Pulmonary Outcomes Associated with Long-Term Azithromycin Therapy in Cystic Fibrosis.

Rationale: Chronic azithromycin is commonly used in cystic fibrosis based on short controlled clinical trials showing reductions in pulmonary exacerbations and improved FEV1. Long-term effects are unknown.Objectives: Examine pulmonary outcomes among chronic azithromycin users compared with matched controls over years of use and consider combined azithromycin use in cohorts using chronic inhaled tobramycin or aztreonam.Methods: This retrospective cohort study used the U.S. cystic fibrosis Foundation Patient Registry. Incident chronic azithromycin users were compared with matched controls by FEV1% predicted rate of decline and rates of intravenous antibiotic use to treat pulmonary exacerbations. Propensity score methods were utilized to address confounding by indication. Predefined sensitivity analyses based on lung function, Pseudomonas aeruginosa (PA) status, and follow-up time intervals were conducted.Measurements and Main Results: Across 3 years, FEV1% predicted per-year decline was nearly 40% less in those with PA using azithromycin compared with matched controls (slopes, -1.53 versus -2.41% predicted per yr; difference: 0.88; 95% confidence interval [CI], 0.30-1.47). This rate of decline did not differ based on azithromycin use in those without PA. Among all cohorts, use of intravenous antibiotics was no different between azithromycin users and controls. Users of inhaled tobramycin and azithromycin had FEV1% predicted per-year decline of -0.16 versus nonusers (95% CI, -0.44 to 0.13), whereas users of inhaled aztreonam lysine and azithromycin experienced a mean 0.49% predicted per year slower decline than matched controls (95% CI, -0.11 to 1.10).Conclusions: Results from this study provide additional rationale for chronic azithromycin use in PA-positive patients to reduce lung function decline.

Assessing noninferiority: Evaluating efficacy of a new treatment without complete data.

The FDA released the final guidance on noninferiority trials in November 2016. In noninferiority trials, validity of the assessment of the efficacy of the test treatment depends on the control treatment's efficacy. Therefore, it is critically important that there be a reliable estimate of the control treatment effect-which is generally obtained from historical trials, and often assumed to hold in the current setting (the assay constancy assumption). Validating the constancy assumption requires clinical data, which are typically lacking. The guidance acknowledges that "lack of constancy can occur for many reasons." We clarify the objectives of noninferiority trials. We conclude that correction for bias, rather than assay constancy, is critical to conducting valid noninferiority trials. We propose that assay constancy not be assumed and discounting or thresholds be used to address concern about loss of historical efficacy. Examples are provided for illustration.

Role of bleeding recognition and evaluation in Black-White disparities in endometrial cancer.

BACKGROUND: Advanced stage at diagnosis is an independent, unexplained contributor to racial disparity in endometrial cancer. OBJECTIVE: We sought to investigate whether, prior to diagnosis, provider recognition of the cardinal symptom of endometrial cancer, postmenopausal bleeding, differs by patient race. STUDY DESIGN: Black and White women diagnosed with endometrial cancer (2001 through 2011) from Surveillance, Epidemiology, and End Results-Medicare who had at least 2 years of claims prior to diagnosis were identified. Bleeding diagnoses along with procedures done prior to diagnosis were captured via claims data. Multinomial logistic regression was used to evaluate the association of race with diagnostic workup and multivariate models built to determine the association of appropriate diagnostic procedures with stage at diagnosis. RESULTS: In all, 4354 White and 537 Black women diagnosed with endometrial cancer were included. Compared to White women, Black women were less likely to have guideline-concordant care: postmenopausal bleeding and appropriate diagnostic evaluation (70% vs 79%, P < .001), with adjusted relative risk ratios of 1.12-1.73 for different nonguideline-concordant pathways: bleeding without diagnostic procedures, alternative bleeding descriptions, and neither bleeding nor procedures. These pathways were associated with higher odds of advanced stage at diagnosis (adjusted odds ratio, 1.90-2.88). CONCLUSION: The lack of recognition and evaluation of postmenopausal bleeding is associated with advanced stage at diagnosis in endometrial cancer. Older Black women are at highest risk for the most aggressive histology types, yet they are less likely to have guideline-concordant evaluation of vaginal bleeding. Efforts aimed at improving recognition-among patients and providers-of postmenopausal bleeding in Black women could substantially reduce disparities in endometrial cancer.

Prostate Needle Biopsy Outcomes in the Era of the U.S. Preventive Services Task Force Recommendation against Prostate Specific Antigen Based Screening.

PURPOSE: We determined whether the characteristics of patients undergoing prostate needle biopsies and prostate needle biopsy results changed after the U.S. Preventive Services Task Force recommendation in 2012 against prostate specific antigen based screening for prostate cancer for men of any age. MATERIALS AND METHODS: A prospective database of patients undergoing prostate needle biopsies at Virginia Mason from 2004 to 2014 was reviewed. Welch's t-test and chi-square tests were used to compare patients seen before to those seen after the USPSTF recommendation. Relative risks and corresponding confidence intervals were estimated by general linear regression. RESULTS: Patients in the post-USPSTF group (310) had a higher prostate specific antigen (p <0.001), were more likely to be diagnosed with higher clinical stage (2b, p=0.003; 2c-3a, p=0.027) and D'Amico high risk prostate cancer (p=0.036), with an adjusted relative risk for high risk prostate cancer of 1.25 (95% CI 1.02-1.52) compared to those in the pre-USPSTF group (1,416). Limiting the pre-USPSTF group to the 30 months before the draft guidelines (448 patients) yielded similar results. The absolute number of biopsies performed decreased by 31%, with the majority of the decrease occurring in the detection of intermediate risk tumors. CONCLUSIONS: In the 2 and a half years after the USPSTF recommendation against prostate specific antigen based screening, patients undergoing prostate needle biopsies were significantly more likely to be diagnosed with high risk disease. However, a reduction in the number of prostate needle biopsies performed occurred concomitantly with a decrease in the detection of intermediate risk, potentially curable prostate cancer. Future focus on informed application of screening techniques may prevent the reversal of decades of improvement in the prostate cancer mortality rate.

Patterns of Care and Survival Outcomes for Malignant Sex Cord Stromal Testicular Cancer: Results from the National Cancer Data Base.

PURPOSE: Sex cord stromal tumors of the testis comprise less than 5% of testicular neoplasms. Consequently, data regarding patterns of care and survival are sparse. Using a large national database, we sought to provide a more definitive analysis of outcomes and management of these malignancies. MATERIALS AND METHODS: Data were obtained from the National Cancer Data Base. Patients diagnosed from 1998 to 2011 with 2 of the most frequent sex cord stromal tumors of the testis, including Leydig and Sertoli cell tumors, were selected for study. Overall survival estimates were assessed by the Kaplan-Meier method. RESULTS: Of the 79,120 cases of testicular cancer between 1998 and 2011, 315 (0.39%) were primary malignant Leydig or Sertoli cell tumors. Median patient age was 43 years for both tumors. Of the 315 patients 250 (79%) had malignant Leydig cell tumors and 65 (21%) had malignant Sertoli cell tumors, of which 94% and 78%, respectively, were stage I. Overall survival at 1 and 5 years for stage I Leydig cell tumors was 98% (95% CI 96-100) and 91% (95% CI 85-96), and for stage I Sertoli cell tumors overall survival was 93% (95% CI 83-100) and 77% (95% CI 62-95), respectively (p = 0.015). Of patients with stage I Leydig and Sertoli cell tumors 94% and 84%, respectively, received no further treatment following orchiectomy. CONCLUSIONS: Five-year survival estimates of stage I Leydig and Sertoli cell tumors are significantly lower compared to those of stage I germ cell tumors with Sertoli cell tumors significantly worse than Leydig cell tumors. These differences in the survival of sex cord stromal tumors indicate the importance of large databases to evaluate the efficacy of treatment for rare neoplasms.

Prospective Quality of Life in Men Choosing Active Surveillance Compared to Those Biopsied but not Diagnosed with Prostate Cancer.

PURPOSE: Active surveillance is an important alternative to definitive therapy for men with low risk prostate cancer. However, the impact of active surveillance on health related quality of life compared to that in men without cancer remains unknown. In this study we evaluated health related quality of life outcomes in men on active surveillance compared to men followed after negative prostate needle biopsy. MATERIALS AND METHODS: A prospective study was conducted on men who were enrolled into the Center for Prostate Disease Research Multicenter National Database and underwent prostate needle biopsy for suspicion of prostate cancer between 2007 and 2014. Health related quality of life was assessed at biopsy (baseline) and annually for up to 3 years using SF-36 and EPIC questionnaires. Health related quality of life scores were modeled using generalized estimating equations, adjusting for baseline health related quality of life, and demographic and clinical characteristics. RESULTS: Of the 1,204 men who met the initial eligibility criteria 420 had a negative prostate needle biopsy (noncancer comparison group). Among the 411 men diagnosed with low risk prostate cancer 89 were on active surveillance. Longitudinal analysis revealed that for most health related quality of life subscales there were no significant differences between the groups in adjusted health related quality of life score trends over time. CONCLUSIONS: In this study most health related quality of life outcomes in patients with low risk prostate cancer on active surveillance did not differ significantly from those of men without prostate cancer. A comparison group of men with a similar risk of prostate cancer detection is critical to clarify the psychological and physical impact of active surveillance.

Metabolic pathways that correlate with post-transfusion circulation of stored murine red blood cells.

Transfusion of red blood cells is a very common inpatient procedure, with more than 1 in 70 people in the USA receiving a red blood cell transfusion annually. However, stored red blood cells are a non-uniform product, based upon donor-to-donor variation in red blood cell storage biology. While thousands of biological parameters change in red blood cells over storage, it has remained unclear which changes correlate with function of the red blood cells, as opposed to being co-incidental changes. In the current report, a murine model of red blood cell storage/transfusion is applied across 13 genetically distinct mouse strains and combined with high resolution metabolomics to identify metabolic changes that correlated with red blood cell circulation post storage. Oxidation in general, and peroxidation of lipids in particular, emerged as changes that correlated with extreme statistical significance, including generation of dicarboxylic acids and monohydroxy fatty acids. In addition, differences in anti-oxidant pathways known to regulate oxidative stress on lipid membranes were identified. Finally, metabolites were identified that differed at the time the blood was harvested, and predict how the red blood cells perform after storage, allowing the potential to screen donors at time of collection. Together, these findings map out a new landscape in understanding metabolic changes during red blood cell storage as they relate to red blood cell circulation.

Bioactive lipids accumulate in stored red blood cells despite leukoreduction: a targeted metabolomics study.

BACKGROUND: Accumulation of bioactive lipids during red blood cell (RBC) storage has been identified as a potential source of posttransfusion sequelae in vulnerable populations. Typically, white blood cells (WBCs) have been implicated in the generation of bioactive lipids, and leukoreduction has been seen as a solution to this issue. STUDY DESIGN AND METHODS: We developed a targeted metabolomics approach with isotope dilution to quantify a panel of bioactive lipids in both leukoreduced (LR) and nonleukoreduced (NLR) RBC units over the course of storage. RESULTS: Leukoreduction greatly attenuated the production of 12-hydroxyeicosatetraenoic acid (HETE), 12-hydroxyeicosapentaenoic acid, and 14-hydroxydocosahexaenoic acid (HDoHE), all three of which are mediated by 12-lipoxygenase present in WBCs and platelets. However, despite leukoreduction, micromolar levels of linoleic acid (LA), arachidonic acid (AA), and docosahexaenoic acid (DHA) were observed in the RBC units stored for 42 days. These major polyunsaturated fatty acids (PUFAs) and their oxidation products (oxylipins) also significantly increased with storage time, including 5-, 8-, 9-, 11-, 12-, and 15- HETEs from AA; 9- and 13-hydroxyoctadecadienoic acid (HODE); 9-, 10-, and 12,13-dihydroxyoctadecenoic acids from LA; and 14-, 16-, and 17-HDoHEs from DHA. The majority of PUFAs and oxylipins accumulated in the supernatant fraction. Large donor-to-donor variations were observed in both LR-RBC and NLR-RBC units. CONCLUSION: While the exact role the accumulation of PUFAs and oxylipins plays in RBC unit quality and transfusion medical outcomes remains undetermined, the analytes of interest in this study may serve as biomarkers for lipid degradation and oxidation during storage and may induce changes in human physiology upon transfusion.

Transfusion-induced alloimmunization and platelet refractoriness in a mouse model: mechanisms and interventions.

BACKGROUND: Platelet (PLT) transfusions can be an essential therapy for patients with thrombocytopenia to maintain hemostasis. However, some patients become alloimmunized to antigens on PLTs (typically HLA), which can prevent efficacy of PLT transfusion due to antibody-mediated clearance. In extreme cases, patients with alloimmunization to multiple HLAs can become "refractory" to PLT transfusion, such that insufficient compatible PLT units can be found to meet transfusion needs. MATERIALS AND METHODS: An in vivo murine model of PLT-induced alloimmunization was refined so as to include both transfusion with allogeneic leukoreduced PLTs and studies of posttransfusion PLT recoveries, allowing assessment of alloimmunization and refractoriness. Basic mechanisms of antibody-mediated PLT clearance were investigated using recipients missing either the C3 complement gene or the common gamma chain for Fc receptors. In addition, the efficacy of using costimulatory blockade as a therapeutic intervention was assessed by testing CTLA4-Ig administration before PLT transfusion. RESULTS: Fcγ receptors (but not complement C3) are required for alloantibody-mediated PLT refractoriness. In addition, levels of anti-MHC predict the extent of refractoriness in a given animal. Finally, costimulatory blockade as a therapeutic modality prevents transfusion-induced PLT refractoriness. CONCLUSIONS: Together these findings introduce new experimental methods, basic mechanistic understanding, and a potential therapeutic intervention for alloimmunization to MHC-based antigens on transfused PLTs.

Metabolites in stored platelets associated with platelet recoveries and survivals.

BACKGROUND: Transfusion of platelets (PLTs) is a common therapy in a number of clinical settings. However, it is well understood that there is substantial donor-to-donor variation in how well PLTs store and thus the quality of the products that are transfused. The basis of such variation is poorly understood, and there are limited metrics by which units of PLTs can be assessed for their posttransfusion performance. It has repeatedly been demonstrated that myriad biologic changes take place during PLT storage; however, which of the changes correlate with quality of the stored PLTs and/or are mechanistically involved in PLT function remains undetermined. STUDY DESIGN AND METHODS: The current study tested stored PLTs from 21 normal subjects, combining high-resolution metabolomics of stored PLTs with in vivo PLT recoveries and survivals. Both individual analytes and metabolic pathways that correlate with posttransfusion PLT viability were identified. RESULTS: Caffeine metabolites were associated with poor PLT recovery; caffeine metabolism was not ongoing in the PLT bag and remained at prestorage levels. Acylcarnitines, particular fatty acid metabolites, and oxidized fatty acids were associated with poor PLT survivals. Of the myriad metabolic changes during PLT storage, these are the first reported metabolic findings to begin distinguishing which changes are of functional importance regarding posttransfusion PLT performance. CONCLUSIONS: Together, these findings provide novel mechanistic insights into the functional biology of the PLT storage lesion as well as identifying potential targets for modifying donor environment (e.g., caffeine consumption) and also metrics of quality assessment for stored human PLTs.

Prospective quality-of-life outcomes for low-risk prostate cancer: Active surveillance versus radical prostatectomy.

BACKGROUND: For patients with low-risk prostate cancer (PCa), active surveillance (AS) may produce oncologic outcomes comparable to those achieved with radical prostatectomy (RP). Health-related quality-of-life (HRQoL) outcomes are important to consider, yet few studies have examined HRQoL among patients with PCa who were managed with AS. In this study, the authors compared longitudinal HRQoL in a prospective, racially diverse, and contemporary cohort of patients who underwent RP or AS for low-risk PCa. METHODS: Beginning in 2007, HRQoL data from validated questionnaires (the Expanded Prostate Cancer Index Composite and the 36-item RAND Medical Outcomes Study short-form survey) were collected by the Center for Prostate Disease Research in a multicenter national database. Patients aged ≤75 years who were diagnosed with low-risk PCa and elected RP or AS for initial disease management were followed for 3 years. Mean scores were estimated using generalized estimating equations adjusting for baseline HRQoL, demographic characteristics, and clinical patient characteristics. RESULTS: Of the patients with low-risk PCa, 228 underwent RP, and 77 underwent AS. Multivariable analysis revealed that patients in the RP group had significantly worse sexual function, sexual bother, and urinary function at all time points compared with patients in the AS group. Differences in mental health between groups were below the threshold for clinical significance at 1 year. CONCLUSIONS: In this study, no differences in mental health outcomes were observed, but urinary and sexual HRQoL were worse for patients who underwent RP compared with those who underwent AS for up to 3 years. These data offer support for the management of low-risk PCa with AS as a means for postponing the morbidity associated with RP without concomitant declines in mental health.

Association between cellular immune activation, target cell frequency, and risk of human immunodeficiency virus type 1 superinfection.

We performed a case-control study of women at risk of HIV-1 superinfection to understand the relationship between immune activation and HIV-1 acquisition. An increase in the frequency of HIV-1 target cells, but not in other markers of T cell activation, was associated with a 1.7-fold increase in the odds of superinfection. This suggests that HIV-1 acquisition risk is influenced more by the frequency of target cells than by the generalized level of immune activation.

HIV-1 superinfection occurs less frequently than initial infection in a cohort of high-risk Kenyan women.

HIV superinfection (reinfection) has been reported in several settings, but no study has been designed and powered to rigorously compare its incidence to that of initial infection. Determining whether HIV infection reduces the risk of superinfection is critical to understanding whether an immune response to natural HIV infection is protective. This study compares the incidence of initial infection and superinfection in a prospective seroincident cohort of high-risk women in Mombasa, Kenya. A next-generation sequencing-based pipeline was developed to screen 129 women for superinfection. Longitudinal plasma samples at <6 months, >2 years and one intervening time after initial HIV infection were analyzed. Amplicons in three genome regions were sequenced and a median of 901 sequences obtained per gene per timepoint. Phylogenetic evidence of polyphyly, confirmed by pairwise distance analysis, defined superinfection. Superinfection timing was determined by sequencing virus from intervening timepoints. These data were combined with published data from 17 additional women in the same cohort, totaling 146 women screened. Twenty-one cases of superinfection were identified for an estimated incidence rate of 2.61 per 100 person-years (pys). The incidence rate of initial infection among 1910 women in the same cohort was 5.75 per 100 pys. Andersen-Gill proportional hazards models were used to compare incidences, adjusting for covariates known to influence HIV susceptibility in this cohort. Superinfection incidence was significantly lower than initial infection incidence, with a hazard ratio of 0.47 (CI 0.29-0.75, p = 0.0019). This lower incidence of superinfection was only observed >6 months after initial infection. This is the first adequately powered study to report that HIV infection reduces the risk of reinfection, raising the possibility that immune responses to natural infection are partially protective. The observation that superinfection risk changes with time implies a window of protection that coincides with the maturation of HIV-specific immunity.

Transperineal Template Guided Prostate Biopsy Selects Candidates for Active Surveillance--How Many Cores are Enough?

PURPOSE: Most prostate cancer active surveillance protocols recommend a confirmatory biopsy within 3 to 6 months of diagnosis. Transperineal template guided biopsy is an approach to improve the detection of high grade prostate cancer. However, to our knowledge the optimal technique is unknown. We evaluated the relative performance of 2 transperineal template guided biopsy approaches. MATERIALS AND METHODS: Institutional review board approved prospective databases at Virginia Mason and University of Michigan were used. Men eligible for active surveillance based on initial 12-core biopsy demonstrating NCCN® guideline low risk prostate cancer were included in study. All men underwent confirmatory transperineal template guided biopsy between 2005 and 2014, and within 6 months of diagnosis. The biopsy technique was based on a 24-core template with 12 anterior and 12 posterior cores or a template based on gland volume with an average of 1 core per cc. Outcome comparisons were made by the chi-square and Fisher exact tests, the Welch t-test and linear regression. RESULTS: Of the 135 men 46 underwent 24-core biopsy and 89 underwent volume based biopsy (median 62 cores). No statistically significant difference was noted in the prevalence of upgrading (35% vs 29%, p = 0.64) or complications (9% vs 16%, p = 0.38) between the 24-core and volume based groups. The difference in the probability of upgrading by volume based biopsy adjusted for age, prostate specific antigen, prostate volume, clinical stage and number of prior biopsies was -4% (95% CI -24 to 14%, p = 0.63). CONCLUSIONS: A significant difference was not detected in upgrading or morbidity between a 24-core template and a more exhaustive volume based template. A less invasive 24-core transperineal template guided biopsy strategy may suffice to accurately identify men who are appropriate for active surveillance.

On robustness of noninferiority clinical trial designs against bias, variability, and nonconstancy.

The regulatory guidelines on noninferiority (NI) trials emphasize constancy not only in the treatment effect over time but also in the trial design, clinical practice, and quality of the trial conduct and execution. In practice, the constancy assumption is generally impossible to justify; often, there are clear reasons to expect a loss of efficacy over time. There are also concerns about the inherent and publication bias in the historical data, and various sources of selection bias in the NI trial design. Thus, a conservative NI margin is often considered. However, different NI margin approaches are largely evaluated under the assumption of constancy and absence of bias, and therefore, controversies arise and are unresolved on the necessary degree of conservativeness. We develop a framework to quantify the robustness of any NI margin approach against inherent and publication bias in historical data, selection bias in trial design, and nonconstancy in reference effects. We introduce a consistency principle to address variability in the historical data. We control across-trial conditional error rates given a final NI trial design over a design specific robust range for reference effects. Following a conditionality principle, we provide a theoretical justification of the framework and the conditions for controlling across-trial unconditional type 1 error rates. We raise the issue of inherent bias in historical data with an illustrative example.

Compartmentalized cytomegalovirus replication and transmission in the setting of maternal HIV-1 infection.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with adverse outcomes in human immunodeficiency virus (HIV)-exposed infants. Determinants of vertical CMV transmission in the setting of maternal HIV-1 infection are not well-defined. METHODS: CMV and HIV-1 levels were measured in plasma, cervical secretions, and breast milk of 147 HIV-1-infected women to define correlates of maternal CMV replication and infant CMV acquisition. RESULTS: Although few women had detectable CMV in plasma (4.8%), the majority had detectable CMV DNA in cervical secretions (66%) and breast milk (99%). There was a strong association between cervical CMV detection during pregnancy and later breast milk levels (ß = 0.47; P = .005). Plasma HIV-1 level and CD4 counts were associated with CMV in the cervix and breast milk. However HIV-1 levels within the cervix and breast milk were not associated with CMV within these compartments. Maternal breast milk CMV levels (hazard ratio [HR], 1.4; P = .003) and maternal CD4 < 450 cells/mm(3) (HR, 1.8; P = .008) were independently associated with infant CMV acquisition; each log10 increase in breast milk CMV was associated with a 40% increase in infant infection. The breast milk CMV level required to attain a 50% probability of CMV transmission increased with higher maternal CD4 counts, increasing from 3.55 log10 CMV DNA copies/mL at a CD4 count of 350 cells/mm(3) to 5.50 log10 CMV DNA copies/mL at a CD4 count of 1000 cells/mm(3). CONCLUSIONS: Breast milk CMV levels and maternal CD4 count are major determinants of CMV transmission in the setting of maternal HIV-1. Maternal immune reconstitution or lowering breast milk CMV levels may reduce vertical CMV transmission.

HIV-specific antibodies capable of ADCC are common in breastmilk and are associated with reduced risk of transmission in women with high viral loads.

There are limited data describing the functional characteristics of HIV-1 specific antibodies in breast milk (BM) and their role in breastfeeding transmission. The ability of BM antibodies to bind HIV-1 envelope, neutralize heterologous and autologous viruses and direct antibody-dependent cell cytotoxicity (ADCC) were analyzed in BM and plasma obtained soon after delivery from 10 non-transmitting and 9 transmitting women with high systemic viral loads and plasma neutralizing antibodies (NAbs). Because subtype A is the dominant subtype in this cohort, a subtype A envelope variant that was sensitive to plasma NAbs was used to assess the different antibody activities. We found that NAbs against the subtype A heterologous virus and/or the woman's autologous viruses were rare in IgG and IgA purified from breast milk supernatant (BMS)--only 4 of 19 women had any detectable NAb activity against either virus. Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (p = 0.58). The low NAb activity in BMS versus plasma was reflected in binding antibody levels: HIV-1 envelope specific IgG titers were 2.2 log(10) lower (compared to 0.59 log(10) lower for IgA) in BMS versus plasma. In contrast, antibodies capable of ADCC were common and could be detected in the BMS from all 19 women. BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (p = 0.0001) and BMS ADCC activity (p = 0.014). Importantly, BMS ADCC capacity was inversely associated with infant infection risk (p = 0.039). Our findings indicate that BMS has low levels of envelope specific IgG and IgA with limited neutralizing activity. However, this small study of women with high plasma viral loads suggests that breastmilk ADCC activity is a correlate of transmission that may impact infant infection risk.

HIV-1 superinfection in women broadens and strengthens the neutralizing antibody response.

Identifying naturally-occurring neutralizing antibodies (NAb) that are cross-reactive against all global subtypes of HIV-1 is an important step toward the development of a vaccine. Establishing the host and viral determinants for eliciting such broadly NAbs is also critical for immunogen design. NAb breadth has previously been shown to be positively associated with viral diversity. Therefore, we hypothesized that superinfected individuals develop a broad NAb response as a result of increased antigenic stimulation by two distinct viruses. To test this hypothesis, plasma samples from 12 superinfected women each assigned to three singly infected women were tested against a panel of eight viruses representing four different HIV-1 subtypes at matched time points post-superinfection (~5 years post-initial infection). Here we show superinfected individuals develop significantly broader NAb responses post-superinfection when compared to singly infected individuals (RR = 1.68, CI: 1.23-2.30, p = 0.001). This was true even after controlling for NAb breadth developed prior to superinfection, contemporaneous CD4+ T cell count and viral load. Similarly, both unadjusted and adjusted analyses showed significantly greater potency in superinfected cases compared to controls. Notably, two superinfected individuals were able to neutralize variants from four different subtypes at plasma dilutions >1∶300, suggesting that their NAbs exhibit elite activity. Cross-subtype breadth was detected within a year of superinfection in both of these individuals, which was within 1.5 years of their initial infection. These data suggest that sequential infections lead to augmentation of the NAb response, a process that may provide insight into potential mechanisms that contribute to the development of antibody breadth. Therefore, a successful vaccination strategy that mimics superinfection may lead to the development of broad NAbs in immunized individuals.

Association between alcohol use and sexually transmitted infection incidence among kenyan women engaged in transactional sex.

Few prospective studies have evaluated the association between alcohol use and STI acquisition among African women. We examined the association between baseline drinking frequency and STIs in a cohort of Kenyan women reporting transactional sex. The association between alcohol use and STI differed significantly by HIV status. Among 139 HIV-positive women, STI acquisition was significantly associated with consuming 1-7 drinks/week and marginally associated with ≥8 drinks/week in unadjusted analyses. However, no association between alcohol use and STIs was observed among 335 HIV-negative women. Addressing alcohol use within comprehensive HIV care may also reduce the burden of STIs among high-risk women.

Adjunctive Systemic Corticosteroids for Pulmonary Exacerbations of Cystic Fibrosis.

RATIONALE: Pulmonary exacerbations (PEx) remain the most common cause of morbidity, recurrent hospitalization and diminished survival in people with CF (PWCF), and are characterized by excess inflammation. Corticosteroids are potent, widely available anti-inflammatory drugs. However, corticosteroid efficacy data from randomized controlled trials (RCTs) in PWCF are limited. OBJECTIVES: To determine whether adjunctive systemic corticosteroid therapy is associated with improved outcomes in acute CF PEx. METHODS: We performed a secondary analysis of STOP2, a large multicenter RCT of antimicrobial treatment durations for adult PWCF presenting with PEx, that included the use of corticosteroids as a stratification criterion in its randomization protocol. Corticosteroid treatment effects were determined after propensity score-matching for covariates including age, sex, baseline FEV1, genotype and randomization arm. The primary outcome measure was the change in percent predicted FEV1 (ppFEV1). Symptoms, time to next PEx and the incidence of adverse events (AEs) and serious adverse events (SAEs) were assessed as secondary endpoints. Phenotypic factors associated with the clinical decision to prescribe steroids were also investigated. RESULTS: Corticosteroids were prescribed for 168 of 982 PEx events in STOP2 (17%). Steroid prescription was associated with decreased baseline ppFEV1, increased age, and female sex. Co-treatment with corticosteroids was independent of treatment arm allocation, and did not result in greater mean ppFEV1 response, longer median time to next PEx or more substantial symptomatic improvement compared to propensity-matched PWCF receiving antibiotics alone. AEs were not increased in corticosteroid-treated PWCF. The total number of SAEs - but not the number of corticosteroid-related or PEx-ralated SAEs - was higher among patients receiving corticosteroids. CONCLUSION: Empiric, physician-directed treatment with systemic corticosteroids, while common, is not associated with improved clinical outcomes in PWCF receiving antibiotics for PEx.