Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model

Objective: We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility. Study Design: Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2α-hydroxyprogesterone, 6β-hydroxyprogesterone (6β-OHP), 16α-hydroxyprogesterone (16α-OHP), or 17-hydroxyprogesterone caproate (17-OHPC) at 10−9 to 10−6 mol/L. Uterine horns were exposed to progestins (10−6 mol/L), followed by increasing concentrations of oxytocin (1-100 nmol/L) to study oxytocin-induced contractility. Contraction parameters were compared for each progestin and matched vehicle control using repeated measures 2-way analysis of variance. In vitro metabolism of progesterone by recombinant cytochrome P450 3A (CYP3A) microsomes (3A5, 3A5, and 3A7) identified major metabolites. Results: Oxytocin-induced contractile frequency was decreased by 16α-OHP (P = .03) and increased by 6β-OHP (P = .05). Progesterone and 17-OHPC decreased oxytocin-induced contractile force (P = .02 and P = .04, respectively) and frequency (P = .02 and P = .03, respectively). Only progesterone decreased spontaneous contractile force (P = .02). Production of 16α-OHP and 6β-OHP metabolites were confirmed in all CYP3A isoforms tested. Conclusion: Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility

Ongoing life stressors and suicidal ideation among HIV-infected adults with depression

Suicidal ideation is the most proximal risk factor for suicide and can indicate extreme psychological distress; identification of its predictors is important for possible intervention. Depression and stressful or traumatic life events (STLEs), which are more common among HIV-infected individuals than the general population, may serve as triggers for suicidal thoughts

When “Need Plus Supply” Does Not Equal Demand: Challenges in Uptake of Depression Treatment in HIV Clinical Care

Depression is common among patients in HIV care and predicts worse HIV-related health behaviors and outcomes. Effective depression treatment is available, yet depression remains widely underdiagnosed and undertreated in HIV care

Implementation of PHQ-9 Depression Screening for HIV-Infected Patients in a Real-World Setting

The prevalence of depression is 20%-30% for people living with HIV, and while it is associated with poorer adherence to antiretrovirals, it is often unrecognized by medical providers. Although it has been challenging for some health care settings to develop consistent depression screening mechanisms, it is feasible to create screening protocols using the 9-item Patient Health Questionnaire (PHQ-9). Establishing a depression screening and response protocol is an iterative process that involves preparing staff, determining screening frequency, and developing procedures for response and appropriate medical record documentation. While there are multiple issues and potential challenges during implementation, it is possible to incorporate systematic depression screening into HIV primary care in a manner that achieves staff buy-in, minimizes patient burden, streamlines communication, and efficiently uses the resources available in the medical setting

Cigarette Smoke-Induced Placental Adrenomedullin Expression and Trophoblast Cell Invasion

Smoking in pregnancy reduces preeclampsia risk, but the mechanism of this effect is unknown. Prior studies have demonstrated that women with preeclampsia have lower placental adrenomedullin (AM) expression, and cigarette smoke extract (CSE) treatment of placental trophoblast cells in culture increases AM cellular production. We hypothesized that CSE alters trophoblast invasion through an AM-mediated mechanism, and that placental AM expression is greater among smokers. HTR-8/SVneo trophoblast cells were incubated for 24 hours in Matrigel-invasion chambers with 6 treatment groups: nonstimulated (NS), AM, AM inhibitor (AM22-52), 1% CSE, AM + AM22-52, and 1% CSE + AM22-52. Cells that penetrated the lower surface of the chambers were quantified, invasion indices were calculated, and compared using a 1-way analysis of variance with Bonferroni corrections for multiple comparisons. Trophoblast cells treated with both AM and 1% CSE demonstrated increased cellular invasion compared to NS controls (1.5-fold [P < .01] and 1.45-fold [P < .01], respectively). Cotreatment with the AM inhibitor significantly attenuated the increased invasion seen with both AM and CSE alone. Next, the placental tissue was obtained from 11 smokers and 11 nonsmokers at term and processed for immunohistochemistry (IHC) and real-time quantitative polymerase chain reaction (PCR) for AM. Placentas from smokers demonstrated more intense AM staining and increased AM gene (ADM) expression compared to placentas from nonsmokers (P = .004 for IHC, P = .022 for PCR). The CSE increases trophoblast cell invasion through an AM-mediated process, and placental AM expression is increased among term smokers compared to nonsmokers. These findings provide evidence that the AM pathway may play a role in the protection from preeclampsia seen in smokers

Improvements in depression and changes in quality of life among HIV-infected adults

Improving QOL for HIV-infected individuals is an important objective of HIV care, given the considerable physical and emotional burden associated with living with HIV. Although worse QOL has been associated with depression, no research has quantified the potential of improvement in depression to prospectively improve QOL among HIV-infected adults. We analyzed data from 115 HIV-infected adults with depression enrolled in a randomized controlled trial to evaluate the effectiveness of improved depression care on antiretroviral drug adherence. Improvement in depression, the exposure of interest, was defined as the relative change in depression at 6 months compared to baseline and categorized as full response (≥50% improvement), partial response (25%–49% improvement) and no response (<25% improvement). Multivariable linear regression was used to investigate the relationship between improvement in depression and four continuous measures of QOL at 6 months: physical QOL, mental QOL, HIV symptoms, and fatigue intensity. In multivariable analyses, physical QOL was higher among partial responders (MD=2.51, 95% CI −1.51, 6.54) and full responders (MD=3.68, 95% CI −0.36, 7.72) compared to individuals who did not respond. Mental QOL was an average of 4.01 points higher (95% CI −1.01, 9.03) among partial responders and 14.34 points higher (95% CI 9.42, 19.25) among full responders. HIV symptoms were lower for partial responders (MD=−0.69; 95% CI −1.69, 0.30) and full responders (MD=−1.51; 95% CI −2.50, −0.53). Fatigue intensity was also lower for partial responders (MD=−0.94; 95% CI −1.94, 0.07) and full responders (MD=−3.00; 95% CI −3.98, −2.02). Among HIV-infected adults with depression, improving access to high-quality depression treatment may also improve important QOL outcomes

Improving Depression Among HIV-Infected Adults: Transporting the Effect of a Depression Treatment Intervention to Routine Care

Depression affects 20-30% of people with HIV. Randomized controlled trials (RCTs) have demonstrated the effectiveness of interventions to improve depression among HIV-infected adults, but typically have highly selected populations which may limit generalizability. Inverse probability of sampling weights (IPSW) are a recently proposed method to transport (or standardize) findings from RCTs to a specific external target population

Balancing Contamination and Referral Bias in a Randomized Clinical Trial: An Application of Pseudo-Cluster Randomization

In randomized trials of provider-focused clinical interventions, treatment allocation often cannot be blinded to participants, study staff, or providers. The choice of unit of randomization (patient, provider, or clinic) entails tradeoffs in cost, power, and bias. Provider- or clinic-level randomization can minimize contamination, but it incurs the equally problematic potential for referral bias; that is, because arm assignment of future participants generally cannot be concealed, differences between arms may arise in the types of patients enrolled. Pseudo-cluster randomization is a novel study design that balances these competing validity threats. Providers are randomly assigned to an imbalanced proportion of intervention-arm participants (e.g., 80% or 20%). Providers can be masked to the imbalance, avoiding referral bias. Contamination is reduced because only a minority of control-arm participants are treated by majority-intervention providers. Pseudo-cluster randomization was implemented in a randomized trial of a decision support intervention to manage depression among patients receiving human immunodeficiency virus care in the southern United States in 2010–2014. The design appears successful in avoiding referral bias (participants were comparable between arms on important characteristics) and contamination (key depression treatment indicators were comparable between usual care participants managed by majority-intervention and majority-usual care providers and were markedly different compared with intervention participants)