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Results: We assessed the impact of pretreatment clitoral HSV-2 infection on the development and presentation of EM, utilizing a Nurses' Health Study cohort. EM typically affects young women. This marked study's ability to address two clinical questions: (1) Does HSV-2 infection increase the risk of EM? (2) Is EM more likely to develop on the right versus left side, or among young women versus older women? As expected, EM was more common in HSV-2 seropositives than in HSV-2 seronegatives, after adjustment for age, sex, race, education, religion, total energy intake, alcohol consumption, cigarette and coffee consumption, BMI, physical activity and breastfeeding (OR, 1.13; 95% CI, 1.11 to 1.16). With a baseline prevalence of 4% in HSV-2 seropositives, the estimated population-attributable risk for EM among all HSV-2 positivity was 1.01% (95% CI, 0.68 to 1.39). The odds of EM were higher for the left versus right clitoris (OR, 1.3; 95% CI, 1.0 to 1.7), and among young women (18-20 years old) compared with older women (41-47 years old) (OR, 1.9; 95% CI, 1.0 to 3.5) (P=0.04 for the interaction term). Consequently, HSV-2 infection increases the risk of EM and it is associated with more severe disease on the left side of the clitoris. The association between twice-weekly oral sex on the right versus the left side of the clitoris and EM raises new questions about sexual practices among young women that warrant further study. This case draws attention to EM, a previously understudied and underrecognized genital lesion, and underscores the importance of the ethical conduct of research. The results support the proposed public health approach to prevent EM by reducing exposure to HSV-2 infection, for example, through protection from sexual exposure among persons with high HSV-2 seropositivity, if a person chooses a seronegative partner (ie, a CDC-condom use recommendation for HSV-2 seropositivity). d2c66b5586