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Medians and inter-decile ranges of estrogens and estrogen metabolites for controls and ovarian cancer cases by subtype, nested case-control study within the Women's Health Initiative-Observational Study.

Supplemental Table 1. Quintile-specific odds ratios and 95% confidence intervals for the risk of endometrial cancer for each estrogen metabolite. Supplemental Table 2. Spearman's rank correlation coefficients of estrogens and estrogen metabolites, measured in controls (n=476)1, nested case-control study, Women's Health Initiative Observational Study Supplementary Table 3. Risk of endometrial cancer comparing the 5th to the 1st quintile for 2-, 4-, and 16-hydroxylation pathway metabolites across categories of BMI, age, and years of oral contraceptive use.

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Background: Although endometrial cancer is clearly influenced by hormonal factors, few epidemiologic studies have investigated the role of endogenous estrogens or especially estrogen metabolites.Methods: We conducted a nested case–control study within the Women's Health Initiative Observational Study (WHI-OS), a cohort of 93,676 postmenopausal women recruited between 1993 and 1998. Using baseline serum samples from women who were non-current hormone users with intact uteri, we measured 15 estrogens/estrogen metabolites via HPLC/MS-MS among 313 incident endometrial cancer cases (271 type I, 42 type II) and 354 matched controls, deriving adjusted ORs and 95% confidence intervals (CI) for overall and subtype-specific endometrial cancer risk.Results: Parent estrogens (estrone and estradiol) were positively related to endometrial cancer risk, with the highest risk observed for unconjugated estradiol (OR 5th vs. 1st quintile = 6.19; 95% CI, 2.95–13.03, Ptrend = 0.0001). Nearly all metabolites were significantly associated with elevated risks, with some attenuation after adjustment for unconjugated estradiol (residual risks of 2- to 3-fold). Body mass index (kg/m2, BMI) relations were somewhat reduced after adjustment for estrogen levels. The association with unconjugated estradiol was stronger for type I than type II tumors (Phet = 0.01).Conclusions: Parent estrogens as well as individual metabolites appeared to exert generalized uterotropic activity, particularly for type I tumors. The effects of obesity on risk were only partially explained by estrogens.Impact: These findings enhance our understanding of estrogen mechanisms involved in endometrial carcinogenesis but also highlight the need for studying additional markers that may underlie the effects on risk of certain risk factors, for example, obesity. Cancer Epidemiol Biomarkers Prev; 25(7); 1081–9. ©2016 AACR.

Introduction: Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals.Methods: This study was nested within the Multicenter AIDS Cohort Study (MACS; men) and Women Interagency HIV Study (WIHS; women) cohorts. Exfoliated oral epithelial cells were collected from 379 HIV-positive and 266 at-risk HIV-negative individuals using a rinse and gargle with Scope mouthwash. Samples were tested for 36 types of HPV DNA using PGMY09/11 consensus primers and reverse line blot hybridization. Risk factors for oral HPV infection were explored using logistic regression with generalized estimating equations in this cross-sectional analysis.Results: Prevalent oral HPV infection was common (34%), including HPV16 infection in 5.7% of participants. HIV-positive individuals had increased odds of prevalent oral HPV infection compared with HIV-negative individuals [adjusted OR = 2.1; 95% confidence interval (CI), 1.6–2.8]. Risk factors for prevalent oral HPV differed in HIV-positive and HIV-negative participants. Among HIV-negative individuals, higher number of recent oral sex or rimming partners were strong risk factors for prevalent oral HPV infection (each Ptrend < 0.01). In contrast, among HIV-positive individuals, lower CD4 T-cell count (Ptrend < 0.001) and higher number of lifetime sexual partners (Ptrend = 0.03) were strong risk factors.Conclusions: Oral HPV prevalence was elevated in HIV-positive individuals after controlling for differences in cigarette smoking and sexual behavior, supporting the possibility that HIV may affect the natural history of oral HPV.Impact: Immunosuppression may contribute to increased persistence or progression of oral HPV infection. Cancer Epidemiol Biomarkers Prev; 21(1); 122–33. ©2011 AACR.

Odds ratios and 95% confidence intervals for the risk of epithelial ovarian cancer comparing the 5th quintile to the 1st quintile for individual estrogens and estrogen metabolites analyzed by time between blood draw and diagnosis among the cases, nested case-control study within the Women's Health Initiative-Observational Study.

Odds ratios and 95% confidence intervals for the risk of epithelial ovarian cancer comparing the 5th quintile to the 1st quintile for individual estrogens and estrogen metabolites stratified by age at blood draw, nested case-control study within the Women's Health Initiative-Observational Study.

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Background: Hormonal and reproductive factors contribute to the development of ovarian cancer, but few studies have examined associations between circulating estrogens and estrogen metabolites and ovarian cancer risk. We evaluated whether serum estrogens and estrogen metabolite levels are associated with ovarian cancer risk among postmenopausal women in a nested case–control study in the Women's Health Initiative (WHI) Observational Study (OS).Methods: We selected all 169 eligible epithelial ovarian cancer cases and 412 matched controls from women enrolled in WHI-OS who were not using menopausal hormones at baseline. Baseline levels of 15 estrogens and estrogen metabolites were measured via liquid chromatography/tandem mass spectrometry. Associations with ovarian cancer risk overall and stratified by histologic subtype (serous/nonserous) were analyzed using logistic regression. The mean time from serum collection to cancer diagnosis was 6.9 years.Results: Overall, we observed modest ovarian cancer risk associations among women with higher levels of estrone [OR (95% confidence interval) quintile (Q)5 vs. Q1: 1.54 (0.82–2.90), Ptrend = 0.05], as well as 2- and 4-methoxyestrone metabolites [2.03 (1.06–3.88), Ptrend = 0.02; 1.86 (0.98–3.56), Ptrend = 0.01, respectively]. Associations of estrogens and estrogen metabolites varied substantially by histologic subtype. Associations with serous tumors were universally null, while estrone [2.65 (1.09–6.45), Ptrend = 0.01, Pheterogeneity = 0.04], unconjugated estradiol [2.72 (1.04–7.14), Ptrend = 0.03, Pheterogeneity = 0.02] and many of the 2-, 4-, and 16-pathway metabolites were positively associated with nonserous tumors.Conclusions: Our study provides novel molecular data showing an association of the parent estrogens and several estrogen metabolites with nonserous ovarian cancers.Impact: These findings further support the heterogeneous etiology of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 648–56. ©2016 AACR.

Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case–cohort study nested within the Women's Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines—adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-α. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of anti-inflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HRQ4–Q1), 1.84; 95% CI, 1.17–2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women. Cancer Res; 72(12); 3029–37. ©2012 AACR.

PDF file - 66K, Median levels of adipokines by colorectal cancer risk factors in subcohort subjects from the WHI-OS Cohort,1994-2004

Background: The influence of sex hormone and insulin/insulin-like growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients. Methods: Stage II–IV patients (N = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of IGF1, IGF2, IGF-binding proteins (IGFBP)-1 and -3, insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade. Results: Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47–0.95), IR positivity (HR, 0.53; 95% CI, 0.29–0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47–0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02–2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02–1.92) were associated with increased recurrence risk. Conclusions: Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer. Impact: This study may inform future clinical trials of endocrine-targeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.

Author(s): Massad, Leslie S; Xie, Xianhong; Minkoff, Howard; Kassaye, Seble; Karim, Roksana; Darragh, Teresa M; Golub, Elizabeth T; Adimora, Adaora; Wingood, Gina; Fischl, Margaret; Konkle-Parker, Deborah; Strickler, Howard D | Abstract: ObjectiveTo describe longitudinal changes in the prevalence of abnormal Papanicolau testing among women living with HIV.DesignProspective cohort study with sequential enrollment subcohorts.MethodsFour waves of enrollment occurred in the Women's Interagency HIV Study, the US women's HIV cohort (1994-1995, 2001-2002, 2011-2012, 2013-2015). Pap testing was done at intake, with colposcopy prescribed for any abnormality. Rates of abnormal Pap test results (atypical squamous cells of uncertain significance or worse) and cervical intraepithelial neoplasia grade 2 (CIN2) or worse were calculated. Logistic regression models assessed changes in prevalence across cohorts after controlling for severity of HIV disease and other risk factors for abnormal Pap tests.ResultsThe unadjusted prevalence of any Pap abnormality was 679/1769 (38%) in the original cohort, 195/684 (29%) in the 2001-2002 cohort, 46/231 (20%) in the 2011-2012 cohort, and 71/449 (16%) in the 2013-2015 cohort. In multivariable analysis, compared with risk in the 1994-1995 cohort, the adjusted risk in the 2001-2002 cohort was 0.79 (95% CI 0.59-1.05), in the 2011-2012 cohort was 0.67 (95% CI 0.43-1.04), and in the 2013-2015 cohort was 0.41 (95% CI 0.27-0.62) with P for trend less than 0.0001.ConclusionRates of abnormal cytology among women with HIV have fallen during the past two decades.

A relatively high healthy lifestyle index (HLI) score, representing a healthy diet, participation in moderate to vigorous physical exercise, no smoking, low to no alcohol intake and a normal body mass index, has been associated with a reduced risk of invasive breast cancer. However, no study has shown an association between the HLI and the risk of ductal carcinoma in situ of the breast (DCIS), which is considered to be a nonobligate precursor of invasive breast cancer. We evaluated this association in a prospective cohort of 132 230 postmenopausal women, aged 50 to 79 years, recruited between 1993 and 1998 across the United States and enrolled in the Women's Health Initiative study. The HLI score was created and categorized into quartiles. During an average follow-up of 15.4 years, 2035 DCIS cases were ascertained. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of HLI with the risk of DCIS. Women in the highest HLI quartile had a lower DCIS risk than those in the lowest quartile (HR

Objectives The relationship between vitamin D deficiency (VDD) and pediatric nonalcoholic fatty liver disease (NAFLD) remains uncertain due to conflicting results and few studies with histologic endpoints. We therefore used multiple imaging and histologic NAFLD endpoints to more comprehensively assess the association between VDD and NAFLD in a large pediatric population. Methods Data were obtained from an ongoing pediatric NAFLD study in Bronx, NY. Briefly, overweight and obese children aged 2-18 years with alanine aminotransferase (ALT) levels ≥ 35 U/L were serially enrolled. Liver biopsy was obtained in accordance with clinical guidelines. All participants had liver imaging, namely, controlled attenuation parameter (CAP; Echosens, France) to assess steatosis and, to assess fibrosis, vibration controlled transient elastography (VCTE; FibroScan™, Echosens, France) and acoustic radiation force impulse (ARFI; Philips, Netherlands) imaging. Levels of 25-hydroxyvitamin D were measured serologically. Results N=276 (88%) of 315 participants had 25-OH vitamin D results, of whom 241 (87%) were Hispanic, 199 (72%) were male, and 92 (33%) underwent liver biopsy. VDD was univariately associated with high waist circumference (p=0.004), high-density lipoprotein level (p=0.01), season (p=0.009), and CAP score (p=0.01). In multivariate analysis, only waist circumference (p=0.0002) and biopsy inflammation grade (p=0.03) were associated with VDD, though the latter had not approximated statistical significance in univariate analysis (p=0.56). There was no association between VDD and hepatic steatosis, ballooning, NAFLD Activity Score, ARFI or VCTE elasticity scores. Conclusions VDD was not associated with NAFLD defined by imaging and histologic endpoints, except for a possible relation with histologic inflammation grade.

Key Points Question Has the introduction of the vaccine for human papillomavirus (HPV) been associated with changes in infection rates among sexually active adolescent girls and young adult women? Findings This cohort study assessed HPV infection rates of vaccinated adolescent and young adult women at a large adolescent-specific health center in New York City. Age-adjusted cervical HPV detection of vaccine-related types were lower year over year, while the prevalence of nonvaccine high-risk HPV types remained flat or higher. Meaning These results indicate the real-world effectiveness of the HPV vaccines in female youth in New York City; nevertheless, rates of some nonvaccine high-risk HPV types were higher., This cohort study of a single health center in New York City examines changes in human papillomavirus (HPV) infection rates among adolescent girls and young women following the introduction of a quadrivalent vaccine., Importance Rates of human papillomavirus (HPV) infection have decreased since the introduction of HPV vaccines in populations with high vaccine uptake. Data are limited for adolescent and young adult populations in US metropolitan centers. Objective To determine HPV infection rates in adolescent girls and young women aged 13 to 21 years in New York City following HPV vaccination. Design, Setting, and Participants This cohort study of type-specific cervical HPV detection was conducted at a large adolescent-specific integrated health center in New York City between October 2007 and September 2019. Participants included an open cohort of adolescent girls and young adult women who received the HPV vaccine (Gardasil; Merck & Co) over a 12-year period following HPV vaccination introduction. Data analysis was concluded September 2019. Exposures Calendar date and time since receipt of first vaccine dose. Main Outcomes and Measures Temporal associations in age-adjusted postvaccine HPV rates. Results A total of 1453 participants, with a mean (SD) age at baseline of 18.2 (1.4) years, were included in the cohort (African American with no Hispanic ethnicity, 515 [35.4%] participants; African American with Hispanic ethnicity, 218 [15.0%] participants; Hispanic with no reported race, 637 [43.8%] participants). Approximately half (694 [47.8%] participants) were vaccinated prior to coitarche. Age-adjusted detection rates for quadrivalent vaccine types (HPV-6, HPV-11, HPV-16, and HPV-18) and related types (HPV-31, and HPV-45) decreased year over year, with the largest effect sizes observed among individuals who had been vaccinated before coitarche (adjusted odds ratio [aOR], 0.81; 95% CI, 0.67-0.98). By contrast, detection was higher year over year for nonvaccine high-risk cervical HPV types (aOR, 1.08; 95% CI, 1.04-1.13) and anal HPV types (aOR, 1.11; 95% CI, 1.05-1.17). The largest effect sizes were observed with nonvaccine types HPV-56 and HPV-68. Conclusions and Relevance Whereas lower detection rates of vaccine-related HPV types were observed since introduction of vaccines in female youth in New York City, rates of some nonvaccine high-risk HPV types were higher. Continued monitoring of high-risk HPV prevalence is warranted.

BACKGROUND: Obesity is a strong risk factor for endometrial cancer, but it is unclear whether metabolic syndrome (MetS) contributes to endometrial cancer risk over and above the contribution of obesity. METHODS: We examined the association of MetS and its components with risk of endometrial cancer in a sub-cohort of 24,210 women enrolled in the Women’s Health Initiative cohort study. Two variants of the National Cholesterol Education Program Adult Treatment Panel III definition of the MetS were used: one including and one excluding waist circumference (WC). Cox proportional hazards models were used to estimate the association of the study exposures with disease risk. RESULTS: When WC was included in the definition, MetS showed an approximately two-fold increase in endometrial cancer risk (HR 2.20; 95% CI 1.61–3.02); however, when WC was excluded, MetS was no longer associated with risk. We also observed that women with hyperglycemia, dyslipidemia and hypertension, in combination, had almost a twofold increased risk of endometrial cancer, independent of WC (HR 1.94; 95% CI 1.09, 3.46). Glucose, and, in particular, WC and body mass index were also positively associated with risk. CONCLUSIONS: Our findings suggest that MetS may predict risk of endometrial cancer independent of obesity among women with the remaining four Mets components.

Background Primary human papillomavirus (HPV) screening (PHS) utilizes oncogenic human papillomavirus (oncHPV) testing as the initial cervical cancer screening method and typically, if positive, additional reflex-triage (eg, HPV16/18-genotyping, Pap testing). While US guidelines support PHS usage in the general population, PHS has been little studied in women living with HIV (WLWH). Methods We enrolled n = 865 WLWH (323 from the Women’s Interagency HIV Study [WIHS] and 542 from WIHS-affiliated colposcopy clinics). All participants underwent Pap and oncHPV testing, including HPV16/18-genotyping. WIHS WLWH who tested oncHPV[+] or had cytologic atypical squamous cells of undetermined significance or worse (ASC-US+) underwent colposcopy, as did a random 21% of WLWH who were oncHPV[−]/Pap[−] (controls). Most participants additionally underwent p16/Ki-67 immunocytochemistry. Results Mean age was 46 years, median CD4 was 592 cells/µL, 95% used antiretroviral therapy. Seventy WLWH had histologically-determined cervical intraepithelial neoplasia grade 2 or greater (CIN-2+), of which 33 were defined as precancer (ie, [i] CIN-3+ or [ii] CIN-2 if concurrent with cytologic high grade squamous intraepithelial lesions [HSILs]). PHS had 87% sensitivity (Se) for precancer, 9% positive predictive value (PPV), and a 35% colposcopy referral rate (Colpo). “PHS with reflex HPV16/18-genotyping and Pap testing” had 84% Se, 16% PPV, 30% Colpo. PHS with only HPV16/18-genotyping had 24% Colpo. “Concurrent oncHPV and Pap Testing” (Co-Testing) had 91% Se, 12% PPV, 40% Colpo. p16/Ki-67 immunochemistry had the highest PPV, 20%, but 13% specimen inadequacy. Conclusions PHS with reflex HPV16/18-genotyping had fewer unnecessary colposcopies and (if confirmed) could be a potential alternative to Co-Testing in WLWH.

INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) has been associated with increased risk of incident diabetes. But such evidence is lacking in the Hispanic/Latino population, which has high prevalence of obesity and NAFLD. METHODS We conducted a prospective cohort study of 6,928 adults of Hispanic/Latino background who had no diabetes, did not report excessive alcohol use, and no hepatitis B and C infection at baseline (2008-2011). We estimated risk ratios (RR) for incident diabetes, identified from visit 2 examination by glucose measurements or antidiabetic medication use, with baseline liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)). RESULTS A total of 738 adults developed diabetes during 6 years of follow-up. After adjusting for participant characteristics at baseline, versus the lowest quartile, highest quartiles of ALT and GGT were associated with risks for incident diabetes (RR for ALT: 1.51 [95% CI 1.03-2.22], p-trend = 0.006; RR for GGT: 2.39 [1.60-3.55], p-trend = 0.001). Higher GGT levels predicted increased risk of incident diabetes even among those with ALT or AST below the median levels. The associations of ALT and GGT with incident diabetes were similar among most Hispanic background but were not seen among Dominicans (p for interaction

To investigate whether routine cervical screening using human papillomavirus (HPV) and cytology co-testing effectively identifies women with endometrial (EC) or ovarian (OvC) cancer.In 2003, Kaiser Permanente Northern California implemented triennial co-testing in women aged ≥30 years. Index screening results (n = 2,385,729) were linked to subsequent EC (n = 3434) and OvC (n = 1113) diagnoses from January 1, 2003 to December 31, 2017. EC were categorized as type 1 or 2, and, selectively, EC and OvC diagnoses were stratified on whether symptoms were present at the time of the co-test. Fractions and absolute risks of EC or OvC of each co-testing result were calculated.Most EC (82.18%) and OvC (88.68%) were preceded by a negative HPV and negative cytology co-test. More EC were preceded by atypical squamous cells of undetermined significance (ASC-US) or more severe (ASC-US+) cytology and negative HPV test (n = 290) (8.44% of EC) compared to a negative cytology and a positive HPV test (n = 31) (0.89% of EC) (p 0.001). The absolute risk of any EC diagnosis following ASC-US+ and negative HPV test was 0.48%. Atypical glandular cells (AGC) cytology and a negative HPV result preceded 6.92% of any EC diagnosis, with an absolute risk of 4.02%, but preceded only 1.13% of type 2 EC cases, with an absolute risk of 0.24%, in asymptomatic women. AGC cytology and a negative HPV result preceded 1.44% of OvC, with an absolute risk of 0.28%.Abnormal cervical screening tests, even AGC cytology, rarely precedes and poorly predict women with EC or OvC.

Infection by human papillomavirus (HPV) type 16, the most oncogenic HPV type, was found to be the least affected by HIV-status and CD4 count of any of the approximately 13 oncogenic HPV types. This relative independence from host immune status has been interpreted as evidence that HPV16 may have an innate ability to avoid the effects of immunosurveillance. However, the impact of immune status on other individual HPV types has not been carefully assessed. We studied type-specific HPV infection in a cohort of 2,470 HIV-positive (HIV[+]) and 895 HIV-negative (HIV[−]) women. Semi-annually collected cervicovaginal lavages were tested for >40 HPV types. HPV type-specific prevalence ratios (PRs), incidence and clearance hazard ratios (HRs), were calculated by contrasting HPV types detected in HIV[+] women with CD4 < 200 to HIV[−] women. HPV71 and HPV16 prevalence had the weakest associations with HIV-status/CD4 count of any HPV, according to PRs. No correlations between PRs and HPV phylogeny or oncogenicity were observed. Instead, higher HPV type-specific prevalence in HIV[−] women correlated with lower PRs (ρ = −0.59; p = 0.0001). An alternative (quadratic model) statistical approach (P(HIV+) = a*P(HIV−) + b*P(HIV−)(2); R(2) = 0.894) found similar associations (p = 0.0005). In summary, the most prevalent HPV types in HIV[−] women were the types most independent from host immune status. These results suggest that common HPV types in HIV[−] women may have a greater ability to avoid immune surveillance than other types, which may help explain why they are common.

Objective To evaluate the natural history of treated and untreated cervical intraepithelial neoplasia-2 (CIN2) among HIV-positive women. Methods Participants were women enrolled in the Women's Interagency HIV Study between 1994 and 2013. One hundred four HIV-positive women diagnosed with CIN2 before age 46 were selected, contributing 2076 visits over a median of 10 years (interquartile range 5-16). The outcome of interest was biopsy-confirmed CIN2 progression, defined as CIN3 or invasive cervical cancer. CIN2 treatment was abstracted from medical records. Results Most women were African American (53%), current smokers (53%), and had a median age of 33 years at CIN2 diagnosis. Among the 104 HIV-positive women, 62 (59.6%) did not receive CIN2 treatment. Twelve HIV-positive women (11.5%) showed CIN2 progression to CIN3; none were diagnosed with cervical cancer. There was no difference in the median time to progression between CIN2-treated and CIN2-untreated HIV-positive women (2.9 vs. 2.7 years, P = 0.41). CIN2 treatment was not associated with CIN2 progression in multivariate analysis (adjusted hazard ratio 1.82; 95% confidence interval: 0.54 to 7.11), adjusting for combination antiretroviral therapy and CD4 T-cell count. In HIV-positive women, each increase of 100 CD4 T cells was associated with a 33% decrease in CIN2 progression (adjusted hazard ratio 0.67; 95% confidence interval: 0.47 to 0.88), adjusting for CIN2 treatment and combination antiretroviral therapy. Conclusions CIN2 progression is uncommon in this population, regardless of CIN2 treatment. Additional studies are needed to identify factors to differentiate women at highest risk of CIN2 progression.

Background Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity and is the most common liver disease in the developed world. In children with suspected NAFLD, present guidelines suggest consideration of alternative diagnoses via extensive blood testing, though the yield of this work up is unknown. Furthermore, the gold standard diagnostic test for NAFLD remains liver biopsy, making the development of non-invasive tests critically important. Objectives Our objectives are: 1) to determine the accuracy of elastography and multiple serum biomarkers – each assessed individually and as algorithms (including those previously tested in adults) – for the diagnosis of nonalcoholic steatohepatitis (NASH) and early fibrosis in children and (2) to examine the utility of extensive testing for rare alternative diagnoses in overweight or obese children with elevated alanine aminotransferase (ALT) suspected to have NAFLD. Design This is an ongoing, cross-sectional study in children 2–18 years of age with up to 2 years of prospective follow up. Eligible patients are asymptomatic, overweight or obese, and have an ALT ≥35 U/L upon enrollment. Two forms of elastography are obtained serially along with anthropometric data and routine laboratory tests. Elastography and serum biomarkers are also performed immediately prior to any clinically-indicated biopsy. Methods Between April 2015 and April 2018, 193 children have been enrolled in this ongoing study and 71 have undergone liver biopsy. Here we carefully report the rationale, methodology, and preliminary data for this study.

ObjectiveRecent studies reported a lower human papillomavirus 16 (HPV16) prevalence in cervical precancer among African American than Caucasian women in the general population. We assessed this relationship in women with HIV.DesignWomen living with or at risk for HIV in the Women's Interagency HIV Study were followed semi-annually with Pap tests, colposcopy/histology (if indicated), and collection of cervicovaginal lavage samples for HPV testing by PCR. Racial and ethnic groups were defined using genomic Ancestry Informative Markers (AIMs).ResultsAmong 175 cases of cervical intraepithelial neoplasia 3 or worse (CIN-3+), 154 were diagnosed in women with HIV. African American (27%) and Hispanic (37%) cases were significantly less likely than Caucasian (62%) women to test positive for HPV16 (P = 0.01). In multivariate logistic regression models, these associations remained significant for African Americans (odds ratio = 0.13; 95% confidence interval (CI) 0.04-0.44; P = 0.001) but not Hispanics, after controlling for HIV status, CD4 count, history of AIDS, age, smoking, and sexual behavior. Limiting the analysis to women with HIV did not change the findings.ConclusionHPV16 prevalence is lower in African American compared with Caucasian women with HIV and cervical precancer, independent of immune status. Future studies to determine why these racial differences exist are warranted, and whether there are similar associations between race and invasive cervical cancer in women with HIV. Further, HPV types not covered by quadrivalent and bivalent vaccines may play an especially important role in cervical precancer among HIV-positive African American women, a possible advantage to using nonavalent HPV vaccine in this population.

Background: CD4 + T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human major histocompatibility complex class II molecules. Methods: We constructed p18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and T cell receptor activation. Apolipoprotein E–deficient ( Apoe −/− ) mice were vaccinated with p18 peptide or adjuvants alone, and atherosclerotic burden in the aorta was determined. Results: In human peripheral blood mononuclear cells from donors without cardiovascular disease, p18 specific CD4 + T cells detected by a new human leukocyte antigen-antigen D related-p18 tetramers were mostly Foxp3 + regulatory T cells (Tregs). Donors with subclinical cardiovascular disease as detected by carotid artery ultrasound had Tregs coexpressing retinoic acid-related orphan receptor gamma t or T-bet, which were both almost absent in donors without cardiovascular disease. In Apoe −/− mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4 + T cells identified by Nur77-GFP (green fluorescent protein) were highly enriched in Tregs. A new mouse I-A b -p18 tetramer identified the expansion of p18-specific CD4 + T cells on vaccination, which were enriched for interleukin-10–producing Tregs. Conclusions: These findings show that APOB p18–specific CD4 + T cells are mainly Tregs in healthy donors, but coexpress other CD4 lineage transcription factors in donors with subclinical cardiovascular disease. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.

ObjectiveThe aim of this study was to evaluate the racial/ethnic disparities in ovarian cancer survival in a diverse population.MethodsWe performed a retrospective cohort study evaluating all patients with epithelial ovarian cancer who received primary treatment at Montefiore Medical Center from 2005 to 2015. Clinicopathologic and survival data were abstracted from medical records. Two-sided statistical analyses were performed using SAS 9.3.ResultsThree hundred forty-four evaluable patients were identified: 85 (25%) black, 107 (31%) white, 74 (21%) Hispanic, and 78 (23%) other. Black patients were more likely to present with stage IV disease (P = 0.01) and receive neoadjuvant chemotherapy (P < 0.01). By Kaplan-Meier survival analysis, black race was associated with worse recurrence-free survival (P = 0.01) when compared with white race. In multivariate Cox regression model including treatment and stage, race was no longer associated with survival. In a separate multivariate analysis, utilization of neoadjuvant chemotherapy was associated with black race (odds ratio 4.03; 95% confidence interval, 1.56–10.38; P < 0.01) and stage IV disease (odds ratio 3.44; 95% confidence interval, 1.66–7.12; P < 0.01).ConclusionsIn a racially/ethnically diverse population with ovarian cancer, black women had poorer disease-free survival than whites, although this was statistically accounted for by stage at diagnosis and use of neoadjuvant therapy. Research is needed to determine how differences in access/utilization of care and genetic differences in tumor biology may impact late stage diagnosis and use of neoadjuvant chemotherapy among black ovarian cancer patients.

Purpose People with HIV infection have an elevated risk of anal cancer. However, recent calendar trends are incompletely described, and which population subgroups might benefit from cancer screening is unknown. Methods We used linked data from HIV and cancer registries in nine US areas (1996 to 2012). We calculated standardized incidence ratios to compare anal cancer incidence in people with HIV infection with the general population, used Poisson regression to evaluate anal cancer incidence among subgroups of people with HIV and to assess temporal trends, and estimated the cumulative incidence of anal cancer to measure absolute risk. Results Among 447,953 people with HIV infection, anal cancer incidence was much higher than in the general population (standardized incidence ratio, 19.1; 95% CI, 18.1 to 20.0). Anal cancer incidence was highest among men who have sex with men (MSM), increased with age, and was higher in people with AIDS than in those without AIDS (ie, HIV only; adjusted incidence rate ratio, 3.82; 95% CI, 3.27 to 4.46). Incidence among people with HIV increased steeply during 1996 to 2000 (annual percentage change, 32.8%; 95% CI, −1.0% to 78.2%), reached a plateau during 2001 to 2008, and declined during 2008 to 2012 (annual percentage change, −7.2%; 95% CI, −14.4% to 0.6%). Cumulative incidence after a 5-year period was high for MSM with HIV only age 45 to 59 or ≥ 60 years (0.32% to 0.33%) and MSM with AIDS age 30 to 44, 45 to 59, or ≥ 60 years (0.29% to 0.65%). Conclusion Anal cancer incidence is markedly elevated among people with HIV infection, especially in MSM, older individuals, and people with AIDS. Recent declines may reflect delayed benefits of HIV treatment. Groups with high cumulative incidence of anal cancer may benefit from screening.

Background Current US cervical cancer screening guidelines recommend screening cessation at the age of 65 years provided women have adequate previous screening and no history of precancer. Women living with HIV are at higher risk of cervical cancer than women living without HIV. Furthermore, limited data exists to quantify the risk of cervical cancer among women who otherwise would qualify for screening cessation. Objective This study aimed to determine whether guidelines recommending women to discontinue cervical cancer screening at the age of 65 years are appropriate for women living with HIV. Study Design Semiannual Papanicolaou testing was performed as part of surveillance visits in the Women’s Interagency HIV Study. Launched in October 1994, the Women’s Interagency HIV Study is a federally funded US multisite cohort study that has enrolled 3678 women living with HIV and 1304 women living without HIV; we included data throughout September 2019 onward. Conventional Papanicolaou tests were collected at scheduled 6-month visits and read centrally according to the 1991 Bethesda System criteria. Results were analyzed among women at least 65 years of age. The primary endpoint was high-grade cytology, including high-grade squamous intraepithelial lesions; atypical glandular cells; atypical squamous cells, cannot exclude high-grade lesions; and malignant cytology. Wilcoxon rank-sum tests were used to compare the continuous variables, and Chi-square tests or the Fisher exact tests were used to compare the categorical variables. The Kaplan-Meier method was used to calculate the cumulative incidence. Poisson regression was used to compare 2 incidence rates. Results Of 169 eligible women (121 women living with HIV and 48 women living without HIV) who contributed 678.4 person-years of observation after reaching the age of 65 years, 2.2% had high-grade cytologic abnormalities. However, no cancer was found. Furthermore, 20 women had previous precancer results, and 74 women had abnormal Papanicolaou test results in the previous decade. Among 50 women (38 women living with HIV and 12 women living without HIV) with a previous hysterectomy and no history of cervical precancer, the cumulative incidence rates of high-grade squamous intraepithelial lesions were 0.6 (95% confidence interval, 0.0–3.2) per 100 person-years for women living with HIV and 0.0 (95% confidence interval, 0.0–8.1) per 100 person-years for women living without HIV (P=.61). Only 48 women (27 women living with HIV and 21 women living without HIV) had cervices and met the current guidelines to discontinue screening; their risk of experiencing high-grade squamous intraepithelial lesions was 2.2 (95% confidence interval, 0.6–5.5) per 100 person-years overall and did not vary by HIV status (2.3 [95% confidence interval, 0.5–6.8] per 100 person-years for women living with HIV and 1.8 [95% confidence interval, 0.0–9.8] per 100 person-years for women living without HIV; P=.81). Conclusion Most women living with HIV do not meet the criteria for cervical cancer screening cessation and will need to continue screening over the age of 65 years; however, women who meet the criteria for screening cessation have risks of high-grade squamous lesions similar to women living without HIV and may choose to discontinue.

IMPACT: The potential to use vaginal pH as a low cost, non-invasive diagnostic test at the point of CIN2 diagnosis to predict worsening of cervical disease. OBJECTIVES/GOALS: We previously reported that persistence/progression of cervical intraepithelial neoplasia-2 (CIN2) was uncommon in women living with HIV (WLH) from the Women’s Interagency HIV Study (WIHS, now MWCCS). Here we examined additional factors that may influence CIN2 natural history. METHODS/STUDY POPULATION: A total of 337 samples from 94 WLH with a confirmed CIN2 diagnosis were obtained from the MWCCS. 42 cervicovaginal HPV types and 34 cervicovaginal cytokines/chemokines were measured at CIN2 diagnosis (94 samples) and 6-12 months prior to CIN2 diagnosis (79 samples). Covariates, including CD4 count and vaginal pH, were abstracted from core MWCCS visits. Logistic regression models were used to explore CIN2 regression (CIN1, normal) vs. persistence/progression (CIN2, CIN3). Log rank tests, Kaplan Meier method, and Cox regression modeling were used to determine CIN2 regression rates. RESULTS/ANTICIPATED RESULTS: The most prevalent HPV types were HPV54 (21.6%) and 53 (21.3%). 33 women (35.1%) had a subsequent CIN2/CIN3 diagnosis (median 12.5 years follow-up). Each additional hr-HPV type detected at the pre-CIN2 visit associated with increased odds of CIN2 persistence/progression (OR 2.27, 95% CI 1.15, 4.50). Higher vaginal pH (aOR 2.27, 95% CI 1.15, 4.50) and bacterial vaginosis (aOR 5.08, 95% CI 1.30, 19.94) at the CIN2 diagnosis visit associated with higher odds of CIN2 persistence/progression. Vaginal pH >4.5 at CIN2 diagnosis also associated with unadjusted time to CIN2 persistence/progression (log rank p=0.002) and a higher rate of CIN2 persistence/progression (adjusted hazard ratio [aHR] 3.37, 95% CI 1.26, 8.99). Cervicovaginal cytokine/chemokine levels were not associated with CIN2 persistence/progression. DISCUSSION/SIGNIFICANCE OF FINDINGS: We found relatively low prevalence of HPV16/18 in this cohort. Elevated vaginal pH at the time of CIN2 diagnosis may be a useful indicator of CIN2 persistence/progression and the rate of persistence/progression.

Longitudinal measurement of biomarkers is important in determining risk factors for binary endpoints such as infection or disease. However, biomarkers are subject to measurement error, and some are also subject to left-censoring due to a lower limit of detection. Statistical methods to address these issues are few. We herein propose a generalized linear mixed model and estimate the model parameters using the Monte Carlo Newton-Raphson (MCNR) method. Inferences regarding the parameters are made by applying Louis's method and the delta method. Simulation studies were conducted to compare the proposed MCNR method with existing methods including the maximum likelihood (ML) method and the ad hoc approach of replacing the left-censored values with half of the detection limit (HDL). The results showed that the performance of the MCNR method is superior to ML and HDL with respect to the empirical standard error, as well as the coverage probability for the 95% confidence interval. The HDL method uses an incorrect imputation method, and the computation is constrained by the number of quadrature points; while the ML method also suffers from the constrain for the number of quadrature points, the MCNR method does not have this limitation and approximates the likelihood function better than the other methods. The improvement of the MCNR method is further illustrated with real-world data from a longitudinal study of local cervicovaginal HIV viral load and its effects on oncogenic HPV detection in HIV-positive women.

Purpose While obesity is an established breast cancer risk factor, information about the influence of weight loss on breast cancer risk in postmenopausal women is mixed precluding generation of a strong public health message regarding potential benefits of weight loss with respect to cancer risk. Therefore, we evaluated associations between weight change and invasive breast cancer risk in postmenopausal women participating in the Women's Health Initiative (WHI) Observational Study. Patients and Methods Postmenopausal women (n=61,335) with no prior breast cancer and normal mammogram who were not underweight (body mass index [BMI] ≥ 18.5 kg/m2), ages 50-79 years at WHI enrollment between 1993 and 1998 at 40 US clinical centers, had body weight and height measured and BMI calculated at the clinical centers at baseline and at year 3. Weight change over 3 years was categorized as: stable (no change ≤ 5%), loss (change ≥ 5%), or gain (change ≥ 5%) with weight lost intentionality determined by self-report response to direct query at year 3. Breast cancers were initially ascertained through annual survey and were centrally confirmed by medical record review. Multi-variable Cox proportional hazards regression models incorporating breast cancer risk factors and baseline BMI were used to evaluate relationships between weight change and breast cancer incidence. Results During 11.4 years (mean) of follow-up, 3,061 women developed invasive breast cancer. In multi-variable analyses, compared with women with stable weight (n=41,139), women with weight loss (≥ 5%) (n=8,175) had a significantly lower breast cancer risk (hazard ratio [HR] 0.88 95% confidence interval [CI] 0.78-0.98). Adjustment for mammography did not alter findings (HR 0.88 95% CI 0.78-0.99). There was no significant interaction for breast cancer effect by weight loss intentionality. Women with weight loss ≥ 15% had even lower breast cancer risk (HR 0.63 95% CI 0.45-0.90). While weight gain (≥ 5%) (n=12,021) was not associated with higher overall breast cancer risk, women with weight gain had a significantly higher risk of triple negative breast cancer (HR 1.54 95% CI 1.16-2.05). Weight change association with breast cancer incidence was examined in four subgroups: by tumor subtype (hormone receptor and HER2 status based), baseline BMI (normal, overweight, obese), race/ethnicity, and age group (50, - Conclusion Weight loss in postmenopausal women is associated with lower breast cancer risk. These findings suggest that postmenopausal women who lose weight may reduce their breast cancer risk. Citation Format: Chlebowski RT, Luo J, Anderson GL, Simon M, Barrington W, Reding K, Manson JE, Rohan T, Wactawki-Wende J, Lane D, Strickler H, Mossavar-Rahmani Y, Freudenheim J, Saquib ATN, Stefanick M. Weight change in postmenopausal women and breast cancer risk in the women's health initiative observational study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-07.

PURPOSE: The goal of this study was to evaluate the effect of pubertal timing, and its interaction with prior childhood maltreatment, on the risk of cervical human papillomavirus (HPV) among sexually active adolescent minority female adolescents and young adults. METHODS: This cross-sectional study includes 842 adolescent girls and young women (aged 12 to 20 years; predominately Black and Hispanic) enrolled in an HPV vaccine surveillance study at a large adolescent health clinic in New York City between 2007 and 2016. Pubertal timing was assessed by self-reported age at menarche at baseline, with “early” and “late” defined as one standard deviation below (13 years) the mean. Childhood exposure to abuse (sexual, physical and emotional) and neglect (physical and emotional) was assessed using the Childhood Trauma Questionnaire. Over 40 types of HPV infection were detected using the polymerase chain reaction in cervical Pap specimens. RESULTS: Results from multivariable logistic regression showed that early and late pubertal timing were marginally associated with a higher risk of HPV infection, adjusting for demographic and health covariates. Childhood maltreatment moderated the association between early pubertal timing and HPV infection: early pubertal timing was associated with a higher risk for HPV infection among maltreated girls (OR=3.32, 95%CI:1.61–6.85), but not among non-maltreated girls (OR=0.96, 95%CI:0.61–1.50; p-interaction

Background Over six million children each year are referred to child protective services for child abuse (sexual, physical and emotional) and neglect (physical and emotional). Objective While the relationship between child sexual abuse and sexually transmitted infections has been documented, there has been little research regarding the effects of other forms of maltreatment. Participants and setting 882 inner-city females aged 12–20 years of age seen at a large adolescent and young adult (AYA) health center in New York City between 2012–2017. Methods History of maltreatment was assessed using the Childhood Trauma Questionnaire. Associations with depressive symptoms, antisocial behavior, peer deviancy, drug/alcohol use, and risky sexual behaviors were assessed. Results History of maltreatment was common in our cohort of inner-city AYA females, with 59.6 % reporting any type of maltreatment, including sexual abuse (17.5 %), physical abuse (19.5 %) or neglect (26.2 %), and emotional abuse (30.7 %) or neglect (40.4 %). We observed significant associations between all forms of maltreatment and risk of depression, drug/alcohol use, antisocial behaviors, peer deviancy, and risky sexual risk behaviors (including having a higher number of sexual partners, having a sexual partner 5+ years older, and anal sex). Physical and emotional abuse were associated with having unprotected sex while under the influence of drugs/alcohol. Conclusions and relevance Reporting a history of maltreatment was associated with an increased likelihood of engaging in risky sexual and antisocial behaviors, as well as depression in inner-city female youth. These data highlight the broad, lingering repercussions of all types of child maltreatment.

Performance of commercially available human papillomavirus (HPV) assays (approved for cervical HPV detection) is unknown for detecting HPV-related oropharyngeal cancer (HPV-OPC). Assays for detection of HPV DNA [ELISA (DEIA) and Cobas], and RNA (Aptima) in oral rinse samples, and serum HPV oncogene antibodies were evaluated. Sensitivity and specificity of each test was explored among HPV-OPC cases and controls. Biomarker prevalence was evaluated among 294 “at-risk” people (screening) and 133 “high-risk” people [known to previously have oral oncogenic HPV (oncHPV) DNA and/or HPV16 E6/E7 antibodies detected]. HPV16 E6 antibodies had the best overall test performance with sensitivity of 88%, compared with oral HPV16 DNA sensitivity of 51% by DEIA and 43% by Cobas (each P < 0.001). Specificity was comparable in each of these tests (≥98%). When positivity for any oncHPV type was compared with HPV16 for the same test, sensitivity was comparable (60% vs. 51%, 40% vs. 43%, and 92% vs. 88% for DEIA, Cobas, and E6 antibodies, respectively), but specificity was reduced (93%–97%). Aptima had poor sensitivity (23%). Sensitivity decreased when cotesting HPV16 oral rinse DNA and E6 antibodies (37%–48%), or multiple E antibodies (69%–72%). HPV16 DNA were detected in ∼2% of the at-risk by either DEIA or Cobas and up to 15% of the high-risk population. HPV16 E6 seroprevalence was 2.3% and 2.4% in the at-risk and high-risk populations, respectively. Oral rinse HPV testing had moderate-to-poor sensitivity for HPV-OPC, suggesting many true positives would be missed in a potential screening scenario. HPV16 E6 serum antibody was the most promising biomarker evaluated.

Introduction: Non-alcoholic fatty liver disease (NAFLD) as measured by ultrasonography or elevated liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT), has been associated with increased risk of incident diabetes. But such evidence is lacking in the Hispanic/Latino population, which has high prevalence of obesity and NAFLD. Methods: We conducted a prospective cohort study of 6928 adults of Hispanic/Latino background who had no diabetes at baseline (2008-2011). Incident diabetes was defined by self-reported diagnosis of diabetes, glucose measurements or antidiabetic medication use at repeat visits on average 6 years from baseline. We examined the associations of baseline liver enzymes (sex-specific quartiles of ALT, AST, GGT) with incident diabetes using survey-weighted Poisson regression with follow-up time as an offset. Results: The weighted mean age was 38 years at baseline. A total of 793 adults developed diabetes during 6 years of follow-up. After adjusting for demographics and socioeconomic status, versus the lowest quartile, highest quartiles of ALT, AST and GGT were significantly associated with 1.5 to 3.5-fold increased risk of incident diabetes. Further adjusting for behavioral variables including diet and exercise, cardiovascular risk factors and cardiovascular medication use, the associations were attenuated and remained statistically significant for ALT (RR quartile 4 vs 1: 1.42[95% CI 1.07-1.90], P-trend=0.001) and GGT (RR quartile 4 vs 1: 1.97[1.34-2.88], P-trend Conclusion: Elevated ALT and GGT levels are associated with increased risk of developing diabetes among Hispanics/Latinos. Additional work is needed to understand the relationship between NAFLD and diabetes risk in this population.

Associations of insulin resistance and hyperglycemia with a panel of liver enzymes have not been well studied in a young, heterogenous Hispanic/Latino population. We aimed to assess the associations of insulin resistance and glycemia with nonalcoholic fatty liver disease (NAFLD), as measured by liver enzymes and the pediatric NAFLD fibrosis index (PNFI), and whether these associations are modified by body mass index and mediated by inflammation or endothelial dysfunction.We conducted a cross-sectional study of 1317 boys and girls aged 8 to 16 years from the Hispanic Community Children's Health Study/Study of Latino Youth. We used Poisson regression to assess the associations of fasting glucose, hemoglobin A1c, and homeostasis model assessment of insulin resistance (HOMA-IR) with elevated alanine aminotransferase (ALT) (25 U/L in boys,22 U/L in girls), aspartate aminotransferase (AST) (≥37 U/L), gamma-glutamyl transpeptidase (GGT) (≥17 U/L), and PNFI (≥9; a function of age, waist circumference, and triglyceride level).HOMA-IR was associated with elevated ALT, AST, GGT, and PNFI [prevalence ratios (95% confidence intervals) for each 1-unit increase in the natural log of HOMA-IR: 1.99 (1.40-2.81), 2.15 (1.12-4.12), 1.70 (1.26-2.30), and 1.98 (1.43-2.74), respectively]. Associations were observed in overweight/obese children, but not in normal weight children (P-interaction=0.04 for AST and P-interaction=0.07 for GGT). After further adjustment for adiponectin, high-sensitivity C-reactive protein, e-selectin, and PAI-1, associations of HOMA-IR with liver enzymes and PNFI were attenuated, but remained statistically significant for AST and PNFI.Insulin resistance was associated with NAFLD in overweight/obese Hispanic/Latino youth, and this association may be partially mediated by inflammation and endothelial dysfunction.

Context:Multiple diseases may explain the association of the growth hormone/insulinlike growth factor-I (GH/IGF-I) axis with longevity.Objective:To relate circulating GH/IGF-I system protein levels with major health eventsDesign and Setting:This is a cohort study set in 4 US communities.Participants:Adults (N = 2268) 65 years and older free of diabetes and cardiovascular diseaseMeasurements:We assessed insulinlike growth factor binding protein-1 (IGFBP-1) and ghrelin in fasting and 2-hour oral glucose tolerance test (OGTT) blood samples, as well as fasting IGF-I and IGFBP-3. Hazard ratios for mortality and a composite outcome for first incident myocardial infarction, stroke, heart failure, hip fracture, or death were adjusted for sociodemographic, behavioral, and physiological covariates.Results:During 13,930 person-years of follow-up, 48.1% of individuals sustained one or more components of the composite outcome and 31.8% died. Versus the lowest quartiles, the highest quartiles of fasting and 2-hour ghrelin were associated with 27% higher (95% confidence interval [CI]: 6%, 53%) and 39% higher (95% CI: 14%, 71%) risks of the composite outcome, respectively. The highest quartile of 2-hour IGFBP-1 was associated with 35% higher (95% CI: 1%, 52%) risk of the composite end point. Similarly, higher mortality was significantly associated with higher fasting and 2-hour ghrelin levels and with 2-hour IGFBP-1 level. When examined together, 2-hour post-OGTT levels of IGFBP-1 and ghrelin tended to predict outcomes better than fasting levels.Conclusions:Circulating IGFBP-1 and ghrelin measured during an OGTT predicted major health events and death in older adults, which may explain the influence of the GH/IGF-I axis on lifespan and health.

Summary Human leucocyte antigen (HLA) genes play a central role in response to pathogens and in autoimmunity. Research to understand the effects of HLA genes on health has been limited because HLA genotyping protocols are labour intensive and expensive. Recently, algorithms to impute HLA genotype data using genome-wide association study (GWAS) data have been published. However, imputation accuracy for most of these algorithms was based primarily on training data sets of European ancestry individuals. We considered performance of two HLA-dedicated imputation algorithms – SNP2HLA and HIBAG – in a multiracial population of n = 1587 women with HLA genotyping data by gold standard methods. We first compared accuracy – defined as the percentage of correctly predicted alleles – of HLA-B and HLA-C imputation using SNP2HLA and HIBAG using a breakdown of the data set into an 80% training group and a 20% testing group. Estimates of accuracy for HIBAG were either the same or better than those for SNP2HLA. We then conducted a more thorough test of HIBAG imputation accuracy using five independent 10-fold cross-validation procedures with delineation of ancestry groups using ancestry informative markers. Overall accuracy for HIBAG was 89%. Accuracy by HLA gene was 93% for HLA-A, 84% for HLA-B, 94% for HLA-C, 83% for HLA-DQA1, 91% for HLA-DQB1 and 88% for HLA-DRB1. Accuracy was highest in the African ancestry group (the largest group) and lowest in the Hispanic group (the smallest group). Despite suboptimal imputation accuracy for some HLA gene/ancestry group combinations, the HIBAG algorithm has the advantage of providing posterior estimates of accuracy which enable the investigator to analyse subsets of the population with high predicted (e.g. >95%) imputation accuracy.