Effect of an educational script on postpartum contraceptive use: a randomized controlled trial.

OBJECTIVES: Short interpregnancy intervals are associated with adverse perinatal outcomes. Increased postpartum use of long-acting reversible contraception (LARC) could reduce short interpregnancy intervals. Therefore, the primary objective of our study was to evaluate if a postpartum educational script about LARC (LARC script) could increase postpartum LARC utilization at the 6-week postpartum visit. STUDY DESIGN: We completed a randomized controlled trial (1:1) of 800 postpartum women in Raleigh, North Carolina. Women were recruited from the postpartum unit and randomized to receive (intervention) or not receive (control) the LARC script prior to hospital discharge. We conducted follow-up phone interviews to assess LARC use after their 6-week postpartum visit. We used Pearson's chi-squared test to compare LARC use between arms. RESULTS: Between May 2011 and January 2012, 400 women were randomized to each arm. Three hundred sixty-nine women (92.3%) in each arm were successfully contacted after their 6-week postpartum visit. LARC use was reported by 17.6% and 13.3% of women in the intervention and control arms, respectively (p=.103). CONCLUSIONS: The LARC script did not increase LARC utilization at the 6-week postpartum visit. Future studies should evaluate interventions that address both educational and systematic barriers to postpartum LARC uptake. IMPLICATIONS: Use of a postpartum educational script focused on the intrauterine device and contraceptive implant did not increase their utilization after the 6-week postpartum visit. Future studies should evaluate interventions that address both educational and systematic barriers to postpartum contraceptive uptake.

Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial.

IMPORTANCE: Long-acting injectable antipsychotics are used to reduce medication nonadherence and relapse in schizophrenia-spectrum disorders. The relative effectiveness of long-acting injectable versions of second-generation and older antipsychotics has not been assessed. OBJECTIVE: To compare the effectiveness of the second-generation long-acting injectable antipsychotic paliperidone palmitate with the older long-acting injectable antipsychotic haloperidol decanoate. DESIGN, SETTING, AND PARTICIPANTS: Multisite, double-blind, randomized clinical trial conducted from March 2011 to July 2013 at 22 US clinical research sites. Randomized patients (n = 311) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a long-acting injectable antipsychotic. INTERVENTIONS: Intramuscular injections of haloperidol decanoate 25 to 200 mg or paliperidone palmitate 39 to 234 mg every month for as long as 24 months. MAIN OUTCOME MEASURES: Efficacy failure, defined as a psychiatric hospitalization, a need for crisis stabilization, a substantial increase in frequency of outpatient visits, a clinician's decision that oral antipsychotic could not be discontinued within 8 weeks after starting the long-acting injectable antipsychotics, or a clinician's decision to discontinue the assigned long-acting injectable due to inadequate therapeutic benefit. Key secondary outcomes were common adverse effects of antipsychotic medications. RESULTS: There was no statistically significant difference in the rate of efficacy failure for paliperidone palmitate compared with haloperidol decanoate (adjusted hazard ratio, 0.98; 95% CI, 0.65-1.47). The number of participants who experienced efficacy failure was 49 (33.8%) in the paliperidone palmitate group and 47 (32.4%) in the haloperidol decanoate group. On average, participants in the paliperidone palmitate group gained weight and those in the haloperidol decanoate group lost weight; after 6 months, the least-squares mean weight change for those taking paliperidone palmitate was increased by 2.17 kg (95% CI, 1.25-3.09) and was decreased for those taking haloperidol decanoate (-0.96 kg; 95% CI, -1.88 to -0.04). Patients taking paliperidone palmitate had significantly higher maximum mean levels of serum prolactin (men, 34.56 µg/L [95% CI, 29.75-39.37] vs 15.41 µg/L [95% CI, 10.73-20.08]; P <.001, and for women, 75.19 [95% CI, 63.03-87.36] vs 26.84 [95% CI, 13.29-40.40]; P<.001). Patients taking haloperidol decanoate had significantly larger increases in global ratings of akathisia (0.73 [95% CI, 0.59-0.87] vs 0.45 [95% CI, 0.31-0.59]; P=.006). CONCLUSIONS AND RELEVANCE: In adults with schizophrenia or schizoaffective disorder, use of paliperidone palmitate vs haloperidol decanoate did not result in a statistically significant difference in efficacy failure, but was associated with more weight gain and greater increases in serum prolactin, whereas haloperidol decanoate was associated with more akathisia. However, the CIs do not rule out the possibility of a clinically meaningful advantage with paliperidone palmitate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01136772.

A pilot study of eptifibatide for treatment of acute pain episodes in sickle cell disease.

INTRODUCTION: The contribution of platelet activation to the pathogenesis of sickle cell disease (SCD) remains uncertain. We evaluated the safety and efficacy of eptifibatide, a synthetic peptide inhibitor of the αIIbß3 receptor, in SCD patients during acute painful episodes. MATERIALS AND METHODS: In this single site, double-blind, placebo-controlled trial, eligible patients with SCD admitted for acute painful episodes were randomized to receive eptifibatide or placebo at a ratio of 2:1. RESULTS: Thirteen patients (SS - 10, Sß(0) - 2, SC - 1) were randomized to receive either eptifibatide (N=9; 6 females; median age - 25years) or placebo (N=4; 3 females; median age - 31years). In the intent-to-treat analysis, there were no major bleeding episodes in either the eptifibatide or placebo arms (point estimate of difference: 0.00, 95% CI; -0.604, 0.372). There was one minor bleeding episode in the eptifibatide arm (point estimate of difference for any bleeding: 0.11, 95% CI: -0.502, 0.494). There was no significant difference in the proportion of patients with thrombocytopenia between the treatment groups (point estimate of difference: 0.11, 95% CI: -0.587, 0.495). There were no differences in the median times to discharge, median times to crisis resolution or the median total opioid use. CONCLUSIONS: In this small study, eptifibatide appeared to be safe, but did not improve the times to crisis resolution or hospital discharge. Adequately powered studies are required to evaluate the safety and efficacy of eptifibatide in SCD. Clinicaltrials.gov Identifier: NCT00834899.

Characteristics associated with interest in long-acting reversible contraception in a postpartum population.

BACKGROUND: Short interpregnancy intervals lead to adverse perinatal outcomes and could be prevented with increased use of long-acting reversible contraception (LARC) in the postpartum period. The primary objective of this study was to assess which baseline characteristics are associated with the intent to use LARC among postpartum women. STUDY DESIGN: This study was a substudy of baseline data from a randomized controlled trial. Eight hundred women completed a pre-intervention survey of demographics and reproductive health history and intentions. We estimated adjusted relative risks (RRs) of intent to use LARC for baseline characteristics of interest. RESULTS: Three hundred three postpartum women (38%) intended to use LARC. Two out of 10 baseline characteristics were significantly associated with intent to use LARC: not trying for pregnancy at time of conception [adjusted RR, 1.6; 95% confidence interval (CI), 1.2-2.1] and no desire for another pregnancy within 2 years (adjusted RR, 1.9; 95% CI, 1.2-2.8). CONCLUSIONS: High interest in LARC exists among postpartum women, particularly among women with a recent unintended pregnancy and women who do not desire pregnancy for at least 2 years. Past and future pregnancy intentions should be incorporated into future models and frameworks that evaluate postpartum contraceptive choice. Educational intervention studies are also needed to assess if LARC interest can be increased among postpartum women who are less likely to intend to use LARC but at risk for future adverse perinatal outcomes.

Effect of hawthorn standardized extract on flow mediated dilation in prehypertensive and mildly hypertensive adults: a randomized, controlled cross-over trial.

BACKGROUND: Hawthorn extract has been used for cardiovascular diseases for centuries. Recent trials have demonstrated its efficacy for the treatment of heart failure, and the results of several small trials suggest it may lower blood pressure. However, there is little published evidence to guide its dosing. The blood pressure lowering effect of hawthorn has been linked to nitric oxide-mediated vasodilation. The aim of this study was to investigate the relationship between hawthorn extract dose and brachial artery flow mediated dilation (FMD), an indirect measure of nitric oxide release. METHODS: We used a four-period cross-over design to evaluate brachial artery FMD in response to placebo or hawthorn extract (standardized to 50 mg oligomeric procyanidin per 250 mg extract). Randomly sequenced doses of hawthorn extract (1000 mg, 1500 mg, and 2500 mg) and placebo were assigned to each participant. Doses were taken twice daily for 3 1/2 days followed by FMD and a 4-day washout before proceeding to the next dosing period. RESULTS: Twenty-one prehypertensive or mildly hypertensive adults completed the study. There was no evidence of a dose-response effect for our main outcome (FMD percent) or any of our secondary outcomes (absolute change in brachial artery diameter and blood pressure). Most participants indicated that if given evidence that hawthorn could lower their blood pressure, they would be likely to use it either in conjunction with or instead of lifestyle modification or anti-hypertensive medications. CONCLUSION: We found no evidence of a dose-response effect of hawthorn extract on FMD. If hawthorn has a blood pressure lowering effect, it is likely to be mediated via an NO-independent mechanism. TRIAL REGISTRATION: This trial has been registered with ClinicalTrials.gov, a service of the U.S. National Institutes of Health: NCT01331486.

Predicting partner HIV testing and counseling following a partner notification intervention.

Provider-assisted methods of partner notification increase testing and counseling among sexual partners of patients diagnosed with HIV, however they are resource-intensive. The sexual partners of individuals enrolled in a clinical trial comparing different methods of HIV partner notification were analyzed to identify who was unlikely to seek testing on their own. Unconditional logistic regression was used to identify partnership characteristics, which were assigned a score based on their coefficient in the final model, and a risk score was calculated for each participant. The risk score included male partner sex, relationship duration 6-24 months, and index education > primary. A risk score of ≥ 2 had a sensitivity of 68% and specificity of 78% in identifying partners unlikely to seek testing on their own. A risk score to target partner notification can reduce the resources required to locate all partners in the community while increasing the testing yield compared to patient-referral.

HIV partner notification is effective and feasible in sub-Saharan Africa: opportunities for HIV treatment and prevention.

BACKGROUND: Sexual partners of persons with newly diagnosed HIV infection require HIV counseling, testing and, if necessary, evaluation for therapy. However, many African countries do not have a standardized protocol for partner notification, and the effectiveness of partner notification has not been evaluated in developing countries . METHODS: Individuals with newly diagnosed HIV infection presenting to sexually transmitted infection clinics in Lilongwe, Malawi, were randomized to 1 of 3 methods of partner notification: passive referral, contract referral, or provider referral. The passive referral group was responsible for notifying their partners themselves. The contract referral group was given seven days to notify their partners, after which a health care provider contacted partners who had not reported for counseling and testing. In the provider referral group, a health care provider notified partners directly. RESULTS: Two hundred forty-five index patients named 302 sexual partners and provided locator information for 252. Among locatable partners, 107 returned for HIV counseling and testing; 20 of 82 [24%; 95% confidence interval (CI): 15% to 34%] partners returned in the passive referral arm, 45 of 88 (51%; 95% CI: 41% to 62%) in the contract referral arm, and 42 of 82 (51%; 95% CI: 40% to 62%) in the provider referral arm (P < 0.001). Among returning partners (n = 107), 67 (64%) of were HIV infected with 54 (81%) newly diagnosed. DISCUSSION: This study provides the first evidence of the effectiveness of partner notification in sub-Saharan Africa. Active partner notification was feasible, acceptable, and effective among sexually transmitted infections clinic patients. Partner notification will increase early referral to care and facilitate risk reduction among high-risk uninfected partners.

Variable reliability of endoscopic findings with white-light and narrow-band imaging for patients with suspected eosinophilic esophagitis.

BACKGROUND & AIMS: Endoscopic findings have been used to support a diagnosis of eosinophilic esophagitis (EoE) and to assess response to therapy, but their reliability is unknown. The aim of the study was to assess inter- and intraobserver reliability of endoscopic findings with white-light endoscopy and to assess changes in interobserver reliability when narrow band imaging (NBI) was added to white light. METHODS: We collected data from 35 academic and 42 community adult gastroenterologists using 2 self-administered, online assessments of endoscopic images in patients with suspected EoE. First, gastroenterologists evaluated 35 single white light images. Next, they examined 35 paired images of the initial white light image and its NBI counterpart. To assess intraobserver reliability, a second survey to re-examine the single white light images was performed ≥2 weeks later. Agreement was determined by calculating κ values for multiple observers. RESULTS: Among all gastroenterologists, interobserver agreement was fair to good when white light was used to identify rings (κ = 0.56) and furrows (κ = 0.48). Interobserver agreement was poor for identification of plaques (κ = 0.29) and for images with no findings (κ = 0.34). Levels of agreement did not change in an analysis stratified by practice setting or patient volume. Agreement did not improve when NBI images were added to white light images. Levels of intraobserver agreement varied greatly and in some cases were not greater than those expected by chance. CONCLUSIONS: Using white light endoscopy and NBI to analyze EoE, gastroenterologists identified rings and furrows with fair to good reliability, but did not reliably identify plaques or normal images. Intraobserver agreement varied. Endoscopic findings might not be reliable for supporting a diagnosis of EoE or for making treatment decisions.

Changes in childhood diarrhea incidence in nicaragua following 3 years of universal infant rotavirus immunization.

BACKGROUND: Although the pentavalent rotavirus vaccine was highly efficacious against rotavirus diarrhea in clinical trials, the effectiveness of vaccine under field conditions in the developing world is unclear. In October 2006, Nicaragua became the first developing nation to implement universal infant immunization with the pentavalent rotavirus vaccine. To assess the effect of the immunization program, we examined the incidence of diarrhea episodes between 2003 and 2009 among children in the state of León, Nicaragua. METHODS: We extracted data on diarrhea episodes from health ministry records. We used scaled Poisson regression models to estimate diarrhea incidence rate ratios for the period following the program's implementation to the period before implementation. RESULTS: Following implementation of the immunization program, diarrhea episodes among infants were reduced (incidence rate ratios: 0.85, 95% confidence interval: 0.71-1.02) during the rotavirus season, but appear to have increased during other months. CONCLUSIONS: Although the immunization program appears effective in reducing diarrhea episodes during the rotavirus season, a large burden of diarrhea still persists during the remainder of the year.

Reproducibility of masked hypertension in adults with untreated borderline office blood pressure: comparison of ambulatory and home monitoring.

BACKGROUND: We examined short-term reproducibility of masked hypertension (MH) among adults with recent "borderline" office blood pressure (BP) and compared agreement of ambulatory BP monitoring (ABPM) and home BP monitoring (HBPM) in detecting MH. METHODS: Fifty participants underwent repeated office BP measurements, 24-h ABPM, and HBPM sessions 1-week apart. Participants with office average <140/90 mm Hg were considered to have MH if daytime ABPM average was ≥135/85 mm Hg; they were considered to have MH by HBPM if the average was ≥135/85 mm Hg. Agreements were quantified using κ. We calculated sensitivity and specificity of daytime ABPM-office average pairing and HBPM session-office average pairing for diagnosing MH using a "standard" of two pairings of office and 24-h average ABPM (using a cutoff ≥130/80 mm Hg). RESULTS: Prevalence rates of MH based on office-daytime ABPM pairings were 54 and 53%, with agreement of 73% (κ = 0.47; 95% confidence interval (CI) 0.21-0.72). MH was less prevalent (43 and 35%) using HBPM-office pairings, with agreement of 69% (κ = 0.34; 95% CI 0.06-0.62). Office-HBPM pairings and office-daytime ABPM pairings had poor agreement on MH classification on both occasions, with κ of -0.06 and 0.10. Sensitivity and specificity of daytime ABPM-office pairing were 93 and 83%. Sensitivity and specificity of HBPM-office pairing were 23 and 67%. CONCLUSIONS: MH appears to have fair-to-moderate reproducibility, favoring the hypothesis that office BP measurement systematically fails to identify some patients who should be treated as hypertensive. HBPM may not be adequate for detecting MH, or may identify a different "type" of MH than ABPM.

Development of instruments to measure the quality of breast cancer treatment decisions.

BACKGROUND: Women with early-stage breast cancer face a multitude of decisions. The quality of a decision can be measured by the extent to which the treatment reflects what is most important to an informed patient. Reliable and valid measures of patients' knowledge and their goals and concerns related to breast cancer treatments are needed to assess the decision quality. OBJECTIVE: To identify a set of key facts and goals relevant to each of three breast cancer treatment decisions (surgery, reconstruction and adjuvant chemotherapy and hormone therapy) and to evaluate the validity of the methods used to identify them. METHODS: Candidate facts and goals were chosen based on evidence review and qualitative studies with breast cancer patients and providers. Cross-sectional surveys of patients and providers were conducted for each decision. The accuracy, importance and completeness of the items were examined. RESULTS: Thirty-eight facts (11-14 per decision) and 27 goals (8-10 per decision) were identified. An average of 17 patients and 21 providers responded to each survey. The sets of facts were accurate and complete for all three decisions. The sets of goals and concerns were important for surgery and reconstruction, but not chemotherapy/hormone therapy. Patients and providers disagreed about the relative importance of several key facts and goals. CONCLUSIONS: Overall, breast cancer patients and providers found the sets of facts and goals accurate, important and complete for three treatment decisions. Because patients' and providers' perspectives are different, it is vital that instrument development should include items reflecting both views.

Prescription refill records as a screening tool to identify antidepressant non-adherence.

PURPOSE: Non-adherence is a significant problem with antidepressants. Identifying patients at highest risk for discontinuing antidepressant treatment can be used to target clinical management. Accordingly, our purpose was to determine the shortest gap in medication supply that is predictive of discontinuation, while minimizing false positive results. METHODS: A retrospective cohort study of medical and prescription claims from a national health plan affiliated with i3 Innovus. Sensitivities, specificities, and positive and negative predictive values were calculated for gap lengths to assess how well they predicted discontinuation. Continuously insured individuals aged 18-65 with newly diagnosed major depression and an antidepressant prescription within 45 days of diagnosis were included. Gap length was defined as the maximum number of continuous days without medication supply during acute phase treatment. Discontinuation was defined as a continuous gap of 30 or more days between an expected refill and actual refill. RESULTS: Of 4545 eligible patients, 73% discontinued antidepressant treatment during the study period. A maximum continuous gap of 14 days had a sensitivity of 87% and a specificity of 82% for predicting discontinuation. In analyses that varied the way gaps and discontinuation were defined, gap lengths between 8 and 19 days were highly predictive of discontinuation without exceeding a 20% false positive rate. CONCLUSIONS: Based on administrative pharmacy records, screening for gaps in medication supply of at least 14 days can accurately identify four of every five patients at risk for discontinuing. This early indicator can be used to target clinical interventions.

Practical depression screening in residential care/assisted living: five methods compared with gold standard diagnoses.

OBJECTIVE: To test the accuracy of five practical depression screening strategies in older adults residing in residential care/assisted living (RC/AL). DESIGN: Cross-sectional screening study. SETTING: Four RC/AL communities in North Carolina. PARTICIPANTS: A total of 112 residents aged > or =65 and 27 staff members involved in their care. MEASUREMENTS: Direct care staff was trained in and completed the Cornell Scale for Depression in Dementia, modified for use by long-term care staff (CSDD-M-LTCS). They additionally responded to a one-item question "Do you believe the resident is often sad or depressed?" and the Minimum Data Set Depression Rating Scale (DRS). Residents responded directly to the Geriatric Depression Scale (15-item version; GDS-15) and the Patient Health Questionnaire, 2-item version (PHQ-2). A geriatric psychiatrist performed gold standard diagnostic interviews using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Sensitivities and specificities were calculated for all instruments at predetermined cutpoints. RESULTS: Gold standard diagnoses yielded 14% prevalence of major or minor depression. The CSDD-M-LTCS and one-item screen completed by caregivers failed to significantly discriminate depressed cases. The DRS yielded high specificity (0.85) but low sensitivity (0.47). For the two resident reported measures, the PHQ-2 had a sensitivity of 0.80 and specificity of 0.71, and the GDS-15, 0.60 and 0.75, respectively. CONCLUSION: Measures completed by caregivers failed to adequately detect depression. Of the measures completed directly by residents, the PHQ-2 seems to have the best mix of brevity, sensitivity, and ease of administration.

SAVVY (C31G) gel for prevention of HIV infection in women: a Phase 3, double-blind, randomized, placebo-controlled trial in Ghana.

OBJECTIVE: The objective of this trial was to determine the effectiveness of 1.0% C31G (SAVVY) in preventing male-to-female vaginal transmission of HIV infection among women at high risk. METHODOLOGY/PRINCIPAL FINDINGS: This was a Phase 3, double-blind, randomized, placebo-controlled trial. Participants made up to 12 monthly visits for HIV testing, adverse event reporting, and study product supply. The study was conducted between March 2004 and February 2006 in Accra and Kumasi, Ghana. We enrolled 2142 HIV-negative women at high risk of HIV infection, and randomized them to SAVVY or placebo gel. Main outcome measures were the incidence of HIV-1 and HIV-2 infection as determined by detection of HIV antibodies from oral mucosal transudate specimens and adverse events. We accrued 790 person-years of follow-up in the SAVVY group and 772 person-years in the placebo group. No clinically significant differences in the overall frequency of adverse events, abnormal pelvic examination findings, or abnormal laboratory results were seen between treatment groups. However, more participants in the SAVVY group reported reproductive tract adverse events than in the placebo group (13.0% versus 9.4%). Seventeen HIV seroconversions occurred; eight in participants randomized to SAVVY and nine in participants receiving placebo. The Kaplan-Meier estimates of the cumulative probability of HIV infection through 12 months were 0.010 in the SAVVY group and 0.011 in the placebo group (p = 0.731), with a hazard ratio (SAVVY versus placebo) of 0.88 (95% confidence interval 0.33, 2.27). Because of a lower-than-expected HIV incidence, we were unable to achieve the required number of HIV infections (66) to obtain the desired study power. CONCLUSIONS/SIGNIFICANCE: SAVVY was not associated with increased adverse events overall, but was associated with higher reporting of reproductive adverse events. Our data are insufficient to conclude whether SAVVY is effective at preventing HIV infection relative to placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT00129532.

Pregnancy risk among oral contraceptive pill, injectable contraceptive, and condom users in Uganda, zimbabwe, and Thailand.

OBJECTIVE: To estimate the probability of pregnancy for oral contraceptive pill (OCP), injectable contraceptive, and condom users in Uganda, Thailand, and Zimbabwe. METHODS: This study is a secondary analysis of 5,224 women who participated in a prospective study evaluating the association between hormonal contraception and human immunodeficiency virus (HIV) acquisition. RESULTS: The overall 12-month cumulative probability of pregnancy of injectable contraceptive users was 0.6% (95% confidence interval [CI] 0.3-1.0), with similar risks in Uganda (0.3%, 95% CI 0-0.7), Thailand (0.6%, 95% CI 0-1.2), and Zimbabwe (1.0%, 95% CI 0.3-1.7). The 12-month cumulative probability of pregnancy for OCP users was 9.5% (95% CI 8.1-11.0%), with similar risks of pregnancy in Uganda and Zimbabwe (14.6%, 95% CI 11.7-17.4; and 10.2%, 95% CI 8.0-12.5, respectively) but substantially lower risk in Thailand (0.5%, 95% CI 0-1.2). The overall 12-month cumulative probability of pregnancy for women intending to use a given method at baseline was 2.0% (95% CI 1.4-2.6%) for injectable contraceptives, 15.7% (95% CI 14.1-17.3%) for OCPs, and 25.8% (95% CI 23.2-28.4) for condoms. Women in Thailand experienced lower pregnancy risk with condoms (18.4%, 95% CI 11.1-25.7) than in Uganda (29.5%, 95% CI 25.7-33.4), and Zimbabwe (23.3%, 95% CI 19.4-27.2). CONCLUSION: The overall risk of pregnancy for injectable contraceptive users was substantially lower than for oral contraceptive pill users. However, Thai participants had similarly low cumulative pregnancy probabilities for both methods. Women receiving contraceptive counseling should be informed that their experience with a given method may differ from the average or typical-use pregnancy rates often discussed during contraceptive counseling. Tailored counseling is necessary for women to make informed choices. LEVEL OF EVIDENCE: II.

Day-specific pregnancy probability estimation in barrier contraceptive effectiveness trials.

We apply an extension of a statistical model developed in the fertility research setting to the barrier contraceptive trial setting to obtain estimates of the probability of pregnancy per cycle day in the presence or absence of barrier use among participants of a randomised trial of female barrier contraceptives. The per cycle day pregnancy curve for the barrier trial participants was similar to previously published results from a fertility study that included a precise indicator of ovulation day. In addition, our analysis showed strong contraceptive effects for the diaphragm. The proposed modelling approach should allow evaluation of the effects of other coitus-specific exposures on the chance of pregnancy in other prospective studies, including fertility studies.

Will microbicide trials yield unbiased estimates of microbicide efficacy?

OBJECTIVE: To evaluate the effect of adherence and condom use on apparent efficacy of microbicides. DESIGN: Hypothetical trial designs and scenarios. METHODS: Mathematical calculations of effectiveness. RESULTS: In a randomized trial of a candidate microbicide and a placebo, nonuse of the microbicide will result in underestimation of microbicide efficacy, with the magnitude of this difference between effectiveness and efficacy increasing directly with the level of microbicide nonuse. Adding condoms to the trial will not change this expected result as long as use of condoms and microbicide is independent, and microbicide use is the same in the trials with and without condoms. However, if microbicide use is lower in the trial with condoms, then effectiveness will be lower than in the trial without condoms, with the magnitude of the difference between effectiveness and efficacy being even greater. Moreover, condom and microbicide use may not be independent. If participants tend to use condoms rather than nothing, the trial result will more closely approximate microbicide efficacy. If, however, participants substitute condom use for microbicide use, then the expected estimate of effectiveness will less closely approximate microbicide efficacy and could be closer to or further away from the expected estimate of effectiveness than in the trial without condoms. In another trial design, where there is either simultaneous use of microbicide and condoms or no use of either (guaranteed when condoms are packaged with either a microbicidal or a placebo gel), expected effectiveness will fall short of microbicide efficacy. If nonuse is the same in a trial without condoms and a trial with microbicidally lubricated condoms, then the trial with condoms will produce an estimate of effectiveness that less closely approximates microbicide efficacy than would the trial without condoms. If there is less nonuse in the trial with condoms, then the expected estimate of effectiveness will more closely approximate microbicide efficacy and could be closer to or further away from the expected estimate of effectiveness than in the trial without condoms. CONCLUSIONS: Nonuse of a microbicide and use of condoms may seriously impair our ability to identify an effective microbicide.

Immunogenicity and protective efficacy of recombinant vaccine based on the receptor-binding domain of the Plasmodium vivax Duffy binding protein in Aotus monkeys.

Invasion of human erythrocytes by Plasmodium vivax requires interaction between Duffy binding protein (PvDBP) and the Duffy blood group antigen. The receptor-binding domain of PvDBP lies in a conserved N-terminal, cysteine-rich region, region II (PvRII). PvRII is a valuable malaria subunit vaccine candidate for asexual blood stages. We have evaluated in Aotus monkeys the immunogenicity and protective efficacy of recombinant PvRII formulated in Freund's and Montanide ISA720 adjuvants. Specific antibody titers were determined by an enzyme-linked immunosorbent assay after each of three doses of 50 microg of protein administered by the subcutaneous route. Immunization with PvRII formulated in Freund's adjuvant yielded higher antibody titers than immunization with the Montanide ISA720 formulation and offered partial protection. Although the Montanide ISA720 formulation was immunogenic, it did not provide any protection. Given the immunogenicity and partial protection observed, further studies are needed to optimize the PvRII vaccine formulation with adjuvants suitable for human use.

Monitoring a three-armed clinical trial with survival endpoints: Fisher's least significant difference approach.

Researchers have long recognized the importance of monitoring trials to determine whether to terminate a trial early or change a trial because of a substantial treatment effect. Fisher's least significant difference (LSD) procedure has been suggested by Proschan et al. [Proschan, M. A., Follmann, D. A., Geller, N. L. (1994). Monitoring multi-armed trials. Stat. Med. 13:1441-1452] to control the overall type I error rate for trials with three or more arms and survival endpoints. In this paper we propose an alternative Fisher's LSD interim monitoring procedure that uses the same adjusted significance levels for the pairwise tests as for the global test; it continues performing a global hypothesis test at looks subsequent to a look where a global null hypothesis was rejected. We also examine revised Proschan et al. approach that uses the O'Brien-Fleming two-armed trial boundaries for pairwise tests. A simulation study shows that compared to the approach proposed by Proschan et al., the procedure we propose is more powerful and produces overall type I error rates closer to the nominal values when all groups are truly equivalent. For the scenarios examined, the overall type I error rates and power of the proposed approach are virtually equivalent to those of the revised Proschan et al. approach.