Discordant Clinical and Microbiological Outcomes Are Associated With Late Clinical Relapse in Clinical Trials for Complicated Urinary Tract Infections.

BACKGROUND: Current US Food and Drug Administration guidance recommends that the primary endpoint for complicated urinary tract infection clinical trials be a composite of the clinical and microbiological responses, assessed at a fixed point after therapy. Although some participants meet the criteria for clinical success, they do not meet the criteria for microbiological eradication and are classified as treatment failures. These discordant outcomes have raised questions about the utility of the microbiological endpoint. METHODS: We analyzed participant data from 13 phase 3 clinical trials submitted to the US Food and Drug Administration (N = 4842). Outcomes were determined at the test of cure (TOC) visit, recommended to occur at least 5 days after therapy and at the late follow-up visit, recommended to occur 21 to 28 days after randomization. Clinical and microbiological success were defined as the resolution of complicated urinary tract infection symptoms present at study entry, with no new symptoms (clinical cure), and a reduction in density of the original pathogen to <103 CFU/mL on urine culture (microbiological eradication). RESULTS: Among included participants, 70.7% were concordant successes at the TOC visit, 18.0% were discordant failures (clinical cure/microbiological persistence), and 6.7% were concordant failures (clinical failure/microbiological persistence). Discordant participants were at an increased risk for clinical failure at the late follow-up visit, and the risk of late clinical failure increased with time. CONCLUSIONS: Discordant clinical and microbiological outcomes at the TOC visit were associated with an increased risk of late clinical failure. Microbiological outcomes appear to be an important component of the endpoint.

Two-step estimation in ratio-of-mediator-probability weighted causal mediation analysis.

This study investigates appropriate estimation of estimator variability in the context of causal mediation analysis that employs propensity score-based weighting. Such an analysis decomposes the total effect of a treatment on the outcome into an indirect effect transmitted through a focal mediator and a direct effect bypassing the mediator. Ratio-of-mediator-probability weighting estimates these causal effects by adjusting for the confounding impact of a large number of pretreatment covariates through propensity score-based weighting. In step 1, a propensity score model is estimated. In step 2, the causal effects of interest are estimated using weights derived from the prior step's regression coefficient estimates. Statistical inferences obtained from this 2-step estimation procedure are potentially problematic if the estimated standard errors of the causal effect estimates do not reflect the sampling uncertainty in the estimation of the weights. This study extends to ratio-of-mediator-probability weighting analysis a solution to the 2-step estimation problem by stacking the score functions from both steps. We derive the asymptotic variance-covariance matrix for the indirect effect and direct effect 2-step estimators, provide simulation results, and illustrate with an application study. Our simulation results indicate that the sampling uncertainty in the estimated weights should not be ignored. The standard error estimation using the stacking procedure offers a viable alternative to bootstrap standard error estimation. We discuss broad implications of this approach for causal analysis involving propensity score-based weighting.

The health and cognitive growth of Latino toddlers: at risk or immigrant paradox?

Epidemiologists have shown how birth outcomes are generally robust for immigrant Latina mothers, despite often situated in poor households, advanced by their strong prenatal and nutritional practices. But little is known about (1) how these protective factors may differ among Latino subgroups, (2) the extent to which birth outcomes, ongoing maternal practices, and family supports advance Latino toddlers' health and physical growth, and (3) whether the same processes advance toddlers' early cognitive growth. We drew on a national probability sample of 8,114 infants born in 2001, including 1,450 of diverse Latino origins. Data come from birth records, maternal interviews when the child was 9 and 24 months of age, and direct assessments of health status, physical growth, and cognitive proficiencies. Descriptive analyses compared Mexican-heritage and other Latino mothers and toddlers relative to middle-class whites. Multivariate regression techniques identified predictors of child health, weight, and BMI, as well as cognitive proficiencies at 24 months. Infants of Mexican-heritage or less acculturated Latina mothers displayed robust birth outcomes, compared with other ethnic groups. The low incidence of premature births and low birthweight among these mothers continued to advance their cognitive growth through 24 months of age. Yet Latino children overall displayed smaller gains in cognitive proficiencies between 9 and 24 months, compared with middle-class populations, attributable to Latinas' lower levels of maternal education, weaker preliteracy practices, and a higher ratio of children per resident adult. Health practitioners should recognize that many Latina mothers display healthy prenatal practices and give birth to robust infants. But these early protective factors do not necessarily advance early cognitive growth. Screening practices, early interventions, and federal policy should become more sensitive to these countervailing dynamics.

Listening for avoidance: narrative form and defensiveness in adolescent memories.

We describe a linguistic clue to speakers' states of mind that has utility for psychotherapists and counselors, and summarize the theoretical and empirical support for using this clue in clinical practice. Specifically, we posit that the degree to which people relate stressful episodes from their lives as a chronological sequence of events is negatively associated with the extent to which they self-protectively avoid experiencing negative affect. We review relevant discussions and findings from linguistics and psychology, and then present a new study that replicates previous research. In this study of the relationship between defensive avoidance and the narrative structure of stressful memories in non-clinical adolescents, 168 high school students spoke for 10 min into a tape recorder about "your most stressful life event." Transcribed interviews were analyzed for narrative immersion, the extent to which the past is retold in chronological order, using a method adopted from Labov and Waletzky. A negative association was found between narrative immersion and avoidance (as operationalized by scores on the Marlowe Crowne Social Desirability Scale). Listening for narrative immersion in the speech of clients discussing past stressful times may therefore represent a useful tool in exploring defensive avoidance of stressful episodic memories.

Sexual risk as an outcome of social oppression: data from a probability sample of Latino gay men in three U.S. cities.

Based on data from a probability sample of 912 Latino gay men in 3 U.S. cities, a multivariate model of sexual risk was tested, including experiences of homophobia, racism, and poverty as predictors. Participants reported multiple instances of verbal and physical abuse, rude mistreatment, and discrimination on account of their sexual orientation and their race or ethnicity. Many reported experiences of poverty, such as inability to pay for basic necessities of food or shelter. Men who reported more instances of social discrimination and financial hardship were more psychologically distressed and more likely to participate in "difficult" sexual situations, as predicted. Participation in difficult sexual situations mediates the effects of social oppression and psychological distress on sexual risk behavior.

Maternal practices that influence Hispanic infants' health and cognitive growth.

OBJECTIVES: Infants born to immigrant mothers, including Hispanic mothers, display birth weight and mortality advantages, compared with other disadvantaged groups. We examined prenatal biological factors and maternal practices that account for this advantage. Then we estimated the extent to which healthy birth outcomes, along with maternal and family factors, contribute to the health and cognitive functioning of Hispanic infants. METHODS: A representative US sample of 8114 newborns, including 1450 newborns of Hispanic mothers, was drawn randomly in 2001. We compared the mean attributes of infants in subgroups that vary in maternal practices, family attributes, and acculturation levels. We accounted for variations in newborns' gestational age and size for gestational age and their health status and cognitive functioning at 9 months of age. RESULTS: Mexican-heritage and less-acculturated mothers were no more likely than white mothers to bear premature or small-for-gestational age infants, despite large social class disparities, which was explained in part by Hispanic women's low level of prenatal tobacco use. Parenting practices and lower class status of Hispanic mothers then began to slow infants' cognitive development, compared with white infants, because of weaker maternal education and cognitive facilitation during interaction tasks and larger family size. CONCLUSIONS: These findings extend earlier research, detailing healthy births among most immigrant Hispanic women. Robust birth outcomes contribute to the early health and cognitive growth of Hispanic infants, but risk factors linked to maternal and home practices overtake these early protective factors by late infancy. Robust births and early health indicators displayed by Hispanic infants should not distract pediatricians from attending to uneven cognitive growth.