Master of Science

thesisRecent research suggests that men in primary relationships engage in condomless sex both within and outside their relationships, and a majority of human immune deficiency virus (HIV) transmission risk may actually occur within primary relationships. Sexual agreements regarding nonmonogamy among men who have sex with men (MSM) are a critical component to understanding HIV prevention in male couples. Consistent associations have been found between relationship factors and sexual agreements. Relationship power is one dyadic construct that likely shapes how sexual agreements function, but has been unexplored. Multilevel modeling was used in a cross- sectional sample of gay male couples (N=566 couples) to examine associations between demographic characteristics of partners traditionally used to define relationship power, a scale of decision-making power, and outcomes related to sexual agreements, including investment, agreement breaks, and break disclosure. Results indicated that decision- making power relative to one's partner was not associated with any agreement outcome, contrary to hypotheses. However, controlling for power, sociodemographics, including age, income, race, and HIV status, were variably associated with sexual agreements' functioning. Specifically, older partners were more invested in and less likely to break their agreements. Lower-earning partners broke their agreements more frequently, but also disclosed breaks more often. White men in interracial relationships broke their agreement more often than their partners. Concordant HIV-positive couples were less invested in their agreements and HIV-positive men disclosed breaks more frequently. HIV prevention efforts for same-sex couples must attend to the social, developmental, and cultural mechanisms that affect sexual nonmonogamy agreements among diverse, same-sex couples

The predominant relationship between sexual environment characteristics and HIV-serodiscordant condomless anal sex among HIV-positive men who have sex with men (MSM)

In some studies, situational factors have been shown to be stronger predictors of condomless sex than individual risk factors. Cross-sectional relationships between condomless anal sex (CAS) with HIV-serodiscordant partners and risk factors across ecological levels (individual, sexual environment) were examined using a sample (N = 60) of HIV-positive men who have sex with men (MSM) who reported multiple recent episodes of CAS. Negative binomial regressions were used to evaluate the association of contextual risk factors (e.g., substance use during sex, transactional sex, public sex, sex at a sex party) with recent condomless sex, controlling for demographics and mental health. Results demonstrated that sexual environment factors, particularly sex under the influence of drugs or alcohol (B = .019, p < .05), transactional sex (B = .035, p < .01), and public sex (B = .039, p < .01) explained a large proportion of the variance in CAS. Only sex at a sex party was not related to CAS (p = .39). For each additional sexual environment in which men engaged, their rates of CAS increased (B = .39, p < .01). Secondary prevention interventions that are tailored to the proximal sexual environment could be maximally effective, particularly if they address substance use and other challenging sexual situations.We are very grateful to the participants for their time and efforts in the study. Support for the current study came from a feasibility grant (PI: Conall O'Cleirigh) from the Harvard University Center for AIDS Research (Parent Grant: P30AI060354, PI: Bruce Walker, MD) awarded to Dr. Conall O'Cleirigh. Investigator support for Dr. Steven Safren also came from NIH Grant K24MH094214. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. (P30AI060354 - Harvard University Center for AIDS Research; K24MH094214 - NIH)Accepted manuscrip

Effect of Polymer Chemistry on the Linear Viscoelasticity of Complex Coacervates

Complex coacervates can form through the electrostatic complexation of oppositely charged polymers. The material properties of the resulting coacervates can change based on the polymer chemistry and the complex interplay between electrostatic interactions and water structure, controlled by salt. We examined the effect of varying the polymer backbone chemistry using methacryloyl- and acryloyl-based complex coacervates over a range of polymer chain lengths and salt conditions. We simultaneously quantified the coacervate phase behavior and the linear viscoelasticity of the resulting coacervates to understand the interplay between polymer chain length, backbone chemistry, polymer concentration, and salt concentration. Time-salt superposition analysis was used to facilitate a broader characterization and comparison of the stress relaxation behavior between different coacervate samples. Samples with mismatched polymer chain lengths highlighted the ways in which the shortest polymer chain can dominate the resulting coacervate properties. A comparison between coacervates formed from methacryloyl vs acryloyl polymers demonstrated that the presence of a backbone methyl group affects the phase behavior, and thus the rheology in such a way that coacervates formed from methacryloyl polymers have a similar phase behavior to those of acryloyl polymers with ∼10× longer polymer chains

The influence of stigma on HIV risk behavior among men who have sex with men in Chennai, India

Stigma has been shown to increase vulnerability to HIV acquisition in many settings around the world. However, limited research has been conducted examining its role among men who have sex with men (MSM) in India, whose HIV prevalence is far greater than the general population. In 2009, 210 MSM in Chennai completed an interviewer-administered assessment, including questions about stigma, sexual-risk, demographics, and psychosocial variables. More than one fifth of the MSM reported unprotected anal sex (UAS) in the past three months. Logistic regression procedures were used to examine correlates of having experienced stigma. The 11-item stigma scale had high internal consistency reliability (Cronbach's alpha=0.99). Almost 2/5ths (39%) reported a high-level of experienced stigma (≥12 mean scale-score) in their lifetime, and the mean stigma scale score was 12 (SD=2.0). Significant correlates of having experienced prior stigma, after adjusting for age and educational attainment, included: identifying as a kothi (feminine acting/appearing and predominantly receptive in anal sex) compared to a panthi (masculine appearing, predominantly insertive) (AOR= 63.23; 95% CI: 15.92, 251.14; p<0.0001); being “out” about one's MSM behavior (AOR=5.63; 95% CI: 1.46, 21.73; p=0.01); having clinically significant depressive symptoms (AOR=2.68; 95% CI: 1.40, 5.12; p=0.003); and engaging in sex work in the prior 3 months (AOR=4.89; 95% CI: 2.51, 9.51; p<0.0001). These findings underscore the need to address psychosocial issues of Indian MSM. Unless issues such as stigma are addressed, effective HIV prevention interventions for this hidden population remain a challenge

Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan.

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes

Health equity issues at the local level: Socio-geography, access, and health outcomes in the service area of the Hôpital Albert Schweitzer-Haiti

<p>Abstract</p> <p>Background</p> <p>Although health equity issues at regional, national and international levels are receiving increasing attention, health equity issues at the local level have been virtually overlooked. Here, we describe here a comprehensive equity assessment carried out by the Hôpital Albert Schweitzer-Haiti (HAS) in 2003. HAS has been operating health and development programs in the Artibonite Valley of Haiti for 50 years.</p> <p>Methods</p> <p>We reviewed all available information arising from a comprehensive evaluation of the programs of HAS carried out in 1999 and 2000. As part of this evaluation, two demographic and health surveys were carried out. We carried out exit interviews with clients receiving primary health care, observations within health facilities, interviews with households related to quality of care, and focus group discussions with community-based health workers. A special study was carried out in 2003 to assess factors determining the use of prenatal care services. Finally, selected findings were obtained from the HAS information system.</p> <p>Results</p> <p>We found markedly reduced access to health services in the peripheral mountainous areas compared to the central plains. The quality of services was more deficient and the coverage of key services was lower in the mountains. Finally, health status, as measured by under-five mortality rates and levels of childhood malnutrition, was also worse in the mountains.</p> <p>Conclusion</p> <p>These findings indicate that local health programs need to give attention to monitoring the health status as well as the quality and coverage of basic services among marginalized groups within the program service area. Health inequities will not be overcome until such monitoring occurs and leaders of health programs ensure that inequities identified are addressed in the local programming of activities. It is quite likely that, within relatively small geographic areas in resource-poor settings around the world, similar, if not even greater, levels of health inequities exist. These inequities need to be measured and addressed in order for health programs to achieve equity and maximum improvement in health status within the population.</p

Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study.

BACKGROUND: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). METHODS AND FINDINGS: We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. CONCLUSIONS: Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips were funded by the French National Foundation on Alzheimer's disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer's Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC–10–196728.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pmed.100184

Using human genetics to understand the disease impacts of testosterone in men and women.

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.A.R.W. and T.M.F. are supported by the European Research Council grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. R.B. is funded by the Wellcome Trust and Royal Society grant 104150/Z/14/Z. J.T. is supported by the Academy of Medical Sciences Springboard award which is supported by the Wellcome Trust and GCRF [SBF004\1079]. This work was supported by the Medical Research Council [Unit Programme numbers MC_UU_12015/1 and MC_UU_12015/2]

Pretreatment HLADQA1-HLADRB1 Testing for the Prevention of Azathioprine-Induced Pancreatitis in Inflammatory Bowel Disease: A Prospective Cohort Study

INTRODUCTION:Azathioprine-induced pancreatitis is an idiosyncratic and unpredictable response, occurring in up to 7% of azathioprine-exposed patients with inflammatory bowel disease (IBD). The haplotype HLADQA1-HLADRB1*07:01A\u3eC is strongly associated with azathioprine-induced pancreatitis in IBD. We aimed to evaluate whether pretreatment HLADQA1-HLADRB1*07:01A\u3eC screening will reduce the risk of azathioprine-induced pancreatitis.METHODS:Participants with IBD were screened for HLADQA1-HLADRB1*07:01A\u3eC, and participants with a variant genotype were excluded from azathioprine treatment. Wild-type participants were started on azathioprine and followed for 3 months. The incidence of pancreatitis was compared with unscreened historical controls.RESULTS:HLADQA1-HLADRB1*07:01A\u3eC screening resulted in an 11-fold reduction in the incidence of azathioprine-induced pancreatitis (n = 1/328 or 0.30% vs n = 13/373 or 3.4%). In propensity score-matched cohorts (age and sex), HLA DQA1-HLADRB1*07:01A\u3eC screening was significantly associated with a reduction in the incidence of AZA-induced pancreatitis independent of weight, glucocorticoid exposure, and smoking status (adjusted odds ratio = 0.075, 95% confidence interval = 0.01-0.58, P = 0.01). Up to 45% (n = 271/599) of participants were excluded from azathioprine therapy based on the haplotype in the HLADQA1-HLADRB1*07:01A\u3eC-screened cohort.DISCUSSION:HLADQA1-HLADRB1*07:01A\u3eC screening reduced the risk of azathioprine-induced pancreatitis; however, using this strategy to guide the use of azathioprine therapy in IBD may eliminate a large proportion of patients from being eligible for treatment with azathioprine. In regions where there is access to other IBD therapies, and given the short-term and long-term toxicities associated with azathioprine, HLADQA1-HLADRB1*07:01A\u3eC-screening may be a clinically relevant strategy for enhancing the safe use of azathioprine in IBD. In addition, cost-effectiveness analyses are needed to further solidify the utility of HLADQA1-HLADRB1*07:01A\u3eC screening in IBD populations