Robust Tobacco Smoking Self-Report in two Cohorts of Vulnerable Pregnant Women and Adults

AbstractBackgroundStigma associated with tobacco smoking, especially during pregnancy, may lead to underreporting and possible bias in studies relying on self-reported smoking data. Cotinine, a nicotine metabolite with a ∼20h half-life in blood, is often used as a biomarker of smoking. The objective of this study was to examine the concordance between self-reported smoking and plasma cotinine concentration among participants enrolled in two related cohorts of vulnerable individuals: human immunodeficiency virus (HIV)-positive and HIV-negative pregnant women enrolled in the CARMA-PREG cohort and HIV-positive and HIV-negative non-pregnant women and men enrolled in the CARMA-CORE cohort.MethodsFor HIV-positive (n=76) and negative (n=24) pregnant women, plasma cotinine was measured by ELISA in specimens collected during the third trimester, between 28 and 38 weeks of gestation. Plasma cotinine was also measured in HIV-positive (n=43) and negative (n=57) women and men enrolled in the CARMA-CORE cohort.ResultsSelf-reported smokers were more likely to have low income (p&lt;0.001) in both cohorts, and to deliver preterm (p=0.007) in CARMA-PREG. In the CARMA-PREG cohort, concordance between plasma cotinine was 95% for self-reported smoking, and 89% for self-reported non-smoking. In the CARMA-CORE cohort we observed similarly high concordances of 96% and 92% for self-reported smoking and non-smoking, respectively. In this sample, the odds of discordance between self-reported smoking status and cotinine levels were not significantly different between self-reported smokers and non-smokers, nor between pregnant women and others. Taken together, the overall concordance between plasma cotinine and self-reported data was 94% with a Cohen’s kappa coefficient of 0.860 among all participants.ConclusionsGiven the high proportion of vulnerable people in the CARMA-PREG and CARMA-CORE cohorts, our results may not be fully generalizable to the general population. However, they demonstrate that participant surveying in a non-judgemental context can lead to accurate and robust self-report data.ImplicationsReliable self-reported smoking data is necessary to account for smoking status in subsequent studies. Our results suggest that future studies should ensure that study participants feel sale to speak candidly to non-judgemental research staff to obtain reliable self-report data.</jats:sec

Exploring Mitochondrial Nephrotoxicity as a Potential Mechanism of Kidney Dysfunction among HIV-Infected Patients on Highly Active Antiretroviral Therapy

BackgroundTenofovir (TDF) exposure has been associated with renal dysfunction. Mitochondrial nephrotoxicity was investigated as an underlying mechanism. Given the interaction between TDF and didanosine (ddI), their concurrent use was also investigated.DesignRelative kidney biopsy mitochondrial DNA (mtDNA) to nuclear DNA ratios were measured retrospectively. HIV+individuals on TDF within 6 months preceeding the biopsy (HIV+/TDF+, n=21) were compared to HIV+individuals who never received TDF (HIV+/TDF-, n=10) and to HIV uninfected controls (HIV–, n=22). Twelve of the HIV+/TDF+individuals received concurrent ddI, 10 of those once at unadjusted ddI dosage. Tubular mitochondria morphology was also examined by electron microscopy. Statistical analyses were done on log-transformed mtDNA/nDNA, using non-parametric tests.ResultsKidney mtDNA levels were different among the three groups ( P=0.046). mtDNA ratios were lower in HIV+/TDF+subjects (7.5 [2.0–12.1]) than in HIV-ones (14.3 [6.0–16.5], P=0.014), but not lower than HIV+/TDF-controls (6.4 [2.8–11.9], P=0.82). Among HIV+subjects, there was a difference between TDF-, TDF+/ddI-and TDF+/ddI+( P=0.005), with concurrent TDF/ddI use associated with lower mtDNA (2.1 [1.9–5.5], n=12) than TDF+/ddI-(13.8 [7.5–16.4], n=9, P=0.003). No TDF–/ddI+biopsies were available. In regression analyses, only HIV infection ( P=0.03), and TDF/ddI use ( P=0.003) were associated with lower mtDNA. At the ultrastructural level, abnormal tubular mitochondria was more prevalent in HIV+/TDF+biopsies than HIV+/TDF-and HIV-ones together ( P&lt;0.001) but not more so in TDF+/ddI+biopsies than TDF+/ddI-ones ( P=0.67).ConclusionsRenal dysfunction in this population may be mediated through mitochondrial nephrotoxicity that involves more than one drug and/or pathogenesis. Kidney mtDNA depletion was associated with HIV infection and concurrent TDF/ddI therapy but not TDF use alone, while kidney ultrastructural mitochondrial abnormalities were seen with TDF use. The interaction between TDF and ddI may be relevant in the kidney where both drugs are cleared. The clinical relevance of our findings needs to be evaluated given the current recommendation for reduced doses of ddI when used in conjunction with TDF.</jats:sec

Robust tobacco smoking self-report in two cohorts: pregnant women or men and women living with or without HIV

Abstract Understanding the true burden of tobacco smoking on adverse pregnancy outcomes is critical in generating appropriate interventions to improve outcomes. Self-reporting of human behaviour that is associated with stigma is associated with underreporting in general and may bias the impact of smoking in studies; however, self-reporting is frequently the most practical method of gleaning this information. The objective of this study was to evaluate concordance between self-reported smoking and concentrations of plasma cotinine, a biomarker of smoking, among participants enrolled in two related HIV cohorts. A total of 100 pregnant women (76 living with HIV [LWH] and 24 negative controls) in their third trimester, and 100 men and non-pregnant women (43 LWH and 57 negative controls) were included. Among all participants, 43 pregnant women (49% LWH and 25% negative controls) and 50 men and non-pregnant women (58% LWH and 44% negative controls) were self-reported smokers. The odds of discordance between self-reported smoking and cotinine levels were not significantly different between self-reported smokers and non-smokers, nor between pregnant women and others, but were significantly increased, regardless of self-reported status, among people LWH compared to negative controls. The overall concordance between plasma cotinine and self-reported data among all participants was 94% with a sensitivity and specificity of 90% and 96%, respectively. Taken together, these data demonstrate that participant surveying in a non-judgemental context can lead to accurate and robust self-report smoking data among both persons LWH and not, including in the context of pregnancy

Evidence of Subclinical mtDNA Alterations in HIV-Infected Pregnant Women Receiving Combination Antiretroviral Therapy Compared to HIV-Negative Pregnant Women.

Combination antiretroviral therapy (cART) can effectively prevent vertical transmission of HIV but there is potential risk of adverse maternal, foetal or infant effects. Specifically, the effect of cART use during pregnancy on mitochondrial DNA (mtDNA) content in HIV-positive (HIV+) women is unclear. We sought to characterize subclinical alterations in peripheral blood mtDNA levels in cART-treated HIV+ women during pregnancy and the postpartum period.This prospective longitudinal observational cohort study enrolled both HIV+ and HIV-negative (HIV-) pregnant women. Clinical data and blood samples were collected at three time points in pregnancy (13-<23 weeks, 23-<30 weeks, 30-40 weeks), and at delivery and six weeks post-partum in HIV+ women. Peripheral blood mtDNA to nuclear DNA (nDNA) ratio was measured by qPCR.Over a four year period, 63 HIV+ and 42 HIV- women were enrolled. HIV+ women showed significantly lower mtDNA/nDNA ratios compared to HIV- women during pregnancy (p = 0.003), after controlling for platelet count and repeated measurements using a multivariable mixed-effects model. Ethnicity, gestational age (GA) and substance use were also significantly associated with mtDNA/nDNA ratio (p≤0.02). Among HIV+ women, higher CD4 nadir was associated with higher mtDNA/nDNA ratios (p<0.0001), and these ratio were significantly lower during pregnancy compared to the postpartum period (p<0.0001).In the context of this study, it was not possible to distinguish between mtDNA effects related to HIV infection versus cART therapy. Nevertheless, while mtDNA levels were relatively stable over time in both groups during pregnancy, they were significantly lower in HIV+ women compared to HIV- women. Although no immediate clinical impact was observed on maternal or infant health, lower maternal mtDNA levels may exert long-term effects on women and children and remain a concern. Improved knowledge of such subclinical alterations is another step toward optimizing the safety and efficacy of cART regimens during pregnancy

Survival of Effector CD8+ T Cells during Influenza Infection Is Dependent on Autophagy

Abstract The activation and expansion of effector CD8+ T cells are essential for controlling viral infections and tumor surveillance. During an immune response, T cells encounter extrinsic and intrinsic factors, including oxidative stress, nutrient availability, and inflammation, that can modulate their capacity to activate, proliferate, and survive. The dependency of T cells on autophagy for in vitro and in vivo activation, expansion, and memory remains unclear. Moreover, the specific signals and mechanisms that activate autophagy in T effector cells and their survival are not known. In this study, we generated a novel inducible autophagy knockout mouse to study T cell effector responses during the course of a virus infection. In response to influenza infection, Atg5−/− CD8+ T cells had a decreased capacity to reach the peak effector response and were unable to maintain cell viability during the effector phase. As a consequence of Atg5 deletion and the impairment in effector-to-memory cell survival, mice fail to mount a memory response following a secondary challenge. We found that Atg5−/− effector CD8+ T cells upregulated p53, a transcriptional state that was concomitant with widespread hypoxia in lymphoid tissues of infected mice. The onset of p53 activation was concurrent with higher levels of reactive oxygen species (ROS) that resulted in ROS-dependent apoptotic cell death, a fate that could be rescued by treating with the ROS scavenger N-acetylcysteine. Collectively, these results demonstrate that effector CD8+ T cells require autophagy to suppress cell death and maintain survival in response to a viral infection.</jats:p

Demographic, clinical and laboratory characteristics of study participants (n = 105).

<p>^a Substance use is defined as self-reported use of substance at ≥3 study visits. Illicit Drugs = heroin, cocaine, opioids, amphetamines, benzodiazepenes and/or MDMA (ecstasy).</p><p>^b P-values are from Fisher’s exact tests for categorical data, and t-tests for continuous data (Platelets</p><p>Demographic, clinical and laboratory characteristics of study participants (n = 105).</p