Melissa F. Wellons

Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects

The risks and benefits of structured treatment interruption (STI) in HIV-1-infected subjects are not fully understood. A pilot study was performed to compare STI with continuous highly active antiretroviral therapy (HAART) in chronic HIV-1-infected subjects with HIV-1 plasma RNA levels (VL) <400 copies per ml and CD4+ T cells >400 per μl. CD4+ T cells, VL, HIV-1-specific neutralizing antibodies, and IFN-γ-producing HIV-1-specific CD8+ and CD4+ T cells were measured in all subjects. STIs of 1-month duration separated by 1 month of HAART, before a final 3-month STI, resulted in augmented CD8+ T cell responses in all eight STI subjects (P = 0.003), maintained while on HAART up to 22 weeks after STI, and augmented neutralization titers to autologous HIV-1 isolate in one of eight subjects. However, significant decline of CD4+ T cell count from pre-STI level, and VL rebound to pre-HAART baseline, occurred during STI (P = 0.001 and 0.34, respectively). CD4+ T cell counts were regained on return to HAART. Control subjects (n = 4) maintained VL <400 copies per ml and stable CD4+ T cell counts, and showed no enhancement of antiviral CD8+ T cell responses. Despite increases in antiviral immunity, no control of VL was observed. Future studies of STI should proceed with caution.

A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Early menopause predicts future coronary heart disease and stroke: the Multi-Ethnic Study of Atherosclerosis.

Objective Cardiovascular disease is the number one killer of women. Identifying women at risk of cardiovascular disease has tremendous public health importance. Early menopause is associated with increased cardiovascular disease events in some predominantly white populations, but not consistently. Our objective was to determine if self-reported early menopause (menopause at an age <46 y) identifies women as at risk for future coronary heart disease or stroke. Methods The study population came from the Multi-Ethnic Study of Atherosclerosis, a longitudinal, ethnically diverse cohort study of US men and women aged 45 to 84 years enrolled in 2000-2002 and followed up until 2008. The association between a personal history of early menopause (either natural menopause or surgical removal of ovaries at an age <46 y) and future coronary heart disease and stroke was assessed in 2,509 women (ages 45-84 y; 987 white, 331 Chinese, 641 black, and 550 Hispanic) from the Multi-ethnic Study Atherosclerosis who were free of cardiovascular disease at baseline. Results Of 2,509 women, 693 (28%) reported either surgical or natural early menopause. In survival curves, women with early menopause had worse coronary heart disease and stroke-free survival (log rank P = 0.008 and P = 0.0158). In models adjusted for age, race/ethnicity, Multi-ethnic Study Atherosclerosis site, and traditional cardiovascular disease risk factors, this risk for coronary heart disease and stroke remained (hazard ratio, 2.08; 95% CI, 1.17-3.70; and hazard ratio, 2.19; 95% CI, 1.11-4.32, respectively). Conclusions Early menopause is positively associated with coronary heart disease and stroke in a multiethnic cohort, independent of traditional cardiovascular disease risk factors.

The North American Menopause Society recommendations for clinical care of midlife women

In celebration of the 25th anniversary of The North American Menopause Society (NAMS), the Society has compiled a set of key points and clinical recommendations for the care of midlife women. NAMS has always been a premier source of information about menopause for both healthcare providers and midli

Childbearing May Increase Visceral Adipose Tissue Independent of Overall Increase in Body Fat

Objective: To examine whether childbearing is associated with increased visceral adiposity and whether the increase is proportionally larger than other depots.

HIV Infection: Treatment Outcomes in Older and Younger Adults

To determine the effect of antiretroviral therapy (ART) on the immunological and virological outcomes of older human immunodeficiency virus (HIV)‐infected patients compared with younger HIV‐infected patients.

Race matters: a systematic review of racial/ethnic disparity in Society for Assisted Reproductive Technology reported outcomes.

OBJECTIVE To systematically review the reporting of race/ethnicity in Society for Assisted Reproductive Technology (SART) Clinic Outcome Reporting System (CORS) publications. DESIGN Systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology of literature published in PubMed on race/ethnicity that includes data from SART CORS. SETTING Not applicable. PATIENT(S) Not applicable. INTERVENTION(S) In vitro fertilization cycles reported to SART. MAIN OUTCOME MEASURE(S) Any outcomes reported in SART CORS. RESULT(S) Seven publications were identified that assessed racial/ethnic disparities in IVF outcomes using SART data. All reported a racial/ethnic disparity. However, more than 35% of cycles were excluded from analysis because of missing race/ethnicity data. CONCLUSION(S) Review of current publications of SART data suggests significant racial/ethnic disparities in IVF outcomes. However, the potential for selection bias limits confidence in these findings, given that fewer than 65% of SART reported cycles include race/ethnicity. Our understanding of how race/ethnicity influences ART outcome could be greatly improved if information on race/ethnicity was available for all reported cycles.

Emergence of drug-resistant HIV-1 variants in patients undergoing structured treatment interruptions.

We report the emergence of drug-resistant viral mutations in chronically HIV-infected individual undergoing structured treatment interruptions (STI). THe protease mutations K101E and K103N were detected at the end of the second or third STI. We concluded that the repeated abrupt termination and resumption of certain antiretroviral drug regimens during STI therapy may lead to the development of drug resistance in chronically HIV-infected individuals.

Polycystic Ovary Syndrome and Risk for Long-Term Diabetes and Dyslipidemia

OBJECTIVE: To estimate whether women aged 20–32 years who fulfilled National Institutes of Health criteria for polycystic ovary syndrome (PCOS) would be at higher risk for subsequent development of incident diabetes, dyslipidemia, and hypertension, and to estimate whether normal-weight women with PCOS would have the same degree of cardiovascular risk as overweight women with PCOS. METHODS: We estimated the association of PCOS with incident diabetes, dyslipidemia, and hypertension over a period of 18 years among 1,127 white and African-American women in the Coronary Artery Risk Development in Young Adults cohort. We classified women at baseline (ages 20–32 years) based on self-reported symptoms and serum androgen measures using National Institutes of Health PCOS criteria. We estimated the association of PCOS and subsequent cardiovascular risk factors, independent of baseline body mass index (BMI), using multivariable logistic regression. Additionally, among 746 women with a second assessment of PCOS at ages 34–46 years, we estimated the association of persistent PCOS with cardiovascular risk factors. RESULTS: Of 1,127 women, 53 (4.7%) met criteria for PCOS at ages 20–32 years. Polycystic ovary syndrome was associated with a twofold higher odds of incident diabetes (23.1% compared with 13.1%, adjusted odds ratio [AOR] 2.4, confidence interval [CI] 1.2–4.9) and dyslipidemia (41.9% compared with 27.7%, AOR 1.9, CI 1.0–3.6) over the course of 18 years; the association with incident hypertension was not significant (26.9% compared with 26.3%, AOR 1.7, CI 0.8–3.3). Normal-weight women with PCOS (n=31) had a threefold higher odds of incident diabetes compared with normal-weight women without PCOS (AOR 3.1, CI 1.2–8.0). Compared with those without PCOS, women with persistent PCOS (n=11) had the highest odds of diabetes (AOR 7.2, CI 1.1–46.5). CONCLUSION: Polycystic ovary syndrome is associated with subsequent incident diabetes and dyslipidemia, independent of BMI. Diabetes risk may be greatest for women with persistent PCOS symptoms. LEVEL OF EVIDENCE: II

Prepregnancy Lipids Related to Preterm Birth Risk: The Coronary Artery Risk Development in Young Adults Study

CONTEXT Preterm birth is associated with maternal cardiovascular risk, but mechanisms are unknown. OBJECTIVE We considered that dyslipidemia may predispose women to both conditions and that prepregnancy lipids may be related to preterm birth risk. We hypothesized that low or high prepregnancy plasma lipids would be associated with preterm birth. DESIGN, SETTING, AND PARTICIPANTS A total of 1010 women (49% black) enrolled in the multicenter, prospective Coronary Artery Risk Development in Young Adults study with at least one singleton birth during 20 yr of follow-up were evaluated. MAIN OUTCOME MEASURE Postbaseline preterm births less than 34 wk or 34 to less than 37 wk vs. greater than 37 wk gestation. RESULTS We detected a U-shaped relationship between prepregnancy cholesterol concentrations and preterm birth risk. Women with prepregnancy cholesterol in the lowest quartile compared with the second quartile (<156 vs. 156-171 mg/dl) had an increased risk for preterm birth 34 to less than 37 wk (odds ratio 1.86; 95% confidence interval 1.10, 3.15) and less than 34 wk (odds ratio 3.04; 1.35, 6.81) independent of race, age, parity, body mass index, hypertension during pregnancy, physical activity, and years from measurement to birth. Prepregnancy cholesterol in the highest quartile (>195 mg/dl) was also associated with preterm birth less than 34 wk among women with normotensive pregnancies (odds ratio 3.80; 95% confidence interval 1.07, 7.57). There were no associations between prepregnancy triglycerides, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol and preterm birth. CONCLUSIONS Both low and high prepregnancy cholesterol were related to preterm birth risk. These may represent distinct pathways to the heterogeneous outcome of preterm birth. Additional studies are needed to elucidate mechanisms that link low or high cholesterol to preterm birth and later-life sequelae.