Dynamic use of historical controls in clinical trials for rare disease research: A re-evaluation of the MILES trial.

BACKGROUND: Randomized controlled trials offer the best design for eliminating bias in estimating treatment effects but can be slow and costly in rare disease research. Additionally, an equal randomization approach may not be optimal in studies in which prior evidence of superiority of one or more treatments exist. Supplementing prospectively enrolled, concurrent controls with historical controls can reduce recruitment requirements and provide patients a higher likelihood of enrolling in a new and possibly superior treatment arm. Appropriate methods need to be employed to ensure comparability of concurrent and historical controls to minimize bias and variability in the treatment effect estimates and reduce the chances of drawing incorrect conclusions regarding treatment benefit. METHODS: MILES was a phase III placebo-controlled trial employing 1:1 randomization that led to US Food and Drug Administration approval of sirolimus for treating patients with lymphangioleiomyomatosis. We re-analyzed the MILES trial data to learn whether substituting concurrent controls with controls from a historical registry could have accelerated subject enrollment while leading to similar study conclusions. We used propensity score matching to identify exchangeable historical controls from a registry balancing the baseline characteristics of the two control groups. This allowed more new patients to be assigned to the sirolimus arm. We used trial data and simulations to estimate key outcomes under an array of alternative designs. RESULTS: Borrowing information from historical controls would have allowed the trial to enroll fewer concurrent controls while leading to the same conclusion reached in the trial. Simulations showed similar statistical performance for borrowing as for the actual trial design without producing type I error inflation and preserving power for the same study size when concurrent and historical controls are comparable. CONCLUSION: Substituting concurrent controls with propensity score-matched historical controls can allow more prospectively enrolled patients to be assigned to the active treatment and enable the trial to be conducted with smaller overall sample size, while maintaining covariate balance and study power and minimizing bias in response estimation. This approach does not fully eliminate the concern that introducing non-randomized historical controls in a trial may lead to bias in estimating treatment effects, and should be carefully considered on a case-by-case basis. Borrowing historical controls is best suited when conducting randomized controlled trials with conventional designs is challenging, as in rare disease research. High-quality data on covariates and outcomes must be available for candidate historical controls to ensure the validity of these designs. Additional precautions are needed to maintain blinding of the treatment assignment and to ensure comparability in the assessment of treatment safety.MILES ClinicalTrials.gov Number: NCT00414648.

Parental Adverse Childhood Experiences and Pediatric Healthcare Use by 2 Years of Age.

OBJECTIVE: To determine whether maternal and paternal exposure to adverse childhood experiences (ACEs) has an association with offspring healthcare use by 2 years of age. STUDY DESIGN: A retrospective cohort study was performed on 454 patients at a large suburban pediatric primary care practice whose mother (n = 374) or father (n = 156) or both (n = 123) completed an ACE survey between October 2012 and June 2014. The association between self-reported parental ACEs and healthcare use by 2 years of age, including number of missed well-child visits, sick visits, and delayed or missed immunizations, was modeled using multivariable negative binomial regression. All analyses adjusted for child sex, payer source, and preterm birth. RESULTS: Maternal, but not paternal, ACE exposure was significantly associated with missed well-child visits by 2 years of age. For each additional maternal ACE, there was a significant 12% increase in the incidence rate of missed well-child visits (relative risk, 1.12; 95% CI, 1.03-1.22; P = .010). Maternal and paternal ACE scores were not significantly associated with increased sick visits or delayed or missed immunizations. CONCLUSIONS: The ACE exposure of mothers is negatively associated with adherence to preventive healthcare visits among their children early in life. Future research is needed to elucidate the mechanisms of this association and to develop and implement family-based intervention strategies.

Graft survival of pediatric kidney transplant recipients selected for de novo steroid avoidance-a propensity score-matched study.

BACKGROUND: Steroid-avoidance protocols have gained popularity in pediatric kidney transplant recipients at low immunologic risk. The long-term safety of steroid avoidance in children with immunologic risk factors remains unknown. METHODS: Pediatric kidney transplant recipients from 2004 to 2014 in the Organ Procurement and Transplantation Network database who received tacrolimus and mycophenolate immunosuppression were investigated. Propensity score matching was used to compare graft survival in 1624 children who received steroid avoidance with 1624 children who received steroid-based immunosuppression. The effect of steroid avoidance on graft failure among immunologic risk strata was estimated using Cox proportional hazards regression in this propensity score-matched cohort. RESULTS: It was observed that 5-year graft survival was mildly improved in children receiving steroid avoidance (84.8% versus 81.2%, P = 0.03). This improvement in graft survival occurred in the first 2 years following transplant, when the hazard ratio (HR) for allograft failure in children receiving steroid avoidance was 0.62 [95% confidence interval (CI) 0.45-0.86]. In contrast, steroid avoidance was not associated with improved allograft survival during Years 2-10 following transplant (HR = 0.93; 95% CI 0.75-1.15). During this time period, HRs (95% CIs) for allograft failure within immunologic risk strata were not significantly different from the null value of 1: repeat kidney transplants, 1.84 (0.84-4.05); African-Americans, 1.02 (0.67-1.56); sensitized recipients, 1.24 (0.63-2.43); recipients of deceased donor kidneys, 1.02 (0.79-1.32); recipients of completely human leukocyte antigen-mismatched kidneys, 0.80 (0.47-1.37); and recipients with pretransplant glomerular disease, 0.94 (0.71-1.23). CONCLUSIONS: In pediatric kidney transplant recipients receiving tacrolimus- and mycophenolate-based immunosuppression, steroid avoidance can be safely practiced in children with immunologic risk factors.

Accounting for misclassification bias of binary outcomes due to underscreening: a sensitivity analysis.

BACKGROUND: Diagnostic tests are performed in a subset of the population who are at higher risk, resulting in undiagnosed cases among those who do not receive the test. This poses a challenge for estimating the prevalence of the disease in the study population, and also for studying the risk factors for the disease. METHODS: We formulate this problem as a missing data problem because the disease status is unknown for those who do not receive the test. We propose a Bayesian selection model which models the joint distribution of the disease outcome and whether testing was received. The sensitivity analysis allows us to assess how the association of the risk factors with the disease outcome as well as the disease prevalence change with the sensitivity parameter. RESULTS: We illustrated our model using a retrospective cohort study of children with asthma exacerbation that were evaluated for pneumonia in the emergency department. Our model found that female gender, having fever during ED or at triage, and having severe hypoxia are significantly associated with having radiographic pneumonia. In addition, simulation studies demonstrate that the Bayesian selection model works well even under circumstances when both the disease prevalence and the screening proportion is low. CONCLUSION: The Bayesian selection model is a viable tool to consider for estimating the disease prevalence and in studying risk factors of the disease, when only a subset of the target population receive the test.

A Qualitative Analysis of Adolescent and Caregiver Acceptability of Universally Offered Gonorrhea and Chlamydia Screening in the Pediatric Emergency Department.

STUDY OBJECTIVE: We qualitatively explore adolescent and parent or guardian attitudes about benefits and barriers to universally offered gonorrhea and chlamydia screening and modalities for assessing interest in screening in the pediatric emergency department (ED). METHODS: A convenience sample of forty 14- to 21-year-olds and parents or guardians of adolescents presenting to an urban and community pediatric ED with any chief complaint participated in individual, semistructured, confidential interviews. Topics included support of universally offered gonorrhea and chlamydia screening, barriers and benefits to screening, and modalities for assessing interest in screening. Data were analyzed with framework analysis. RESULTS: Almost all adolescents (37/40; 93%) and parents (39/40; 98%) support offering ED gonorrhea or chlamydia screening. Benefits included earlier diagnosis and treatment, convenience and transmission prevention (cited by both groups), and improved education and long-term health (cited by parents/guardians). Barriers included concerns about confidentiality and cost (cited by both groups), embarrassment (cited by adolescents), and nondisclosure to parents or guardians (cited by parents/guardians). Adolescents preferred that the request for gonorrhea or chlamydia screening be presented in a private room, using tablet technology. Both groups noted that the advantages to tablets included confidentiality and adolescents' familiarity with technology. Adolescents noted that tablet use would address concerns about bringing up gonorrhea or chlamydia screening with clinicians, whereas parents or guardians noted that tablets might increase screening incidence but expressed concern about the lack of personal interaction. CONCLUSION: Universally offered gonorrhea and chlamydia screening in a pediatric ED was acceptable to the adolescents and parents or guardians in this study. Offering a tablet-based method to assess interest in screening may increase participation.

Sexual Relationship Power and Semen Exposure Among Female Patients at a Sexually Transmitted Infection Clinic in Kingston, Jamaica.

Women's power in sexual relationships is thought to be an important predictor of condom use. However, research on correlates of condom use often relies on participant reporting of behavior, which has questionable validity. We evaluated the association between scores from the modified Sexual Relationship Power Scale (SRPS-M) and biological detection of semen exposure in a prospective study of adult women attending a sexually transmitted infection clinic in Kingston, Jamaica with cervicitis or abnormal vaginal discharge in 2010-2011. At enrollment, women were counseled to avoid sex while on treatment and were asked to return in 6 days for a follow-up visit. At both study visits, women were administered a questionnaire and had vaginal swabs collected to test for prostate-specific antigen (PSA), a biological marker of recent semen exposure. We found no significant association at enrollment or follow-up between SRPS-M scores and semen exposure, as measured with either self-reported data or PSA positivity. Semen biomarkers could be used to develop and validate new scales on relationship power and self-efficacy related to condom use.

Fertility treatments and multiple births in the United States.

BACKGROUND: The advent of fertility treatments has led to an increase in the rate of multiple births in the United States. However, the trends in and magnitude of the contribution of fertility treatments to the increase are uncertain. METHODS: We derived the rates of multiple births after natural conception from data on distributions of all births from 1962 through 1966 (before fertility treatments were available). Publicly available data on births from 1971 through 2011 were used to determine national multiple birth rates, and data on in vitro fertilization (IVF) from 1997 through 2011 were used to estimate the annual proportion of multiple births that were attributable to IVF and to non-IVF fertility treatments, after adjustment for maternal age. Trends in multiple births were examined starting from 1998, the year when clinical practice guidelines for IVF were developed with an aim toward reducing the incidence of multiple births. RESULTS: We estimated that by 2011, a total of 36% of twin births and 77% of triplet and higher-order births resulted from conception assisted by fertility treatments. The observed incidence of twin births increased by a factor of 1.9 from 1971 to 2009. The incidence of triplet and higher-order births increased by a factor of 6.7 from 1971 to 1998 and decreased by 29% from 1998 to 2011. This decrease coincided with a 70% reduction in the transfer of three or more embryos during IVF (P<0.001) and a 33% decrease in the proportion of triplet and higher-order births attributable to IVF (P<0.001). CONCLUSIONS: Over the past four decades, the increased use of fertility treatments in the United States has been associated with a substantial rise in the rate of multiple births. The rate of triplet and higher-order births has declined over the past decade in the context of a reduction in the transfer of three or more embryos during IVF. (Funded by the Centers for Disease Control and Prevention.).

Lung Ultrasonography: A Viable Alternative to Chest Radiography in Children with Suspected Pneumonia?

OBJECTIVE: To determine the interrater reliability (IRR) of lung ultrasonography (LUS) and chest radiography (CXR) and evaluate the accuracy of LUS compared with CXR for detecting pediatric pneumonia compared with chest computed tomography (CT) scan. STUDY DESIGN: This was a prospective cohort study of children aged 3 months to 18 years with a CXR and LUS performed between May 1, 2012, and January 31, 2014 with or without a clinical diagnosis of pneumonia. Four pediatric radiologists blinded to clinical information reported findings for the CXR and LUS images. IRR was estimated for 50 LUS and CXR images. The main outcome was the finding from CT ordered clinically or the probability of the CT finding for patients clinically requiring CT. Two radiologists reviewed CT scans to determine an overall finding. Latent class analysis was used to evaluate the sensitivity and specificity for findings (eg, consolidation) for LUS and CXR compared with CT. RESULTS: Of the 132 patients in the cohort, 36 (27%) had CT performed for a clinical reason. Pneumonia was clinically documented in 47 patients (36%). The IRR for lung consolidation was 0.55 (95% CI, 0.40-0.70) for LUS and 0.36 (95% CI, 0.21-0.51) for CXR. The sensitivity for detecting consolidation, interstitial disease, and pleural effusion was statistically similar for LUS and CXR compared with CT; however, specificity was higher for CXR. The negative predictive value was similar for CXR and LUS. CONCLUSIONS: LUS has a sufficiently high IRR for detection of consolidation. Compared with CT, LUS and CXR have similar sensitivity, but CXR is more specific for findings indicating pneumonia.

Homocysteinemia is Associated with a Lower Degree of PBMC LINE-1 Methylation and a Higher Risk of CIN 2C in the U.S. Post-Folic Acid Fortification Era.

The primary aim of the study was to determine whether plasma concentrations of homocysteine (Hcy), a functional indicator of methyl donor nutrients, are associated with altered risk of higher grades of cervical intraepithelial neoplasia (CIN 2+) and the degree of methylation in long interspersed nucleotide elements (LINE-1s) of peripheral blood mononuclear cells, a potential biomarker of CIN 2+ in a population of women exposed to the United States folic acid fortification program. The secondary aim was to assess the determinants of plasma Hcy in the same population. The study included 457 women diagnosed with either CIN 2+ (cases, n = 132) or ≤ CIN 1 (non-cases, n = 325). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors of cervical cancer. Women with higher Hcy concentrations were at a greater risk of being diagnosed with CIN 2+ [odds ratio (OR) = 1.86, P = 0.005]. Higher plasma folate concentrations were a significant determinant of lower Hcy (OR = 0.40, P = 0.0002). Women with higher Hcy concentrations were more likely to have a lower degree of LINE-1 methylation (OR = 2.30, P = 0.0007). These results suggested that further improvement in folate status in this population may be beneficial for lowering Hcy and improving the degree of LINE-1 methylation.

Endocrine Disruptors: A Potential Risk Factor for Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) has increased dramatically in the past 20 years together with the obesity epidemic. Mirroring the increase in incidence of GDM is increasing use of endocrine disrupting chemicals (EDCs). EDCs are structurally similar to endogenous hormones and interfere with synthesis, secretion, activity, or elimination of natural hormones, resulting in adverse health effects, including diabetes, obesity, developmental disorders, etc. Although the association between bisphenol A (BPA), a well-studied EDC, and type 2 diabetes has been repeatedly investigated in epidemiological and animal studies, there is a dearth of studies examining EDCs and GDM. In fact, the impact of environmental toxins on perinatal health outcomes has largely been overlooked.Recognizing this research gap, the American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, and International Federation of Gynecology and Obstetrics recently joined leading scientists and clinicians in a call for action to prioritize research in the consequences of exposure to toxic environmental agents on women's health. Evidence is emerging to suggest signaling molecules and EDCs are involved in the control of microRNA (miRNA) expression in trophoblast cells. We reviewed existing scientific evidence of EDCs as a risk factor for GDM as well as the potential role of miRNA in this association.

Impact of Health Insurance Type on Trends in Newborn Circumcision, United States, 2000 to 2010.

OBJECTIVES: We explored how changes in insurance coverage contributed to recent nationwide decreases in newborn circumcision. METHODS: Hospital discharge data from the 2000-2010 Nationwide Inpatient Sample were analyzed to assess trends in circumcision incidence among male newborn birth hospitalizations covered by private insurance or Medicaid. We examined the impact of insurance coverage on circumcision incidence. RESULTS: Overall, circumcision incidence decreased significantly from 61.3% in 2000 to 56.9% in 2010 in unadjusted analyses (P for trend = .008), but not in analyses adjusted for insurance status (P for trend = .46) and other predictors (P for trend = .55). Significant decreases were observed only in the South, where adjusted analyses revealed decreases in circumcision overall (P for trend = .007) and among hospitalizations with Medicaid (P for trend = .005) but not those with private insurance (P for trend = .13). Newborn male birth hospitalizations covered by Medicaid increased from 36.0% (2000) to 50.1% (2010; P for trend < .001), suggesting 390,000 additional circumcisions might have occurred nationwide had insurance coverage remained constant. CONCLUSIONS: Shifts in insurance coverage, particularly toward Medicaid, likely contributed to decreases in newborn circumcision nationwide and in the South. Barriers to the availability of circumcision should be revisited, particularly for families who desire but have less financial access to the procedure.

Functional variants in CYP1A1 and GSTM1 are associated with clearance of cervical HPV infection.

OBJECTIVE: We evaluated time to clearance of high risk (HR) HPV infection in relation to functional variants in three genes (CYP1A1, GSTT1, and GSTM1). METHODS: The study group consisted of 450 HR-HPV infected women from the Atypical squamous cells of undetermined significance-low-grade squamous intraepithelial Lesion Triage Study (ALTS) cohort followed up at the clinical center at Birmingham, Alabama. The Cox proportional hazard model with the Wei-Lin-Weisfeld (WLW) approach was used, controlling for relevant covariates. RESULTS: Women who were polymorphic for CYP1A1 experienced an HR-HPV clearance rate that was 20% (HR=0.80, p=0.04) lower than women without the polymorphism for CYP1A1, adjusting for all other cofactors. The GSTM1 null genotype was associated with higher HR-HPV clearance rate (HR=1.39, p=0.006). The polymorphism in GSTT1 was not significantly associated with time to clearance of HR-HPV. CONCLUSIONS: Xenobiotic metabolism genes may influence the natural history of HR-HPV infection and its progression to cervical cancer.

GnRH agonist and GnRH antagonist protocols: comparison of outcomes among good-prognosis patients using national surveillance data.

Implantation and live birth rates resulting from IVF cycles using gonadotropin-releasing hormone (GnRH) agonist and (GnRH) antagonist IVF protocols were compared among good-prognosis patients using the Centers for Disease Control and Prevention's National Assisted Reproductive Technology Surveillance System 2009-2010 data (n = 203,302 fresh, autologous cycles). Bivariable and multivariable analyses were conducted between cycles to compare outcomes. Cycles were restricted as follows: age younger than 35 years, maximum FSH less than 10 mIU/mL, first assisted reproduction technology cycle and FSH dose less than 3601 IU. A subgroup analysis including only elective single embryo transfer was also carried out. Among good-prognosis patients, the GnRH-agonist protocol was associated with a lower risk of cancellation before retrieval (4.3 versus 5.2%; P < 0.05) or transfer (5.5 versus 6.8%; P < 0.05), and a higher live birth rate per transfer (adjusted odds ratio [OR] 1.13, confidence interval [CI] 1.03 to 1.25) than the GnRH-antagonist group. Among the elective single embryo transfer group, the GnRH-agonist protocol was associated with a higher implantation rate (adjusted odds ratio [OR] 1.36, CI 1.08 to 1.73) and a higher live birth rate (adjusted OR 1.33, CI 1.07 to 1.66) compared with the GnRH-antagonist protocol. The GnRH-antagonist group had lower rates of ovarian hyperstimulation syndrome. Among good-prognosis patients, agonist protocols decreased cancellation risk and increased odds of implantation and live birth. Antagonist protocols may confer decreased risk of hyperstimulation.

Accuracy of assisted reproductive technology information on birth certificates: Florida and Massachusetts, 2004-06.

BACKGROUND: Assisted Reproductive Technology (ART) includes fertility procedures where both egg and sperm are handled in the lab. ART use has increased considerably in recent years, accounting for 47,090 livebirths in the U.S. in 2010. ART increases the probability of multiple gestation births, which are at higher risks than singletons for adverse outcomes. Additionally, ART is associated with a greater risk of complications during pregnancy, labour, and delivery, and increased risk of adverse perinatal outcomes in singleton births. METHODS: We merged Florida and Massachusetts birth records from 2004-06 with the National ART Surveillance System (NASS) and using NASS as the gold standard, calculated sensitivity, specificity, and positive predictive value (PPV) of ART reporting on the birth certificates by maternal, infant, and hospital characteristics. We fit random-effects logistic regression models to evaluate simultaneously the association of ART reporting with these predictors while accounting for correlation among births occurring in the same hospital. RESULTS: Sensitivity of ART reporting on the birth certificate was 28.9% in Florida and 41.4% in Massachusetts. Specificity was >99% in both states. PPV was 45.5% in Florida and 54.6% in Massachusetts. The odds of ART reporting varied by state and by several maternal and delivery characteristics including age, parity, history of fetal loss, plurality, race/Hispanic ethnicity, delivery payment source, pre-existing conditions, and complications during pregnancy or labour and delivery. CONCLUSIONS: There was significant under-reporting of ART procedures on the birth certificates. Using data on ART births identified only from birth certificates yields a biased sample of the population of ART births.

Impact of the COVID-19 Pandemic on People Living With Rare Diseases and Their Families: Results of a National Survey.

BACKGROUND: With more than 103 million cases and 1.1 million deaths, the COVID-19 pandemic has had devastating consequences for the health system and the well-being of the entire US population. The Rare Diseases Clinical Research Network funded by the National Institutes of Health was strategically positioned to study the impact of the pandemic on the large, vulnerable population of people living with rare diseases (RDs). OBJECTIVE: This study was designed to describe the characteristics of COVID-19 in the RD population, determine whether patient subgroups experienced increased occurrence or severity of infection and whether the pandemic changed RD symptoms and treatment, and understand the broader impact on respondents and their families. METHODS: US residents who had an RD and were <90 years old completed a web-based survey investigating self-reported COVID-19 infection, pandemic-related changes in RD symptoms and medications, access to care, and psychological impact on self and family. We estimated the incidence of self-reported COVID-19 and compared it with that in the US population; evaluated the frequency of COVID-19 symptoms according to self-reported infection; assessed infection duration, complications and need for hospitalization; assessed the influence of the COVID-19 pandemic on RD symptoms and treatment, and whether the pandemic influenced access to care, special food and nutrition, or demand for professional psychological assistance. RESULTS: Between May 2, 2020, and December 15, 2020, in total, 3413 individuals completed the survey. Most were female (2212/3413, 64.81%), White (3038/3413, 89.01%), and aged ≥25 years (2646/3413, 77.53%). Overall, 80.6% (2751/3413) did not acquire COVID-19, 2.08% (71/3413) acquired it, and 16.58% (566/3413) did not know. Self-reported cases represented an annual incidence rate of 2.2% (95% CI 1.7%-2.8%). COVID-19 cases were more than twice the expected (71 vs 30.3; P<.001). COVID-19 was associated with specific symptoms (loss of taste: odds ratio [OR] 38.9, 95% CI 22.4-67.6, loss of smell: OR 30.6, 95% CI 17.7-53.1) and multiple symptoms (>9 symptoms vs none: OR 82.5, 95% CI 29-234 and 5-9: OR 44.8, 95% CI 18.7-107). Median symptom duration was 16 (IQR 9-30) days. Hospitalization (7/71, 10%) and ventilator support (4/71, 6%) were uncommon. Respondents who acquired COVID-19 reported increased occurrence and severity of RD symptoms and use or dosage of select medications; those who did not acquire COVID-19 reported decreased occurrence and severity of RD symptoms and use of medications; those who did not know had an intermediate pattern. The pandemic made it difficult to access care, receive treatment, get hospitalized, and caused mood changes for respondents and their families. CONCLUSIONS: Self-reported COVID-19 was more frequent than expected and was associated with increased prevalence and severity of RD symptoms and greater use of medications. The pandemic negatively affected access to care and caused mood changes in the respondents and family members. Continued surveillance is necessary.

Biological markers of sexual activity: tools for improving measurement in HIV/sexually transmitted infection prevention research.

Research on interventions to prevent HIV and other sexually transmitted infections (STIs) is heavily influenced by participant reporting of sexual behavior, despite uncertainty about its validity. Exclusive reliance on participant self-report often is based, overtly or by implication, on 4 assumptions: (1) no feasible alternatives exist; (2) misreporting can be minimized to levels that can be disregarded; (3) misreporting tends to underreport sensitive behaviors; and (4) misreporting tends to be nondifferential with respect to the groups being compared. The objective of this review are to evaluate these assumptions, including a review of studies using semen biomarkers to evaluate the validity of self-reported data, and to make recommendations for applying biological markers of semen exposure detectable in women to further strengthen research on HIV/STI prevention. Increasing evidence shows that semen biomarkers provide an important means of assessing and augmenting the validity of studies on HIV/STI prevention. Additional biomarkers are needed to assess male exposure to vaginal sex and both male and female exposure to anal sex. Methods and study designs that incorporate biomarkers into studies collecting self-reported behavioral data should be considered where possible.

Randomized controlled trial on the effectiveness of counseling messages for avoiding unprotected sexual intercourse during sexually transmitted infection and reproductive tract infection treatment among female sexually transmitted infection clinic patients.

BACKGROUND: The effectiveness of counseling messages to avoid unprotected sex during short-term treatment for curable sexually transmitted infections is unknown. METHODS: We randomized 300 female STI clinic patients 18 years or older with cervicitis and/or vaginal discharge in Kingston, Jamaica, in 2010 to 2011, to 1 of 2 counseling messages for their course of syndromic treatment: abstinence only or abstinence backed up by condom use. At a follow-up visit 6 days afterward, we collected vaginal swabs to test for prostate-specific antigen (PSA), a biological marker of recent semen exposure, and administered a questionnaire assessing sexual behavior. RESULTS: No differences were found in the proportions of women testing positive for PSA at follow-up in the abstinence-plus-condom group (11.9%) and abstinence-only group (8.4%) (risk difference, 3.5; 95% confidence interval, -3.5 to 10.5). There also was no significant difference in reporting of unprotected sex between groups. Reporting a history of condom use before enrollment significantly modified the effect of counseling arm on PSA positivity (P = 0.03). Among those reporting recent condom use, 10.3% in the abstinence-only arm and 4.8% in the abstinence-plus-condom arm tested positive for PSA. Conversely, among those not reporting recent condom use, 6.5% in the abstinence-only arm and 17.3% in the abstinence-plus-condom arm had PSA detected. CONCLUSIONS: We found no evidence to support the superiority of either counseling message. Post hoc analyses suggest that women with recent condom experience may benefit significantly more from abstinence-plus-condom messages, whereas women without such experience may benefit significantly more from abstinence-only messages. Providers should weigh individual condom use history when determining the most appropriate counseling message.

Safe conception for HIV-discordant couples: insemination with processed semen from the HIV-infected partner.

OBJECTIVE: The objective of the study was to evaluate the safety of semen washing with intrauterine insemination (SW-IUI) for achieving pregnancy when the man is human immunodeficiency virus (HIV) infected and the woman is HIV negative. STUDY DESIGN: We conducted a retrospective analysis of 635 HIV-discordant couples enrolled in a SW-IUI program and followed up 367 Italian women. We computed pregnancy, live birth, and multiple delivery rates and assessed the women's postinsemination HIV status. RESULTS: The retrospective analysis included 635 couples (2113 SW-IUI cycles): 41% of the women (95% confidence interval [CI], 37-45%) had a live birth (per-cycle live birth rate 13%; 95% CI, 11-14%). HIV status after SW-IUI was negative when available but unknown for 26% of the women: missing HIV status was not associated with correlates of HIV risk. The follow-up study included 367 couples (1365 cycles): 47% of the women (95% CI, 42-52%) had a live birth (per-cycle rate 14%; 95% CI, 12-16%). Ascertainment of postinsemination HIV status was complete and confirmed no HIV transmission attributable to SW-IUI. The upper 95% confidence limit of the HIV transmission rate was 1.8 per 1000 cycles in the retrospective analysis and 2.7 per 1000 cycles in the follow-up study. CONCLUSION: SW-IUI appears to be a safe and effective method for achieving pregnancy in HIV-discordant couples in which the man is HIV infected.

Exploring discordance between biologic and self-reported measures of semen exposure: a qualitative study among female patients attending an STI clinic in Jamaica.

We explored the use of qualitative interviews to discuss discrepancies between two sources of information on unprotected sex: biomarker results and self-reported survey data. The study context was a randomized trial in Kingston, Jamaica examining the effect of STI counseling messages on recent sexual behavior using prostate-specific antigen (PSA) as the primary study outcome. Twenty women were interviewed. Eleven participants were selected because they tested positive for PSA indicating recent semen exposure, yet reported no unprotected sex in a quantitative survey ("discordant"): 5 reported abstinence and 6 reported condom use. Nine participants who also tested positive for PSA but reported unprotected sex in the survey were interviewed for comparison ("concordant"). Qualitative interviews with 6 of the 11 discordant participants provided possible explanations for their PSA test results, and 5 of those were prompted by direct discussion of those results. Rapid PSA testing combined with qualitative interviews provides a novel tool for investigating and complementing self-reported sexual behavior.

Obesity, assisted reproductive technology, and early preterm birth--Florida, 2004-2006.

Florida resident birth certificates for 2004-2006 were linked to the Centers for Disease Control and Prevention's National ART Surveillance System and were used to investigate 1) whether the association of assisted reproductive technology (ART) with preterm birth varies by prepregnancy body mass index and 2) whether the association varies by plurality. Preterm birth was defined as early preterm birth (gestation <34 weeks) and late preterm birth (gestation 34-36 weeks). Descriptive statistics and multinomial logistic regression were used to explore maternal and infant differences by ART status and plurality. Of 581,403 women included in the study, 24.0% were overweight, 18.6% were obese, 7.3% had late preterm birth, 2.6% had early preterm birth, and 0.67% conceived through ART. Among singleton births, ART was associated with increased early preterm birth risk among underweight (odds ratio (OR) = 2.94, 95% confidence interval (CI): 1.27, 6.81), overweight (OR = 1.75, 95% CI: 1.12, 2.72), and obese (OR = 2.37, 95% CI: 1.51, 3.71) women. Among twins, ART was significantly associated with increased risk among overweight (OR = 1.61, 95% CI: 1.12, 2.32) and obese (OR = 1.85, 95% CI: 1.18, 2.90) women. Differences in the associations between ART and early preterm birth by body mass index and plurality warrant further investigation.