Application of the case-crossover design to reduce unmeasured confounding in studies of condom effectiveness

This analysis examined how unmeasured confounding affects estimates of the effectiveness of condoms in preventing sexually transmitted infections. Data were analyzed from a prospective cohort study of 1,122 female sexually transmitted disease clinic patients in Alabama (1992-1995), wherein participants were evaluated for sexually transmitted infections at six 1-month intervals. Associations between condom use and incident gonorrhea and chlamydia infection were compared between case-crossover and cohort analyses. In a case-crossover analysis of 228 follow-up visits ending in gonorrhea/chlamydia ("case intervals") and 743 self-matched follow-up visits not ending in gonorrhea/chlamydia ("noncase intervals") (183 women), consistent condom use without breakage or slippage was associated with significantly reduced risk of infection relative to nonuse (adjusted risk odds ratio = 0.49, 95% confidence interval: 0.26, 0.92). Conversely, a cohort analysis of 245 case intervals and 3,896 noncase intervals (919 women) revealed no significant reduction in infection risk from consistent use of condoms (adjusted risk odds ratio = 0.79, 95% confidence interval: 0.53, 1.17). Dose-response relations between the number of unprotected sex acts and infection were stronger in the case-crossover analysis (p for trend = 0.009) than in the cohort analysis (p for trend = 0.18). These findings suggest that epidemiologic studies confounded by unmeasured differences between condom users and nonusers underestimate condom effectiveness against these infections. The case-crossover method provides an additional technique for reducing unmeasured confounding in studies of condom effectiveness.     

Exploiting cross-priming to generate protective CD8 T-cell immunity rapidly

The number of memory CD8 T cells generated by infection or vaccination correlates strongly with the degree of protection observed in infection and tumor models. Therefore, rapid induction of protective numbers of effector and memory CD8 T cells may be crucial in the case of malignancy, pandemic infection, or bioterrorism. Many studies have shown that amplifying T-cell numbers by prime-boost vaccination is most effective with a substantial time interval between immunizations. In contrast, immunization with peptide-coated mature dendritic cells (DCs) results in a CD8 T-cell response exhibiting accelerated acquisition of memory characteristics, including the ability to respond to booster immunization within days of initial priming. However, personalized DC immunization is too costly, labor intensive, and time-consuming for large-scale vaccination. Here, we demonstrate that in vivo cross-priming with cell-associated antigens or antigen-coated, biodegradable microspheres in the absence of adjuvant quickly generates CD8 T cells that display the phenotype and function of long-term memory populations. Importantly, cross-primed CD8 T cells can respond to booster immunization within days of the initial immunization to generate rapidly large numbers of effector and memory T cells that can protect against bacterial, viral, and parasitic infections, including lethal influenza and malaria-causing Plasmodium infection. Thus, accelerated CD8 T-cell memory after in vivo cross-priming in the absence of adjuvant is generalizable and can be exploited to generate protective immunity rapidly.     

TGFbeta2-induced changes in human trabecular meshwork: implications for intraocular pressure

PURPOSE: Transforming growth factor (TGF)-beta2 levels are elevated in glaucomatous human aqueous humor. TGFbeta is a cytokine that alters extracellular matrix (ECM) metabolism, and excess ECM has been proposed to increase aqueous outflow resistance in the trabecular meshwork (TM) of glaucomatous eyes. This study was undertaken to investigate effects of TGFbeta2 on secretion of fibronectin and the protease inhibitor plasminogen activator inhibitor (PAI)-1 from human TM cell cultures and perfused human ocular anterior segments. METHODS: Total RNA was isolated from pooled human TM cell monolayers and used for a gene microarray expression analysis. Supernatants from treated human TM cells were analyzed by ELISA for fibronectin or PAI-1 content. TGFbeta2 effects on intraocular pressure (IOP) were evaluated in a perfused organ culture model using human anterior segments, and eluates were analyzed for fibronectin and PAI-1 content. RESULTS: Overnight treatment of TM cells with TGFbeta2 upregulated multiple ECM-related genes, such as PAI-1. TGFbeta2 also increased secretion of both fibronectin and PAI-1 from TM cells. TGFbeta2 effects on TM cells were blocked by inhibitors of the TGFbeta type I receptor. In perfused human anterior segments, TGFbeta2 treatment elevated IOP and increased eluate fibronectin and PAI-1 content. CONCLUSIONS: TGFbeta2 effects on IOP may be transduced by TGFbeta type-I receptor-mediated changes in TM secretion of ECM-related factors such as fibronectin and PAI-1. Modulation of TGFbeta2-induced changes in the ECM may provide a novel and viable approach to the management of glaucoma.     

Participation and retention in a study of female condom use among women at high STD risk

PURPOSE: Differential participation and retention can bias the findings of a follow-up study. This problem was evaluated in a study of barrier contraception among women at high STD risk. The goal of this study was to identify predictors of participation and retention and determine whether they could influence study results. METHODS: Six-month follow-up study of women attending STD clinics. Determinants of participation and retention were evaluated using logistic and proportional hazards models. RESULTS: Agreement to participate was associated with young age, black race, low education and income, older age at first intercourse, the number of lifetime partners, and STD history. Early attrition was associated with young age, non-black race, higher income, lack of interest/commitment to using the female condom, high coital frequency, no STD history, not using a birth control method at baseline, and with inconsistent condom use, high coital frequency, and pregnancy during follow up. CONCLUSIONS: There was little evidence that differential participation influenced the validity of the study. Differential attrition may have biased behavioral measures of intervention effectiveness, but not necessarily measures of condom use effectiveness.