Fertility desires and preferences for safer conception strategies among people receiving care for HIV at a publicly-funded clinic in Seattle,WA

Understanding fertility desires and preferences for HIV prevention among individuals living with HIV, including the potential use of pre-exposure prophylaxis (PrEP) by HIV uninfected partners, can inform the delivery of safer conception counseling to reduce the risk of HIV transmission during pregnancy attempts. Men and women, predominantly heterosexual, engaged in HIV care in Seattle, WA, self-administered a questionnaire and we abstracted antiretroviral therapy (ART) status and HIV viral levels from medical records. We summarized participants’ sexual behavior, fertility desires, and preferences for safer conception strategies and used log-binomial regression to identify demographic, sexual, and behavioral factors associated with perceived acceptability of PrEP for HIV uninfected partners during pregnancy attempts. 52% of the 150 participants were female and the mean age was 48 years (range 23–74). 94.7% of participants were using ART and 79.3% had HIV viral load < 40 copies/mL. 22.2% of men and 34.6% of women reported that a healthcare provider had initiated discussion about fertility desires. 28.7% of participants were reproductive-age and desired children. Among sexually active reproductive-age participants with fertility desires, 56.3% reported inconsistent condom use and 62.5% did not report using effective birth control. 74.4% of reproductive age participants with fertility desires perceived that PrEP would be acceptable to an HIV uninfected partner and there were no significant predictors of PrEP acceptability. Nearly one third of reproductive-aged individuals living with HIV expressed fertility desires, highlighting a need for safer conception counseling in this setting. PrEP and ART were favored safer conception strategies.     

Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy

The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R² = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa.     

Outcomes in splenic marginal zone lymphoma: analysis of 107 patients treated in British Columbia

Splenic marginal zone lymphoma (SMZL) accounts for less than 2% of all non‐Hodgkin lymphomas. We identified 107 cases diagnosed with SMZL between 1985 and 2012 from the British Columbia Cancer Agency Centre for Lymphoid Cancer and Lymphoma Pathology Databases. Patient characteristics were: median age 67 years (range 30–88), male 40%, stage IV 98%, splenomegaly 93%, bone marrow involvement 96%, peripheral blood involvement 87%. As initial treatment, 52 underwent splenectomy (10 with chemotherapy), 38 chemotherapy alone (21 chemoimmunotherapy containing rituximab, 1 rituximab alone), two antivirals for hepatitis C, and 15 were only observed. The 10‐year overall survival for first‐line splenectomy versus chemotherapy was 61% and 42%, respectively [Hazard Ratio (HR) 0·48, 95% confidence interval (CI) 0·26–0·88, P = 0·017]. The 10‐year failure‐free survival (FFS) after first‐line splenectomy vs chemotherapy was 39% and 14%, respectively (HR 0·48, 95% CI 0·28–0·80, P = 0·004). Among the 38 patients who received first‐line chemotherapy, FFS was similar between those receiving rituximab (n = 22) and those who did not (n = 16) (HR 0·64, 95% CI 0·31–1·34, P = 0·238). Fifteen patients transformed to aggressive lymphoma with median time to transformation of 3·5 years (range 6 months to 12 years) and the 10‐year transformation rate was 18%. In conclusion, splenectomy remains a reasonable treatment for patients with SMZL.     

Young people's sexual health in South Africa: HIV prevalence and sexual behaviors from a nationally representative household survey

OBJECTIVES: To determine the prevalence of HIV infection, HIV risk factors, and exposure to national HIV prevention programs, and to identify factors associated with HIV infection among South African youth, aged 15-24 years. DESIGN: A cross-sectional, nationally representative, household survey. METHODS: From March to August 2003 we conducted a national survey of HIV prevalence and sexual behavior among 11 904 15-24 year olds. Multivariable models for HIV infection were restricted to sexually experienced youth. RESULTS: Young women were significantly more likely to be infected with HIV in comparison with young men (15.5 versus 4.8%). Among men, a history of genital ulcers in the past 12 months was associated with HIV infection [adjusted odds ratio (AOR), 1.91; 95% confidence interval (CI), 1.04-3.49) whereas among women a history of unusual vaginal discharge in the past 12 months was associated with HIV infection (AOR, 1.75; 95% CI, 1.26-2.44). Young women with older partners were also at increased risk of HIV infection. Among both men and women, increasing partner numbers and inconsistent condom use were significantly associated with HIV infection. Males and females who reported participation in at least one loveLife program were less likely to be infected with HIV (AOR, 0.60; 95% CI, 0.40-0.89; AOR, 0.61; 95% CI, 0.43-0.85, respectively). CONCLUSION: This survey confirms the high HIV prevalence among young people in South Africa and, in particular, young women's disproportionate risk. Programs for youth must continue to promote partner reduction, consistent condom use and prompt treatment for sexually transmitted infections while also addressing contextual factors that make it difficult for them to implement behavior change.     

CTLA‐4 (CD152) enhances the Tc17 differentiation program

Although CD8⁺ T cells that produce IL‐17 (Tc17 cells) have been linked to host defense, Tc17 cells show reduced cytotoxic activity, which is the characteristic function of CD8⁺ T cells. Here, we show that CTLA‐4 enhances the frequency of IL‐17 in CD8⁺ T cells, indicating that CTLA‐4 (CD152) specifically promotes Tc17 differentiation. Simultaneous stimulation of CTLA‐4^+/+ and CTLA‐4^?/? T cells in cocultures and agonistic CTLA‐4 stimulation unambiguously revealed a cell‐intrinsic mechanism for IL‐17 control by CTLA‐4. The quality of CTLA‐4‐induced Tc17 cells was tested in vivo, utilizing infection with the facultative intracellular bacterium Listeria monocytogenes (LM). Unlike CTLA‐4^+/+ Tc17 cells, CTLA‐4^?/? were nearly as efficient as Tc1 CTLA‐4^+/+ cells in LM clearance. Additionally, adoptively transferred CTLA‐4^?/? Tc17 cells expressed granzyme B after rechallenge, and produced Tc1 cytokines such as IFN‐γ and TNF‐α, which strongly correlate with bacterial clearance. CTLA‐4^+/+ Tc17 cells demonstrated a high‐quality Tc17 differentiation program ex vivo, which was also evident in isolated IL‐17‐secreting Tc17 cells, with CTLA‐4‐mediated enhanced upregulation of Tc17‐related molecules such as IL‐17A, RORγt, and IRF‐4. Our results show that CTLA‐4 promotes Tc17 differentiation that results in robust Tc17 responses. Its inactivation might therefore represent a central therapeutic target to enhance clearance of infection.     

Treatment Recommendations Following 3-Day Masked Continuous Glucose Monitoring (CGM) in Youth With Type 1 Diabetes

Glycemic control remains suboptimal in youth with type 1 diabetes. Retrospective continuous glucose monitoring (CGM) has demonstrated utility in fine-tuning diabetes management by detecting postprandial hyperglycemia and hypoglycemia. In this study, we explored the process of 3-day masked CGM use, subsequent treatment recommendations, and impact on A1c in a clinic-based sample of youth with type 1 diabetes. Over 2 years, 122 youth were referred for masked CGM. Patients/families completed a diary of blood glucose levels, insulin doses, food intake, and exercise during CGM use. A1c was assessed pre- and 2-3 months post-CGM. Treatment recommendations were formulated using data from CGM reports and diaries. Mean age was 14.3 ± 3.9 years, diabetes duration was 7.5 ± 4.7 years, and A1c was 8.5 ± 1.1% (69 ± 12 mmol/mol); 61% were pump-treated. Patients received an average of 3.1 ± 1.1 treatment recommendations following review of the CGM report. Most (80%) received reinforcement of the importance of preprandial bolusing; 37% received a recommendation regarding advanced insulin management (use of combination boluses/attend to active insulin). Receipt of the latter recommendation was related to A1c improvement ≥0.5% (OR: 4.0, P < .001). Masked CGM offers opportunities to guide advanced insulin management (by injection or pump), which may yield A1c improvements in youth with type 1 diabetes.