospinal fluid biomarkers in twins with schizophrenia and bipolar disorder

Previously identified cerebrospinal fluid (CSF) biomarkers were studied in 37 twins with schizophrenia or bipolar disorder to determine their genetic and environmental properties. Further, comorbidities and sibling risks were investigated in patients with schizophrenia (n=22,781), bipolar disorder (n=30,761) and depression (n=172,479) in relation to multiple sclerosis (MS) (n=16,467) in a nationwide cohort. In Study I, CSF was analyzed using scanning electron microscopy in twins with schizophrenia and bipolar disorder to identify microscopic structures that had previously been established in patients with schizophrenia and bipolar disorder. Microscopic structures were found not only in the patients but also in the non-affected twin siblings to a higher degree than in healthy controls. The results indicate that genetic and shared environmental mechanisms might be involved in the development of CSF structures. Study II was a case series in which microparticles were studied in the CSF of healthy controls and in patients with schizophrenia. Microparticles may be indicative of stressinduced cell activation. In the patients with schizophrenia microparticles that originated from leukocyte and endothelial cells were accumulated in higher levels as compared with the healthy controls. In Study III, immune and amyloid biomarkers previously associated with psychotic disorders were analyzed in the CSF of twins. Soluble cluster of differentiation 14 (sCD14), a protein expressed by microglia in the central nervous system, was found to highly correlate within monozygotic twins. In the co-twin control analysis higher levels were observed in patients with schizophrenia and bipolar disorder compared with the nonaffected co-twins. sCD14 was also associated with negative psychotic symptoms and schizotypal and paranoid personality traits. The results strengthen previous findings of microglia activation in psychotic disorders. In Study IV, tryptophan metabolites and cytokines were analyzed in twins with schizophrenia and bipolar disorder. None of the substances correlated within the monozygotic twin pairs, which indicates the influence of environmental factors. Kynurenic and quinolinic acid were shown to be associated with schizotypal personality traits, strengthening previous results of an association between the tryptophan metabolites and psychosis. In Study V, comorbidity between the neuroinflammatory disorder MS and schizophrenia, bipolar disorder and depression was analyzed in a nationwide cohort. Consistent with previous studies an increased MS risk was noted in patients with bipolar disorder and depression. An increased MS risk was also found in males with a diagnosis of bipolar disorder and previous manic episodes. Decreased MS risk was seen in patients with schizophrenia. No change in MS risk was detected in the siblings to patients with schizophrenia, bipolar disorder and depression. Possible inflammatory mechanisms may account for the comorbidity between affective disorders and MS, whereas the protective effect of schizophrenia on MS risk remains to be further investigated. Biomarker analysis in CSF using twin methodology revealed some promising findings for future biomarker studies. However, larger twin cohorts are desirable for conclusive confirmation. The potential mechanisms underlying the associations between MS and psychiatric disorders require further study

Building reliable evidence from real-world data: methods, cautiousness and recommendations

Routinely stored information on healthcare utilisation in everyday clinical practice has proliferated over the past several decades. There is, however, some reluctance on the part of many health professionals to use observational data to support healthcare decisions, especially when data are derived from large databases. Challenges in conducting observational studies based on electronic databases include concern about the adequacy of study design and methods to minimise the effect of both misclassifications (in the absence of direct assessments of exposure and outcome validity) and confounding (in the absence of randomisation). This paper points out issues that may compromise the validity of such studies, and approaches to managing analytic challenges. First, strategies of sampling within a large cohort, as an alternative to analysing the full cohort, will be presented. Second, methods for controlling outcome and exposure misclassifications will be described. Third, several techniques that take into account both measured and unmeasured confounders will also be presented. Fourth, some considerations regarding random uncertainty in the framework of observational studies using healthcare utilisation data will be discussed. Finally, some recommendations for good research practice are listed in this paper. The aim is to provide researchers with a methodological framework, while commenting on the value of new techniques for more advanced users

Fighting “Low Equilibria” by Doubling the Minimum Wage ? Hungary’s Experiment

In January 2001 the Hungarian government increased the minimum wage from Ft 25,500 to Ft 40,000. One year later the wage floor rose further to Ft 50,000. The paper looks at the short-run impact of the first hike on small-firm employment and flows between employment and unemployment. It finds that the hike significantly increased labor costs and reduced employment in the small firm sector; and adversely affected the job retention and job finding probabilities of low-wage workers. While the conditions for a positive employment effect were mostly met in depressed regions spatial inequalities were amplified rather than reduced.http://deepblue.lib.umich.edu/bitstream/2027.42/40030/3/wp644.pd

Measuring labour market slack in Portugal : an outcome-based approach

Mestrado em Economia Monetária e FinanceiraO presente artigo fornece um estudo extensivo da heterogeneidade no mercado de trabalho português. Utilizam-se microdados referentes ao Inquérito ao Emprego cobrindo um ciclo económico completo, desde 1998:1 a 2018:1, para avaliar a ligação ao mercado de trabalho de vários estados de trabalho e analisam-se as alocações mais apropriadas de indivíduos entre estados. Simultaneamente, avalia-se a adequação dos critérios de classificação de desemprego convencionais. É adoptada uma classificação de estados de mercado de trabalho com base na evidência das transições entre estados. Para o efeito, aplicam-se modelos multinomiais e binários logit para os determinantes das transições, com vista a testar a equivalência entre grupos de não-emprego. Conclui-se que o mercado de trabalho português é caracterizado pela existência de considerável heterogeneidade, tanto entre como dentro dos convencionais estados de não-emprego. Em particular, a evidência aponta para que o grupo de indivíduos em inactividade que expressam desejo em trabalhar constitui um estado distinto no mercado de trabalho, exibindo um comportamento de transição mais próximo do desemprego do que do grupo de indivíduos em inactividade que não expressa desejo em trabalhar. Os resultados também indicam que a classificação enquanto inactivos de indivíduos que pretendem emprego mas que não procuram por razões de espera, os indivíduos em inactividade que procuram trabalho e os indivíduos que têm um emprego para iniciar daí a mais de três meses pode não ser a mais adequada, considerando que estes exibem substancial ligação ao mercado de trabalho e se rejeita a sua equivalência para com os seus pares.This paper provides a comprehensive study of the heterogeneity in the Portuguese labour market. We use rich Labour Force Survey (LFS) microdata covering a complete business cycle, from 1998:1 to 2018:1, to evaluate the labour market attachment of several labour states and assess the most suitable allocation of individuals across statuses. In addition, we evaluate the adequacy of the conventional unemployment criteria. We apply an outcome-based categorisation of labour market status by exploiting the information on the results of the behaviour of non-employed persons. To that end, we employ multinomial and binary logit models of the determinants of transitions of workers to test for the equivalence between non-employed groups. Overall, we conclude that heterogeneity is an evident feature of the Portuguese labour market, both between and within the conventional non-employment states. In particular, we find that the status comprising those inactive workers which want work constitutes a distinct state in the labour market and displays a transition behaviour closer to unemployment than to the group of inactive workers which do not want work. Moreover, the classification as inactive workers of individuals which report "waiting" as a reason for not having searched for a job, those individuals who have searched for a job but are still considered to be out-of-the-labour-force, as well as those individuals which are due to start work in more than three months might not be reasonable, since they show considerable attachment to the labour market and we reject the pooling of such states with their counterparts.info:eu-repo/semantics/publishedVersio

Rental Market Discrimination against Same-Sex Couples: Evidence from an Email Correspondence Audit

I present the results of a randomized pair-email correspondence audit of 6,490 property owners in 94 U.S. cities to provide a nationally-representative estimate of the level of discrimination that same-sex couples experience when inquiring about rental housing. I find that same-sex male couples, especially non-White same-sex male couples, are less likely to receive a response to inquiries about rental units. I also find that same-sex male Black couples are subject to more subtle forms of discrimination than heterosexual Black couples. I also examine if state and local anti-discrimination laws covary with rates of housing discrimination against same-sex couples. While my results are not causal, I find that anti-discrimination laws have an ambiguous relationship with rates of discrimination faced by same-sex couples. State-level housing protections, for example, covary positively with response rates (state laws appear to correlate with less discrimination) for same-sex Black male couples. However, local-level laws covary negatively with response rates for same-sex Black male couples. JEL No

The Dual Faces of Misery

Major Depression (MD) and Generalized Anxiety Disorder (GAD) are psychiatric disorders that arise from dysfunction of the core human capacities for emotion. Sapience is inextricably bound up with the potential for feelings of regret, worry and concern. When these emotions lead to clinically significant impairment or distress, they may result in one or both of the disorders of MD and GAD. The occurrence of MD and GAD in the same person, known as comorbidity, is remarkably high; substantially higher than would be expected by chance. MD and GAD have been studied since the mid-20th century, resulting in a substantial body of literature. The personality trait of neuroticism is also known to correlate highly with these disorders. This project was designed to compare the etiological structure of MD and GAD using a range of psychosocial and genetic methods in three datasets, while also assessing the correlated trait of neuroticism. Results are used to inform theoretical formulation of an approximate model of comorbidity for the two disorders. Psychosocial findings suggest that MD and GAD have similar relationships with most risk factors, and that neuroticism displays results consistent with it composing a portion of the liability to MD and GAD. Efforts to detect specific genetic loci involved in the etiology of MD and GAD are modestly successful. Two genome-wide significant variants were found for MD (one already identified in the literature); two for GAD, and one for neuroticism. There were also a number of significant genomic regions for each outcome. The use of aggregate genetic methods to estimate heritability based on genotypes was less successful. Estimation was only successful in one sample of the three, and produced modest estimates of heritability (0.2-0.25) for MD and comorbid MD+GAD. Genetic correlation was estimated to be very high between neuroticism and MD. Models of comorbidity are evaluated in light of these results, and a model comprising multiple liability distributions, one shared entirely by MD and GAD, and two additional correlated ones for the two disorders, with reciprocal phenotypic causation, is deemed most consistent with observed evidence

Factors Associated with Success in PARE Testing Among RCMP Officers

The purpose of this integrated article dissertation was to examine the predictive factors for success in the RCMP’s Physical Abilities Requirement Evaluation (PARE) in a retrospective observational study of 13, 709 unique records and a divisional subset of 620 for study two and three. Study one assessed the relative predictive power of the pursuit and body control times, while including covariates of height, weight, age. Significant (p\u3c 0.05) and equally strong effects were for pursuit log odds (LO) of 2.95% CI [2.49, 3.11], and body control time LO of 2.80, 95% CI [2.51, 3.14] with a weak predictor , LO of 0.53, 95% CI [0.38, 0.72]. Not significant were height, weight, and sex with 99 % modeling accuracy. Study two compared sex and performance factors on six repeated PARE pursuit circuit laps for pacing for both divisional data (535 men, 85 women) and 61 age and BMI matched male/female pairs. Results divisional data: significant strong performance (pass/fail) effects F(1,616)=288.3, p\u3c .00, partial η2 = .32 but weak sex (male/female) effects F(1,616) = 27.2, p =.03, partial η2= .01, interaction was significant, F(1,616)=50.7, p\u3c .01, but weak, partial η2 = 0.014. Repeat laps were significant, F(3.7, 229)=195.1, p2=0.24; performance*laps interaction was significant F(3.7, 229)=4.5, p =.02, with weak effects, partial η2 = .007. Significant repeat lap contrasts were lap 1-2, strong effects and lap 2-3, lap 3-4, lap 4-5 weak effects, and not significant was lap 5-6. Results matched pairs data supported significant strong performance effects, F(1,118)=90.9, p2=.44 and weak sex effects, F(1,118)=13.5, p2=.10 not clinically significant. Significant repeat laps contrasts: laps 1-2, strong effect, lap 3-4 and lap 4-5, weak effect, lap 2-3 and lap 5-6 contrast was not significant. Men and women officers paced PARE repeat laps with slight ordinal interaction at lap three and six. The purpose of study three was to assess self-reported physical activity (PA) frequency and intensity as potential additional significant predictors of PARE success. PA frequency of 3.5 day/week, and intensity of 2.2 of 3.0, did not support additional predictors. There appears to be insufficient PA to affect a maximal test. Additional self-reported mode and dimensions of PA might increase PA predictability