A Per-Protocol Analysis Using Inverse-Probability-of-Censoring Weights in a Randomized Trial of Initial Protease Inhibitor Versus Nonnucleoside Reverse Transcriptase Inhibitor Regimens in Children.

Protocol adherence may influence measured treatment effectiveness in randomized controlled trials. Using data from a multicenter trial (Europe and the Americas, 2002-2009) of children with human immunodeficiency virus type 1 who had been randomized to receive initial protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral therapy regimens, we generated time-to-event intention-to-treat (ITT) estimates of treatment effectiveness, applied inverse-probability-of-censoring weights to generate per-protocol efficacy estimates, and compared shifts from ITT to per-protocol estimates across and within treatment arms. In ITT analyses, 263 participants experienced 4-year treatment failure probabilities of 41.3% for PIs and 39.5% for NNRTIs (risk difference = 1.8% (95% confidence interval (CI): -10.1, 13.7); hazard ratio = 1.09 (95% CI: 0.74, 1.60)). In per-protocol analyses, failure probabilities were 35.6% for PIs and 29.2% for NNRTIs (risk difference = 6.4% (95% CI: -6.7, 19.4); hazard ratio = 1.30 (95% CI: 0.80, 2.12)). Within-arm shifts in failure probabilities from ITT to per-protocol analyses were 5.7% for PIs and 10.3% for NNRTIs. Protocol nonadherence was nondifferential across arms, suggesting that possibly better NNRTI efficacy may have been masked by differences in within-arm shifts deriving from differential regimen forgiveness, residual confounding, or chance. A per-protocol approach using inverse-probability-of-censoring weights facilitated evaluation of relationships among adherence, efficacy, and forgiveness applicable to pediatric oral antiretroviral regimens.

Frequent Development of Broadly Neutralizing Antibodies in Early Life in a Large Cohort of Children With Human Immunodeficiency Virus.

BACKGROUND: Recent studies have indicated that broadly neutralizing antibodies (bnAbs) in children may develop earlier after human immunodeficiency virus (HIV) infection compared to adults. METHODS: We evaluated plasma from 212 antiretroviral therapy-naive children with HIV (1-3 years old). Neutralization breadth and potency was assessed using a panel of 10 viruses and compared to adults with chronic HIV. The magnitude, epitope specificity, and immunoglobulin (Ig)G subclass distribution of Env-specific antibodies were assessed using a binding antibody multiplex assay. RESULTS: One-year-old children demonstrated neutralization breadth comparable to chronically infected adults, whereas 2- and 3-year-olds exhibited significantly greater neutralization breadth (P = .014). Likewise, binding antibody responses increased with age, with levels in 2- and 3-year-old children comparable to adults. Overall, there was no significant difference in antibody specificities or IgG subclass distribution between the pediatric and adult cohorts. It is interesting to note that the neutralization activity was mapped to a single epitope (CD4 binding site, V2 or V3 glycans) in only 5 of 38 pediatric broadly neutralizing samples, which suggests that most children may develop a polyclonal neutralization response. CONCLUSIONS: These results contribute to a growing body of evidence suggesting that initiating HIV immunization early in life may present advantages for the development of broadly neutralizing antibody responses.

The genetic architecture of larval aggregation behavior in Drosophila.

Many insect species exhibit basal social behaviors such as aggregation, which play important roles in their feeding and mating ecologies. However, the evolutionary, genetic, and physiological mechanisms that regulate insect aggregation remain unknown for most species. Here, we used natural populations of Drosophila melanogaster to identify the genetic architecture that drives larval aggregation feeding behavior. By using quantitative and reverse genetic approaches, we have identified a complex neurogenetic network that plays a role in regulating the decision of larvae to feed in either solitude or as a group. Results from single gene, RNAi-knockdown experiments show that several of the identified genes represent key nodes in the genetic network that determines the level of aggregation while feeding. Furthermore, we show that a single non-coding variant in the gene CG14205, a putative acyltransferase, is associated with both decreased mRNA expression and increased aggregate formation, which suggests that it has a specific role in inhibiting aggregation behavior. Our results identify, for the first time, the genetic components which interact to regulate naturally occurring levels of aggregation in D. melanogaster larvae.

MD-PhD Program Graduates' Engagement in Research: Results of a National Study.

PURPOSE: To determine if specialty, among other professional development and demographic variables, predicted MD-PhD program graduates' research engagement. METHOD: The authors merged the 2015 Association of American Medical Colleges (AAMC) National MD-PhD Program Outcomes Survey database with selected data from the AAMC Student Records System, Graduation Questionnaire, and Graduate Medical Education (GME) Track Resident Survey. At the person level, they tested variables of interest for independent associations with MD-PhD graduates' research engagement using chi-square, Pearson correlations, and analysis of variance tests and logistic and linear regressions. RESULTS: Of 3,297 MD-PhD graduates from 1991-2010 who were no longer in GME training in 2015, 78.0% (2,572/3,297) reported research engagement. In models controlling for several variables, a neurology (vs internal medicine; adjusted odds ratio [AOR]: 2.48; 95% confidence interval [CI]: 1.60-3.86) or pathology (vs internal medicine; AOR: 1.89; 95% CI: 1.33-2.68) specialty, full-time faculty/research scientist career intention at graduation (vs all other career intentions; AOR: 3.04; 95% CI: 2.16-4.28), and ≥ 1 year of GME research (vs no GME research year[s]; AOR: 2.45; 95% CI: 1.96-3.06) predicted a greater likelihood of research engagement. Among graduates engaged in research, the mean percentage of research time was 49.9% (standard deviation 30.1%). Participation in ≥ 1 year of GME research (beta [ß] coefficient: 7.99, P < .001) predicted a higher percentage of research time, whereas a radiation oncology (ß: -28.70), diagnostic radiology (ß: -32.92), or surgery (ß: -29.61) specialty, among others, predicted a lower percentage of research time (each P < .001 vs internal medicine). CONCLUSIONS: Most MD-PhD graduates were engaged in research, but the extent of their engagement varied substantially among specialties. Across specialties, participation in research during GME may be one factor that sustains MD-PhD graduates' subsequent early- to midcareer research engagement.

Time to treatment disruption in children with HIV-1 randomized to initial antiretroviral therapy with protease inhibitors versus non-nucleoside reverse transcriptase inhibitors.

BACKGROUND: Choice of initial antiretroviral therapy regimen may help children with HIV maintain optimal, continuous therapy. We assessed treatment-naïve children for differences in time to treatment disruption across randomly-assigned protease inhibitor versus non-nucleoside reverse transcriptase inhibitor-based initial antiretroviral therapy. METHODS: We performed a secondary analysis of a multicenter phase 2/3, randomized, open-label trial in Europe, North and South America from 2002 to 2009. Children aged 31 days to <18 years, who were living with HIV-1 and treatment-naive, were randomized to antiretroviral therapy with two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Time to first documented treatment disruption to any component of antiretroviral therapy, derived from treatment records and adherence questionnaires, was analyzed using Kaplan-Meier estimators and Cox proportional hazards models. RESULTS: The modified intention-to-treat analysis included 263 participants. Seventy-two percent (n = 190) of participants experienced at least one treatment disruption during study. At 4 years, treatment disruption probabilities were 70% (protease inhibitor) vs. 63% (non-nucleoside reverse transcriptase inhibitor). The unadjusted hazard ratio (HR) for treatment disruptions comparing protease inhibitor vs. non-nucleoside reverse transcriptase inhibitor-based regimens was 1.19, 95% confidence interval [CI] 0.88-1.61 (adjusted HR 1.24, 95% CI 0.91-1.68). By study end, treatment disruption probabilities converged (protease inhibitor 81%, non-nucleoside reverse transcriptase inhibitor 84%) with unadjusted HR 1.11, 95% CI 0.84-1.48 (adjusted HR 1.13, 95% CI 0.84-1.50). Reported reasons for treatment disruptions suggested that participants on protease inhibitors experienced greater tolerability problems. CONCLUSIONS: Children had similar time to treatment disruption for initial protease inhibitor and non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy, despite greater reported tolerability problems with protease inhibitor regimens. Initial pediatric antiretroviral therapy with either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor may be acceptable for maintaining optimal, continuous therapy.

"It's Almost Like Gay Sex Doesn't Exist:" Parent-Child Sex Communication According to Gay, Bisexual, and Queer Adolescent Sons.

Sex communication interventions facilitate positive sexual health outcomes with heterosexual adolescents. The same has yet to be established for male youth with same-sex attractions, behaviors, and identities. Our study describes the experiences of gay, bisexual and queer-identifying adolescent males with parent-child sex communication. We conducted 30 in-depth semi-structured interviews with a diverse group of 15 to 20 year-old gay, bisexual, and queer (GBQ) males. Interview transcripts were coded and themes were identified using thematic and content analysis. Narratives revealed that sex communication with parents occurs rarely, is heteronormative in content prior to adolescent males' disclosure as GBQ, and after disclosure is reactionary and based on stereotypes that associate this population with negative health outcomes. Parents were rated poorly as sex educators by adolescent males and the findings are mixed regarding perception of parents' knowledge about GBQ-specific information. Parents and healthcare providers were identified as preferred sources of sex information by GBQ adolescent males. Sex communication with parents throughout adolescence that excludes GBQ males' same-sex concerns is a missed opportunity for targeted sexual risk reduction. There are multiple ways healthcare providers can assist parents to plan age-appropriate, sexuality-inclusive, home-based discussions about sex for this group.

Obtaining waivers of parental consent: A strategy endorsed by gay, bisexual, and queer adolescent males for health prevention research.

BACKGROUND: Requiring parental consent in studies with sexual minority youth (SMY) can sometimes be problematic as participants may have yet to disclose their sexual orientation, may not feel comfortable asking parents' permission, and may promote a self-selection bias. PURPOSE: We discuss rationale for waiving parental consent, strategies to secure waivers from review boards, and present participants' feedback on research without parents' permission. METHODS: We share our institutional review board proposal in which we made a case that excluding SMY from research violates ethical research principles, does not recognize their autonomy, and limits collection of sexuality data. DISCUSSION: Standard consent policies may inadvertently exclude youth who are at high risk for negative health outcomes or may potentially put them at risk because of forced disclosure of sexual orientation. Securing a waiver addresses these concerns and allows for rich data, which is critical for providers to have a deeper understanding of their unique sexual health needs. CONCLUSION: To properly safeguard and encourage research informed by SMY, parental consent waivers may be necessary.

The Daunting Career of the Physician-Investigator.

For many years, physician-investigators have had a particularly difficult time with their academic careers, so that they have been labeled an endangered species. In this Invited Commentary, the author defines three career paths for physician-investigators-clinical researcher, clinician-scientist, and physician-scientist. Each of these pathways has common and distinct challenges that should be studied and potential improvements that should be evaluated through pilot research projects.The first challenge that all physician-investigators face is securing funding. Physicians are funded by their clinical activities, which often lures physician-investigators to increase their clinical work, particularly when research funding from the National Institutes of Health is difficult to secure and seemingly arbitrarily granted. The second challenge is an appointments, promotion, and tenure system that is not responsive to the needs of faculty working across clinical care and research, particularly when it comes to evaluating team science. Physician-investigators not working full-time in either discipline then may have trouble being promoted. The third challenge is the increasing burdens of clinical activities, particularly with the advent of electronic medical records.In this issue, two articles address overcoming the challenges faced by physician-investigators, one from the National Institutes of Health to grow the workforce and the other to offer organizational and individual solutions to support these investigators in faculty roles. These solutions are encouraging, but data about the extent of the challenges and the potential effects of the solutions are needed to make the physician-investigator career path less daunting.