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Interactive stories are a relatively newer form of storytelling with great potential to correct misinformation while increasing self-efficacy, which is crucial to vaccine acceptance. To address COVID-19 vaccine hesitancy and medical mistrust in young Black adults (BYA), we sought to adapt a pre-existing application ("app"; Tough Talks) designed to address HIV disclosure decision-making through choose-your-own adventure (CYOA) narratives and other activities. The adapted app (Tough Talks - COVID) uses a similar approach to situate COVID-19 vaccination decision-making within social contexts and to encourage greater deliberation about decisions. To inform content for the CYOA narratives, we conducted an online survey that was used to elicit the behavioral, cognitive, and environmental determinants influencing COVID-19 vaccine hesitancy among 150 BYA (ages 18-29) in Georgia, Alabama, and North Carolina. The survey included scenario questions that were developed with input from a youth advisory board to understand responses to peer and family influences. In two scenarios that involved discussions with family and friends about vaccination status, most respondents chose to be honest about their vaccination status. However, vaccinated individuals perceived more social pressure and stigma about not being vaccinated than unvaccinated respondents who were not as motivated by social pressure. Personal choice/agency in the face of perceived vaccine risks was a more common theme for unvaccinated respondents. Results suggest that relying on changing social norms alone may not impact barriers to vaccination in unvaccinated young adults without also addressing other barriers to vaccination such as concerns about autonomy and vaccine safety. Based on these findings, CYOA narratives in the app were adapted to include discussions with family and friends but also to touch on themes of personal choice as well as other topics that influence behaviors besides norms such as safety, side effects, and risk of COVID-19 in an evolving pandemic.

Background Despite international support for increasing access to contraceptives among adolescents, gaps in use still exist worldwide. Past research has identified barriers to use across all levels of the socioecological model including restrictive policies, a lack of youth friendly services, and knowledge gaps. This study was conducted to further identify influences on contraceptive use among adolescent girls in Nigeria in hopes of guiding future policies and programs. Methods In 2018, 12 focus group discussions (FGD) were conducted in three cities in Nigeria with young women ages 15–24 with the objective of determining what and who influence adolescents’ contraceptive seeking behaviors. A vignette structure was used to identify perceptions on injunctive and descriptive community norms that influence adolescent contraceptive behaviors. The FGDs were conducted by members of the University of Ibadan Centre for Population and Reproductive Health (CPRH) and analyzed by a researcher at the University of North Carolina-Chapel Hill’s Carolina Population Center using a thematic analysis approach. Results Participants identified community level resistance to sex and contraceptive use among unmarried adolescents though also acknowledged that these adolescent behaviors are still occurring despite established norms. Concerns about side effects and the preservation of fertility were frequently attached to contraceptive use and pointed to as a reason for community resistance to contraceptive use among this population. Participants saw peers, parents and partners as influencers on a girl’s decision to seek a method, though each were believed to play a different role in that decision. Conclusion The findings show that that despite barriers created by established injunctive norms, young women with a supportive social network can access contraceptive methods despite these barriers. By harnessing the influence of peers, partners and parents, the Nigerian family planning efforts can strive to improve the health and well-being of young people.

HPTN 065 utilized financial incentives to promote viral suppression among HIV-positive participants. Exit interviews were conducted in a sub-study of participants in Washington, DC and Bronx, NY. The present analyses explored lived experiences of social ties and stigma as individuals navigated the HIV care continuum, including gender differences in lived experiences. Using viral load data and informed by stages-of-change theory, participants were categorized into "Low-Adherers (n = 13)", "Action (n = 29)" and "Maintenance (n = 31)" stages. Secondary analyses of qualitative data were informed by grounded theory, and instances of social ties and stigma discussed by participants were quantified with descriptive statistics. Participants (N = 73) were mostly male (64%), African American (58%), with yearly income under $10,000 (52%). Low-adherers identified fewer, and sometimes more combative social ties than those in other adherence stages. Maintainers identified supportive ties as motivation for medication adherence (68%) but relied less on them for motivation than individuals in other adherence stages. Low-adherers described current experiences of stigma related to being diagnosed with HIV more than other adherence stages (23%). Individuals in Action reported stigma related to disclosing their HIV status to others (52%), while individuals in Maintenance mostly stigmatized others engaging in "risky" behaviors (32%). Findings suggest that women may perceive greater HIV stigma than men, perceive less supportive social ties, and were the majority of Low-adherers. Gender-informed approaches can facilitate community de-stigmatization of HIV, as African American women may be at greater risk of negative HIV health outcomes.

Growing evidence highlights an association between an imbalance in the composition and abundance of bacteria in the breast tissue (referred as microbial dysbiosis) and breast cancer in women. However, studies on the breast tissue microbiome have not been conducted in non-Hispanic Black (NHB) women. We investigated normal and breast cancer tissue microbiota from NHB and non-Hispanic White (NHW) women to identify distinct microbial signatures by race, stage, or tumor subtype. Using 16S rRNA gene sequencing, we observed that phylum Proteobacteria was most abundant in normal (n = 8), normal adjacent to tumor (normal pairs, n = 11), and breast tumors from NHB and NHW women (n = 64), with fewer Firmicutes, Bacteroidetes, and Actinobacteria. Breast tissues from NHB women had a higher abundance of genus Ralstonia compared to NHW tumors, which could explain a portion of the breast cancer racial disparities. Analysis of tumor subtype revealed enrichment of family Streptococcaceae in TNBC. A higher abundance of genus Bosea (phylum Proteobacteria) increased with stage. This is the first study to identify racial differences in the breast tissue microbiota between NHB and NHW women. Further studies on the breast cancer microbiome are necessary to help us understand risk, underlying mechanisms, and identify potential microbial targets.

Researchers and advocates have increasingly called for adolescent participation in clinical trials for new HIV prevention products, particularly adolescent girls in areas most affected by the epidemic. However, recent trials have highlighted the challenges for young women and adolescents to be able to effectively use new products that require daily dosing. This analysis provides a highly relevant context for this challenging environment by examining community members acceptability of adolescent girls' participation in clinical trials for new HIV prevention products. We conducted 41 in-depth interviews in Dar es Salaam, Tanzania and Pune, India with 22 key informants (KIs). Cultural perspectives on adolescent sexuality varied between countries, with KIs in Tanzania more readily acknowledging adolescent girls' sexual activity than KIs in India. KIs in both countries felt strongly adolescents must be well-informed about research concepts prior to participation, and emphasis should be given to preventative misconception. Despite concern in both countries that the trials might be seen as encouraging sexual behavior, KIs in Tanzania overwhelmingly supported adolescent inclusion, whereas KIs in India were more cautious. Involving adolescent girls in clinical trials for new HIV prevention products is potentially acceptable, although meaningful community engagement will be necessary.

Introduction Oral, vaginal and other pre-exposure prophylaxis (PrEP) products for HIV prevention are in various stages of development. Low adherence poses a serious challenge to successful evaluation in trials. In a previous study, we developed tools to screen for general adherence and specifically monitor intravaginal ring adherence within the context of HIV prevention clinical trials. This study aimed to further validate the screening tool and to adapt and provide initial psychometric validation for an oral pill monitoring tool. Materials and methods We administered a cross-sectional survey between June and October 2018 at a trial site located near Cape Town, South Africa, and another in Thika, Kenya, with 193 women who had experience using daily oral pills. We fit confirmatory factor analysis models on the screening tool items to assess our previously-hypothesized subscale structure. We conducted an exploratory factor analysis of oral PrEP monitoring items to determine the underlying subscale structure. We then assessed the construct validity of each tool by comparing subscales against each other within the current sample and against our original sample, from a study conducted in four sites in South Africa, including Cape Town. Results The screening tool structure showed moderate evidence of construct validity. As a whole, the tool performed in a similar way to the original sample. The monitoring tool items, which were revised to assess perceptions about and experiences using daily oral PrEP, factored into five subscales that showed moderate to good reliability. Four of the five subscales had a similar structure overall to the vaginal ring monitoring tool from which they were adapted. Conclusions Accurate measurement of HIV-prevention product adherence is of critical importance to the assessment of product efficacy and safety in clinical trials, and the support of safe and effective product use in non-trial settings. In this study, we provide further validation for these measures, demonstrating the screening tool’s utility in additional populations and adapting the monitoring tool’s utility for different HIV-prevention products.

In HIV prevention trials, male partners have influenced women’s ability to adhere to investigational products, including antiretroviral (ARV) containing vaginal rings. Validated scales can be useful tools to systematically measure complex constructs, such as those related to male partner engagement. Although multiple scales exist to assess physical, psychological and sexual violence within intimate relationships, fewer scales focus on supportive behaviors within these relationships. Our intervention involved development of a Healthy Relationship Assessment Tool (HEART) that assessed both positive and negative aspects of male partner involvement in women’s HIV prevention. We identified and refined 127 potential items, representing intimate partner violence, agency and social support. A structured survey, including potential items and other sociodemographic and behavioral variables was administered to former microbicide trial and non-trial participants. We conducted an exploratory factor analysis (EFA) to identify a reduced set of constructs and items to screen women who might experience social harms or benefits from vaginal ring use. We examined associations between constructs and with other survey variables to assess content and construct validity. In a subset of 10 women who participated in the survey and qualitative interviews, we used qualitative data to predict survey scores. We retained five constructs with theoretical relevance and good-to-strong reliability for the tool, including: Traditional Values; Partner Support; Partner Abuse & Control; Partner Resistance to HIV Prevention; and HIV Prevention Readiness. Predicted associations between HEART constructs, and correspondence between participants’ qualitative data and HEART scores were generally correct, while those between constructs and other sociodemographic variables were more mixed. Initial validation of the HEART tool was promising. The tool will be used during the CHARISMA pilot study at the Johannesburg MTN 025/HOPE site and validated as part of a randomized controlled trial of CHARISMA within a PrEP demonstration project. Beyond clinical trial settings, HEART could assist PrEP or antiretroviral treatment (ART) providers with an easy-to-administer tool to identify risk and tailor risk reduction, empowerment and adherence counseling for microbicides, PrEP or ART related services.

Long-acting injectable PrEP could offer an alternative to daily oral PrEP, improve adherence and protection, if found acceptable, safe and effective. HPTN 077 evaluated injectable cabotegravir safety, tolerability and pharmacokinetics among HIV-uninfected males and females in sequentially-enrolled cohorts of two dosing strategies. We compared acceptability of product attributes, prevention preferences and future interest in injectable PrEP (FIIP) by region, sex-at-birth, arm and cohort and used multivariable analysis to identify FIIP determinants. Baseline injectable PrEP preferences were higher in non-U.S. sites and increased in both regions over time. In multivariable models, FIIP was most strongly associated with acceptability of product attributes, was higher in non-U.S. sites and more altruistic participants. Treatment arm and report of pain were not associated with FIIP. Injectable acceptability was highest in non-U.S. sites. Preferences for injectable versus other PrEP methods were higher among U.S. males than females, but higher among males and females in non-U.S. settings. Electronic supplementary material The online version of this article (10.1007/s10461-020-02808-2) contains supplementary material, which is available to authorized users.

The stages of change (SOC) theory suggests individuals adapt incrementally to behaviors like adherence, requiring different strategies over the behavior change continuum. Offering financial incentives (FIs) is one strategy to motivate adherence. This qualitative sub-study examined adherence barriers and the role of FIs to increase viral suppression (VS) among HIV Prevention Trials Network (HPTN) 065 study participants categorized into SOC-related adherence stages based on changes from baseline to follow-up viral load tests. Of 73 participants, most were in Maintenance stage (n = 31), defined as having achieved VS throughout HPTN 065, or in Action stage (n = 29), defined as moving from virally unsuppressed to suppressed in 50% or more of tests. Only 13 were Low Adherers, having achieved VS in fewer than 50% of tests. The latter group faced substantial social and structural adherence barriers. Participants in the Action stage made positive changes to adherence routines to achieve VS. Those in Maintenance were less incentivized by FIs, as they were already committed. Results from this sub-study suggest FI effectiveness may vary across the SOC continuum, with greatest impact for those initiating antiretroviral or without explicit adherence routines. FIs may be insufficient to overcome strong social or structural barriers, and unnecessary for those intrinsically committed to remaining adherent.

This article describes the development of the Community Health clinic model for Agency in Relationships and Safer Microbicide Adherence intervention (CHARISMA), an intervention designed to address the ways in which gender norms and power differentials within relationships affect women's ability to safely and consistently use HIV pre-exposure prophylaxis (PrEP). CHARISMA development involved three main activities: (1) a literature review to identify appropriate evidence-based relationship dynamic scales and interventions; (2) the analysis of primary and secondary data collected from completed PrEP studies, surveys and cognitive interviews with PrEP-experienced and naïve women, and in-depth interviews with former vaginal ring trial participants and male partners; and (3) the conduct of workshops to test and refine key intervention activities prior to pilot testing. These steps are described along with the final clinic and community-based intervention, which was tested for feasibility, acceptability, and preliminary effectiveness in Johannesburg, South Africa.

Anal health and anal cancer are rarely addressed in HIV primary care. We sought to understand factors that impeded or promoted addressing anal health in HIV primary care from providers' perspectives. In this exploratory study, HIV primary care providers from the Mid-South region of the United States participated in brief individual interviews. We analyzed transcribed data to identify barriers and facilitators to addressing anal health. Our study sample included five physicians and four nurse practitioners. The data revealed a number of barriers such as perception of patient embarrassment, provider embarrassment, external issues such as time constraints, demand of other priorities, lack of anal complaints, lack of resources, and gender discordance. Facilitators included awareness, advantageous circumstances, and the patient-provider relationship. Anal health education should be prioritized for HIV primary care providers. Preventive health visits should be considered to mitigate time constraints, demands for other priorities, and unequal gender opportunities.

Background: Teaching–learning experience involving more than one health care discipline is a topic of great interest in the health sciences. Few such experiences are known in which medical students taught nursing students a clinical skill. Method: The authors evaluated the effect of fourth-year medical students teaching the correct use of a metered-dose inhaler (MDI) to bachelor of science nursing (BSN) students. An fourth-year medical student investigator taught BSN students the correct use of an MDI in individual, private educational sessions, approximately 10 minutes in length, in a large health sciences center. BSN students were scored in use of MDI preeducation and posteducation. Instruction included both discussion and demonstration by the M4S. Results: Among 20 BSN students, posteducation scores were markedly improved for total steps ( p < .0001), and six of nine individual steps for MDI use. Conclusion: Brief teaching–learning sessions are effective in teaching nursing students the correct use of MDI. [ J Nurs Educ. 2017;56(2):120–122.]

Background African American patients with uncontrolled diabetes living in medically underserved areas need effective clinic-based interventions to improve self-care behaviors. Text messaging (TM) and health coaching (HC) are among the most promising low-cost population-based approaches, but little is known about their comparative effectiveness in real-world clinical settings. Objective Use a pragmatic randomized controlled trial design to determine the comparative effectiveness of TM and HC with enhanced usual care (EC) in African American adults with uncontrolled diabetes and multiple chronic health conditions. Methods/design The Management of Diabetes in Everyday Life (MODEL) study is randomizing 646 patients (n = 581with anticipated 90% retention) to 3 intervention arms: TM, HC, and EC. Participants are African American adults living in medically underserved areas of the Mid-South, age ≥ 18, with uncontrolled diabetes (A1c ≥ 8), one or more additional chronic conditions, and who have a phone with texting and voicemail capability. Primary outcome measures: the general diet, exercise, and medication adherence subscales of the revised Summary of Diabetes Self-Care Activities questionnaire assessed at one year. Secondary outcomes: diabetes-specific quality of life, primary care engagement, and average blood sugar (A1c). The study will also assess heterogeneity of treatment effects by six key baseline participant characteristics. Conclusions We describe the design and methods of the MODEL study along with design revisions required during implementation in a pragmatic setting. This trial, upon its conclusion, will allow us to compare the effectiveness of two promising low-cost primary care-based strategies for supporting self-care behaviors among African Americans individuals with uncontrolled diabetes. ClinicalTrials.gov registration number: NCT02957513

Background Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. Methods and findings HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18–65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. Conclusions In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. Trial registration ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800., In a phase 2a trial, Raphael Landovitz and colleagues investigate the safety of injectable cabotegravir in HIV-uninfected people, Author summary Why was this study done? Daily oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine is highly effective in preventing HIV infection when taken as prescribed, but adherence challenges have compromised full effectiveness in some populations. Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor in development as a long-acting injectable preparation for HIV treatment and HIV prevention. HIV Prevention Trials Network study 077 (HPTN 077) aimed to establish the safety, tolerability, and pharmacokinetics of 2 dose/interval regimens of long-acting CAB in HIV-uninfected, low-risk individuals globally. What did the researchers do and find? Participants were randomized to active CAB or placebo. All participants received a 4-week daily oral lead-in of CAB or placebo, followed by a series of injections of CAB or placebo. Participants received either 800 mg as a split 2-ml injection every 12 weeks, or 600 mg as a single 3-ml injection every 8 weeks, after receiving 2 injections 4 weeks apart. We observed frequent injection site reactions (mostly injection site pain), and they were more common with CAB than placebo, but only led to discontinuation of injections in rare cases. No other safety concerns were noted. Pharmacokinetics, using target values from nonhuman primate simian/human immunodeficiency virus challenge prevention studies, support the 600 mg every 8 weeks dose, meeting prespecified targets. What do these findings mean? We found that CAB was generally well tolerated in HIV-uninfected males and females in diverse geographic locations. Injection site reactions, although frequent, did not deter continued dosing, albeit with short courses. Studies are ongoing to evaluate efficacy in at-risk populations and to further evaluate the safety of the 600 mg every 8 weeks dose.

Although significant progress has been made in improving breast cancer survival, disparities among racial, ethnic, and underserved groups still exist. The goal of this investigation is to quantify racial disparities in the context of breast cancer care, examining the outcomes of recurrence and mortality in the city of Memphis. Patients with a biopsy-proven diagnosis of breast cancer from January 1, 2002, through December 31, 2012, were obtained from the tumor registry. Black patients were more likely to have advanced (II, III, or IV) clinical stage of breast cancer at diagnosis versus white patients. Black breast cancer patients had a two times higher odds of recurrence (95% confidence interval: 1.4, 3.0) after adjusting for race and clinical stage. Black breast cancer patients were 1.5 times more likely to die (95% confidence interval: 1.2, 1.8), after adjusting for race; age at diagnosis; clinical stage; ER, PR, HER2 status; and recurrence. Black women with stages 0, I, II, and III breast cancer all had a statistically significant longer median time from diagnosis to surgery than white women. Black patients were more likely to have advanced clinical stages of breast cancer at diagnosis versus white patients on a citywide level in Memphis. Black breast cancer patients have higher odds of recurrence and mortality when compared with white breast cancer patients, after adjusting for appropriate demographic and clinical attributes. More work is needed to develop, evaluate, and disseminate interventions to decrease inequities in timeliness of care for breast cancer patients.

Objective We aimed to assess use of and interest in mobile health (mHealth) technology and in-person services for diabetes self-care in vulnerable populations. Methods We delivered a self-administered cross-sectional survey. Participants were recruited at two primary care practices (P1 and P2) with P1 located in a medically underserved area and P2 in an affluent suburb. Two-sample t-tests and chi-square tests were used with p Results Of 75 eligible patients, 60 completed the survey (80% response rate). P1 patients had significantly higher interest in three of five categories of in-person diabetes support services, one of four categories of health-related text messages (TM), and three of eight categories of mHealth applications ( p Discussion This study shows substantial patient interest in TM and mHealth applications for diabetes self-care and suggests that patients in underserved areas may have particularly high interest in using mHealth solutions in primary care. Younger patients and smartphone users were more likely to be interested in using applications to manage their diabetes. As more patients use smartphones, interest in using mHealth to support patient self-care and strengthen primary care infrastructure will continue to grow.

Results of recent microbicide and pre-exposure prophylaxis clinical trials have shown adherence to be a significant challenge with new HIV prevention technologies. As the vaginal ring containing dapivirine moves into two open label follow-on studies (HOPE/MTN-025 and DREAM) and other antiretroviral-based and multi-purpose prevention technology ring products advance through the development pipeline, there is a need for more accurate and reliable measures of adherence to microbicide ring products. We previously conducted a comprehensive landscape analysis to identify new technologies that could be applied to adherence measurement of vaginal rings containing antiretrovirals. To explore attitudes and perceptions towards the approaches that we identified, we conducted a survey of stakeholders with experience and expertise in microbicide and HIV prevention clinical trials. From May to July 2015 an electronic survey was distributed via email to 894 stakeholders; a total of 206 eligible individuals responded to at least one question and were included in the data analysis. Survey respondents were presented with various objective measures and asked about their perceived acceptability to trial participants, feasibility of implementation by study staff, usefulness for measuring adherence and ethical concerns. Methods that require no additional input from the participant and require no modifications to the existing ring product (i.e., measurement of residual drug or excipient, or a vaginal analyte that enters the ring) were viewed as being more acceptable to trial participants and more feasible to implement in the field. Respondents saw value in using objective measures to provide real-time feedback on adherence. However, approaches that involve unannounced home visits for sample collection or spot checks of ring use, which could provide significant value to adherence feedback efforts, were met with skepticism. Additional research on the acceptability of these methods to potential trial participants and trial staff is recommended.

Unique attributes of a longer-acting injectable would likely appeal to both existing injectable users and new clients, both for spacing and for limiting births, and allow health systems to operate more efficiently. Considerations for enhancing successful introduction of this potential new method include keeping the cost low, expanding access through community-based distribution, and training providers to improve practices about injectables in general., Background: More than 40 million women use injectable contraceptives to prevent pregnancy, and most current or previous injectable users report being satisfied with the method. However, while women may find injectables acceptable, they may not always find them accessible due to stock-outs and difficulties with returning to the clinic for reinjections. FHI 360 is spearheading efforts to develop a longer-acting injectable (LAI) contraceptive that could provide at least 6 months of protection against pregnancy. This article addresses systems-level considerations for the introduction of a new LAI. Methods: We conducted qualitative case studies in Kenya and Rwanda—two countries that have high levels of injectable use but with different service delivery contexts. Between June and September 2012, we conducted in-depth interviews with 27 service providers and 19 policy makers and program implementers focusing on 4 themes: systems-level barriers and facilitators to delivering LAI services; process for introducing an LAI; LAI distribution approaches; and potential LAI characteristics. We also obtained electronic feedback from 28 international family planning opinion leaders. Results: Respondents indicated strong interest in an LAI and thought it would appeal to existing injectable users as well as new family planning clients, both for spacing and for limiting births. Providers appreciated the potential for a lighter workload due to fewer follow-up visits, but they were concerned that fewer visits would also decrease their ability to help women manage side effects. The providers also appreciated the 1-month grace period for follow-up LAI injections; some seemed unaware of the latest international guidance that had increased the grace period from 2 weeks to 4 weeks for the currently available 3-month injectable. The majority of policy makers and program implementers were supportive of letting community health workers provide the method, but many nurses and midwives in Kenya had reservations about the approach. At the policy level, respondents indicated that obtaining regulatory approvals before introducing the new method could be costly and time-consuming. Manufacturing and procurement decisions could also affect cost and availability. Conclusions: Successful introduction of a potential longer-acting injectable may be enhanced by considering broader systemic issues, including managing cost to the health system and users, expanding access through community-based distribution, and training providers on the latest service delivery guidelines.

tudy Objectives The effect of chronic kidney disease (CKD) on warfarin has gained attention because of an increased risk of thromboembolism and an increased risk of bleeding associated with warfarin treatment in these patients. Data suggest that patients with reduced kidney function require lower warfarin doses; however, relatively few patients with end-stage renal disease (ESRD) were included in previous studies. The goal of this study was to evaluate warfarin dosing requirements and time to reach therapeutic international normalized ratio (INR) in patients with CKD stages 3–5 and ESRD compared with patients with normal kidney function (NKF). Methods A historical cohort was identified to evaluate warfarin response in 210 hospitalized adults with varying degrees of kidney function initiated or maintained on warfarin for 4 or more consecutive days including 49 patients with NKF (glomerular filtration rate [GFR] higher than 60 ml/min/1.73 m2), 44 with CKD stage 3, 27 with CKD stage 4/5, and 90 with ESRD. The average daily dose (ADD), time to achieve a therapeutic INR, and adverse effects were compared. Measurements and Main Results The ADD to maintain a therapeutic INR was 5.6 ± 1.7 mg in the NKF group, 4.3 ± 1.6 mg in CKD stage 3, 4.6 ± 1.9 mg in CKD stage 4/5, and 4.8 ± 1.9 mg in ESRD. The ADD was lower in CKD/ESRD patients compared with NKF patients (p=0.001), especially among whites. The time to reach a therapeutic INR in patients newly initiated on warfarin was significantly lower in the CKD/ESRD group when compared with the NKF group (p=0.02). No differences in bleeding episodes were observed during hospitalization or within 30 days of discharge in patients with CKD stage 3 or higher compared with patients with NKF. Conclusions Our findings suggest that CKD and ESRD patients require ~20% lower warfarin doses to maintain a therapeutic INR and may require less time to achieve a therapeutic INR compared with patients with NKF.

OBJECTIVE:: To estimate whether continuous combined oral contraceptive pill (OCP) use leads to higher continuation and lower pregnancy rates over 12 months than cyclic use in a developing country setting. METHODS:: We enrolled healthy women aged 18 to 30 years in Santo Domingo Dominican Republic. We randomly assigned women to cyclic or continuous use of OCPs. Participants made quarterly clinic visits for 12 months. During follow-up we reviewed OCP adherence and continuation side effects and bleeding and we tested for pregnancy. RESULTS:: We enrolled 358 women (mean age 22.7 years) and 335 (93.6%) completed the study. In intent-to-treat analyses 77.6% of the continuous use group and 71.7% of the cyclic group continued OCPs at 12 months (P=.21). The main reason for OCP discontinuation in both groups was running out of OCPs or forgetting. Across all visits 26.1% of women in the continuous use group and 22.3% of women in the cyclic group ever reported missing three or more OCPs in the past month (P=.43). In multivariable analyses regimen was not associated with discontinuation but both previous birth and perceived ease of use of OCPs decreased risk of discontinuation whereas desire for reduced menstruation increased risk of discontinuation. Although more women reported amenorrhea or infrequent bleeding in the continuous use group more women in the cyclic group found their bleeding patterns acceptable. Bleeding was not associated with discontinuation in multivariable analyses. Pregnancy rates at 12 months were similar (16.2% continuous and 17.4% cyclic). CONCLUSIONS:: Continuous and cyclic OCP regimens were associated with similar 12-month continuation and pregnancy rates. Few factors predicted OCP discontinuation or pregnancy. CLINICAL TRIAL REGISTRATION:: ClinicalTrials.gov www.clinicaltrials.gov NCT00570440. LEVEL OF EVIDENCE:: I.

Under-representation of female adolescents in HIV clinical trials may inhibit their access to future prevention technologies. Domestic violence, broadly defined as violence perpetrated by intimate partners and/or family members, may affect trial participation. This study describes violence in the lives of adolescents and young women in Tanzania, explores use of the Women's Experience with Battering (WEB) Scale to measure battering, and examines the associations between battering and socio-demographic and HIV risk factors. Community formative research (CFR) and a mock clinical trial (MCT) were conducted to examine the challenges of recruiting younger (15-17) versus older (18-21) participants into HIV prevention trials. The CFR included qualitative interviews with 23 participants and there were 135 MCT participants. The WEB was administered in both the CFR and MCT. Nineteen CFR participants experienced physical and/or sexual violence and 17 % scored positive for battering. All married participants reported partner-related domestic violence, and half scored positive for battering. Many believed beatings were normal. None of the single participants scored positive on battering, but one-third reported abuse by relatives. Among MCT participants, 15 % scored positive for battering; most perpetrators were relatives. Younger participants were more likely to report battering. Adolescents experienced high rates of domestic violence and the WEB captured battering from both partners and relatives. The level of familial violence was unexpected and has implications for parental roles in study recruitment. Addressing adolescent abuse in HIV prevention trials and in the general population should be a public health priority.

High effectiveness, predictable return to fertility, and a single, prepackaged, disposable delivery system ranked high. Side effects were generally acceptable to women if they did not last long or disrupt daily activities. Cost was considered important for providers but not so much for most potential users., Background: Between 1995 and 2005, injectable use doubled worldwide. However, discontinuation rates remain high, partly because of side effects but also because of missed appointments for reinjection. A longer-acting injectable (LAI) may improve compliance by reducing the required number of reinjection visits, thereby reducing unintentional discontinuation. This study examined acceptability of LAI characteristics comprising the target product profile (TPP). Methods: In 2012, we conducted qualitative case studies in Kenya and Rwanda, consisting of 19 focus group discussions (FGDs) with 177 current, previous, or never users of injectables and 46 in-depth interviews (IDIs) with providers, program implementers, and policy makers. FGDs and IDIs assessed current injectable experiences; attitudes toward potential LAI products; and perceptions of TPP attributes, including ranking preferences for the most and least important characteristics. In addition, we obtained completed electronic surveys from 28 international family planning opinion leaders about the perceived need for an LAI, important product characteristics, and challenges to LAI development or introduction. Results: Many FGD participants and interviewees spontaneously expressed strong interest in an LAI, but there was some variation in TPP preferences. The majority of participants ranked effectiveness as the most important TPP attribute. Providers were generally more concerned about side effects than potential users; some potential users suggested that side effects were related less to the product than to their own body chemistry and that side effects were acceptable as long as they did not last a long time or disrupt daily activities. Women and providers, especially in Kenya, preferred a method with a predictable return to fertility. Some participants associated amenorrhea with delayed or reduced fertility. Most women and providers preferred delivery of the LAI in a single, prepackaged, disposable injection system to facilitate injections by providers and to reduce the risk of pain or discomfort for women. While providers and policy makers ranked cost as one of the most important issues, it was among the least important issues for most potential users. Many Kenyan, but few Rwandan, participants appeared willing to pay for an LAI, with some presuming cost savings from reduced menstruation and fewer clinic visits. Conclusions: Some TPP preferences for an LAI have implications for product development decisions about formulation, delivery mechanism, or presentation, while others point to the need for tailored communication and counseling approaches to ensure acceptability and adherence within clinical trials and beyond.

The HPTN 065 (TLC-Plus) study tested the feasibility and effectiveness of using financial incentives (FIs) to increase linkage to care (L2C) among individuals with newly diagnosed HIV and those out of care in the Bronx, NY and Washington, DC. Qualitative data collection with a subset of participating patients and staff focused on experiences with and attitudes about the FI intervention. Semi-structured interviews were conducted with 15 patients and 14 site investigators. Four focus group discussions were conducted with a total of 15 staff members. The use of FIs for L2C was generally viewed favorably. Patients were grateful and benefited financially, but sites had some challenges implementing the program. Challenges included the timing and sensitive introduction of the intervention immediately after an HIV diagnosis, negative attitudes towards paying people for health behaviors, and the existence and strength of existing linkage programs. Future programs should consider optimal timing and presentation of FIs.

Purpose:In some recipients, significant weight gain occurs after kidney transplantation. Weight gain is associated with poor outcomes, particularly increased cardiovascular risk. In this study, we characterized changes in body mass index and body fat mass and compared them based on gender and race.Methods:Fifty-two kidney transplant recipients (aged ≥18 years old, 50% men, 58% African American) were enrolled into a prospective study. Body mass index and body fat mass were measured at baseline and 12 months posttransplant. Body fat mass was determined by dual-energy X-ray absorptiometry.Results:The mean increase in body weight was 3.7kg at 12 months; 36.5% (n=19) gained at least 10% of their baseline body weight. Body mass index, percentage of total body fat, and trunk fat were significantly increased. In subgroups, women and African American showed significant increases in body mass index and body fat measures. More participants were classified as obese based on total body fat compared to body mass index. Calories from fat were significantly increased at 12 months and associated with increased body mass index, total body fat, and trunk fat. Days of physical activity were significantly increased.Conclusion:Both body mass index and total body fat mass were significantly increased at 12 months following kidney transplantation, especially for women and African Americans. Importantly, more participants were classified as obese based on total body fat compared to body mass index. Relevant nutrition and physical intervention should be provided, and both body mass index and body fat mass should be evaluated when monitoring weight gain.

Researchers have raised concerns that microbicide use during clinical trials would displace condom use. We sought to understand whether condom use changed for participants in a microbicide clinical trial in Pune, India, to understand whether condom shifts were a legitimate concern. We hypothesize that women participating in a microbicide clinical trial in Pune, India, were more likely, on average, to report condom use at follow-up. We further hypothesize that men, whose female partners participated in a microbicide clinical trial were more likely, on average, to report condom use at follow-up. The outcome measure for reported condom use was a dichotomous variable to indicate whether or not the participant had used a male or female condom with a sexual partner since 2 months before enrollment or since the last survey, depending on the visit. Data are from semi-structured interviews at baseline, 2 months, 4 months, and 6 months with HPTN 059 clinical trial participants (100 women and 57 male partners). We used generalized estimating equations with a logit link function, exchangeable correlation, and a binomial family to model condom use. The odds of condom use for clinical trial women increased from baseline to 6 months by a factor of 3.7 (95% CI: 1.84-7.63) and the change in odds of condom use for clinical trial men from baseline to 6 months increased by a factor of 2.58 (95% CI: 1.37-4.85). We found concerns about microbicide use displacing condom use were not merited in this study population. The percent of participants reporting condom use declined from 4 to 6 months, suggesting that increases in condom use may only be during active study participation. Information about clinical trial factors that enabled these men and women to enact this important HIV prevention behavior is needed to develop interventions.

In the last decade, three randomized controlled trials in Kenya, South Africa, and Uganda have shown that medical male circumcision (MMC) reduces the sexual transmission of HIV from women to men. Objectives of this assessment were to measure acceptability of adult MMC and circumcision of children to inform policies regarding whether and how to promote MMC as an HIV prevention strategy. This mixed-method study, conducted across four Ugandan districts, included a two-stage household survey of 833 adult males and 842 adult females, focus group discussions, and a health provider survey. Respondents' acceptability of MMC was positive and substantial after being informed about the results of recent randomized trials. In uncircumcised men, between 40% and 62% across the districts would consider getting circumcised. Across the four districts between 60% and 86% of fathers and 49% and 95% of mothers were supportive of MMC for sons. Widespread support exists among men and women in this study for promoting MMC as part of Uganda's current 'ABC + ' HIV prevention strategy.

HIV prevention trials typically randomize thousands of participants to active or control intervention arms, with regular (e.g. monthly) clinic visits over one or more years of follow-up. Because HIV infection rates are often lower than 3 per 100 person-years even in high prevalence settings, tens of thousands of clinic visits may take place before the number of infections required to achieve adequate study power has been observed. In addition to clinical outcomes, the multitude of study visits provides an opportunity to assess adherence and related participant behaviors in great detail. These data may be used to refine counseling messages, gain insight into patterns of behavior, and perform supporting analyses in an attempt to obtain more precise estimates of treatment efficacy. Exploratory analyses were performed to assess how our understanding of participant behaviors and their relationships to biological outcomes in two recent prevention trials might have been impacted had the frequency of routine behavioral data collection been reduced from monthly to just months 1, 3, 6, 9, and 12. Results were comparably informative in the reduced case, suggesting that unnecessarily extensive amounts of routine behavioral data may be collected in these trials.

BackgroundLow adherence in recent HIV prevention clinical trials highlights the need to better understand, measure, and support product use within clinical trials. Conventional self-reported adherence instruments within HIV prevention trials, often relying on single-item questions, have proven ineffective. While objective adherence measures are desirable, none currently exist that apply to both active and placebo arms. Scales are composed of multiple items in the form of questions or statements that, when combined, measure a more complex construct that may not be directly observable. When psychometrically validated, such measures may better assess the multiple factors contributing to adherence/non-adherence. This study aimed to develop and psychometrically evaluate tools to screen and monitor trial participants' adherence to HIV prevention products within the context of clinical trial research.Methods and findingsBased on an extensive literature review and conceptual framework, we identified and refined 86 items assessing potential predictors of adherence and 48 items assessing adherence experience. A structured survey, including adherence items and other variables, was administered to former ASPIRE and Ring Study participants and similar non-trial participants (n = 709). We conducted exploratory factor analyses (EFA) to identify a reduced set of constructs and items that could be used at screening to predict potential adherence, and at follow-up to monitor and intervene on adherence. We examined associations with other variables to assess content and construct validity. The EFA of screener items resulted in a 6-factor solution with acceptable to very good internal reliability (α: .62-.84). Similar to our conceptual framework, factors represent trial-related commitment (Distrust of Research and Commitment to Research); alignment with trial requirements (Visit Adherence and Trial Incompatibility); Belief in Trial Benefits and Partner Disclosure. The EFA on monitoring items resulted in 4 Product-specific factors that represent Vaginal Ring Doubts, Vaginal Ring Benefits, Ring Removal, and Side Effects with good to very good internal reliability (α = .71-.82). Evidence of content and construct validity was found; relationship to social desirability bias was examined.ConclusionsThese scales are easy and inexpensive to administer, available in several languages, and are applicable regardless of randomization. Once validated prospectively, they could (1) screen for propensity to adhere, (2) target adherence support/counselling, and (3) complement biomarker measures in determining true efficacy of the experimental product.

Vitamin D deficiency may have implications for cardiovascular health. The purpose of this study was to determine the relationship of 25-hydroxyvitamin D (25[OH]D) to cholesterol and lipoprotein particles and to determine whether increasing 25(OH)D through ultraviolet (UV) irradiation impacted on these parameters in healthy young men and women. This was a randomized trial of 51 adults exposed to suberythemal doses of whole-body irradiation using UV lamps that emitted UV-A and UV-B radiation, compared with a control group, twice weekly for 12 weeks. 25-Hydroxyvitamin D, cholesterol, and lipoprotein subfractions were measured at baseline and after 12 weeks. There was a significant (P < .03) positive association between 25(OH)D and apolipoprotein A-I (Apo A-I) and lipoprotein A-I (Lp A-I). The ratio of low-density lipoprotein to high-density lipoprotein was significantly (P < or = .044) negatively correlated with 25(OH)D levels. The levels of 25(OH)D increased significantly in the treated compared with control group (P < .05). Overall, there were no significant differences between the treated and control groups in any lipoproteins or apolipoproteins after administration of UV irradiation. Subgroup analysis for Apo A-II confined to those with 25(OH)D insufficiency (25[OH]D

The purpose of this study is to assess the predictive value of proteinuria and creatinine clearance (CrCl) in relation to mortality in patients with spinal cord injury.Computerized medical records covering 6 to 11 years were reviewed in 2004 to determine all-cause mortality. Long-term survival was assessed by means of Kaplan-Meier analysis. Multiple and stepwise Cox proportional hazards models were used to identify risk factors for mortality. The dependent variable was duration of survival in months. Potential predictors included proteinuria, CrCl, age, duration and type of injury, type of bladder management, ethnicity, diabetes mellitus, hypertension, coronary artery disease, hematocrit, serum albumin level, and serum cholesterol level.With the Cox model, proteinuria with protein of 500 mg/d or greater (hazard ratio [HR], 2.98), CrCl less than 60 mL/min (1.00 mL/s; HR, 3.89), or both (HR, 7.86) were associated independently with increased mortality. When added individually to the base Cox model, bladder catheter use (HR, 1.70) and age (HR, 1.05) also were independently predictive of time to death. Patients with preserved CrCl (or=60 mL/min) and no proteinuria (protein500 mg/d) had a significantly greater duration of survival compared with patients with proteinuria (proteinor= 500 mg/d), decreased CrCl (60 mL/min), or both (median survival, 120, 86, 87, and 47 months, respectively; P0.0001). There was no significant difference in survival in patients with proteinuria (proteinor= 500 mg/d) and preserved CrCl (or=60 mL/min) compared with those with no proteinuria (protein500 mg/d) and decreased CrCl (60 mL/min; P = 0.90). However, those with both proteinuria and decreased CrCl had significantly worse survival compared with those with only 1 condition (P0.01). Kidney disease was associated with an increase in both cardiovascular and noncardiovascular mortality.The presence of either proteinuria with protein of 500 mg/d or greater or CrCl less than 60 mL/min is associated independently with increased mortality in the chronic spinal cord injury population. The presence of both conditions further increases this risk.

The concept of acceptability involves a complex set of individual, couple and socio-cultural factors. Within a specific focus on microbicides, this article sets forth the relevant behavioral issues demanding attention as scientists and product developers strive to identify microbicides that will be used in a sustained, long-term fashion to prevent HIV/AIDS. The paper re-conceptualizes long-term acceptability within the ARRM framework, reviews the basic issues and research related to microbicide acceptability, discusses couple relationships (especially the nature of intimate relationships), and identifies related gender and power factors. The importance of the cultural context within various international settings pervades all of these issues. Finally, a set of challenges is discussed for those contemplating such research.

Objectives. We analyzed qualitative and quantitative data for 98 HIV-negative, low-risk women in Malawi, Zimbabwe, India, and Thailand who participated in a safety and acceptability study of BufferGel, a vaginal microbicide to determine the across-country acceptability of vaginal microbicides among women and their partners. Methods. Quantitative survey data were collected at 7 and 14 days after use among enrolled women, and exit interviews were conducted with women and their partners in separate focus group discussions. Results. Acceptability was high in all sites (73% of women approved of the microbicide). Women in Africa, where HIV infection rates are highest, were virtually unanimous in their desire for such a product, suggesting that an individual’s perception of being at risk for HIV will outweigh concerns about side effects, problems applying a product, or other factors, when products are shown to be efficacious. But men and women reported that use, which was kept secret from an intimate partner, would be difficult and might “break the trust” of a relationship. Conclusions. Acceptability research across diverse settings through all stages of microbicide research, development, and postlicensure dissemination can help maximize acceptability and use.

Qualitative and quantitative changes in intraluminal bile acid composition may alter cholesterol absorption and synthesis and LDL receptor expression. In a randomized crossover design outpatient study, 12 adults aged 24-36 years took 15 mg/kg/day ursodeoxycholic acid (UDCA) or no bile acid supplement (control) for 20 days while being fed a controlled diet (AHA Step II). A liquid meal of defined composition was then given and luminal samples collected. Cholesterol absorption and cholesterol fractional synthetic rate (FSR) were assessed by stable isotopic methods. With UDCA treatment, bile was enriched significantly (P < 0.0001) to 40.6 +/- 2.6% (mean +/- SEM) compared with 2.2 +/- 2.6% for controls. Regardless, plasma total, HDL, and LDL cholesterol were unchanged with UDCA treatment. Intraluminal cholesterol solubilized in the aqueous phase during the entire collection was decreased (P = 0.012) in UDCA-treated subjects (101.0 +/- 7.2 mg/ml/120 min) compared with controls (132.5 +/- 7.2 mg/ml/120 min.). Percent micellar cholesterol was increased in UDCA-treated versus controls after meal ingestion. No changes were found in cholesterol absorption, FSR, or LDL receptor mRNA with UDCA treatment compared with controls. Thus, despite marked enrichment in luminal bile with UDCA and decreased cholesterol solubilization, no differences in cholesterol absorption or metabolism are found when diet and genetic differences in absorption are carefully controlled.

Background: Identification of risks for development of ventilator-associated pneumonia (VAP), which might be identified early after injury, would allow for prognostic estimates and targeting of high-risk cohorts for clinical trials of preventive strategies. This study was performed to develop an equation that can be applied to estimate the probability of pneumonia based on parameters collected in the early postinjury interval. Methods: Over a 28-month period, patient admissions were reviewed for mechanism and severity of injury, patterns of injury, shock, and need for emergent intubation. Early deaths (

Background HPTN 065 (TLC-Plus) evaluated the feasibility and effectiveness of providing quarterly $70 gift card financial incentives to HIV-infected patients on antiretroviral therapy (ART) to encourage ART adherence and viral suppression, and represents the largest study to-date of a financial incentive intervention for HIV viral suppression. A post-trial qualitative substudy was undertaken to examine acceptability of the financial incentives among those receiving and implementing the intervention. Methods Between July and October 2013, semi-structured interviews were conducted with 72 patients and 12 investigators from 14 sites; three focus groups were conducted with 12 staff from 10 sites. Qualitative data collection elicited experiences with and attitudes about the intervention, including philosophical viewpoints and implementation experiences. Transcripts were analyzed in NVivo 10. Memos and matrices were developed to explore themes from different participant group perspectives. Results Patients, investigators, and staff found the intervention highly acceptable, primarily due to the emotional benefits gained through giving or receiving the incentive. Feeling rewarded or cared for was a main value perceived by patients; this was closely tied to the financial benefit for some. Other factors influencing acceptability for all included perceived effectiveness and health-related benefits, philosophical concerns about the use of incentives for health behavior change, and implementation issues. The termination of the incentive at the end of the study was disappointing to participants and unexpected by some, but generally accepted. Conclusion Positive experiences with the financial incentive intervention and strategies used to facilitate implementation led to high acceptability of the intervention, despite some reluctance in principle to the use of incentives. The findings of this analysis provide encouraging evidence in support of the acceptability of a large-scale financial incentive intervention for HIV viral suppression in a clinical setting, and offer valuable lessons for future applications of similar interventions.

Methylprednisolone (MP) disposition was evaluated in 20 individuals who participated in an ongoing randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of MP in the treatment of acute respiratory distress syndrome (ARDS). MP (1 mg/kg) was given as a loading infusion over 30 minutes followed by a 1 mg/kg/day continuous i.v. infusion. Patients were switched to oral MP upon restoration of oral intake. MP plasma concentrations (n = 110) were determined using a specific HPLC method. Population pharmacokinetic analysis was performed using nonlinear mixed-effects models, implemented in NONMEM, version V. MP plasma concentration data were described by a one-compartment open model with a time-dependent, non-linear increase in the clearance (CL) of MP during the course of therapy. Initial clearance of MP (CLo) in ARDS patients at the start of therapy increased to a maximal value (CLmax) after approximately 7 days. The estimate of CLmax was similar to the CL of MP in healthy individuals reported previously. Population mean estimates (+/- SE) of parameters in the model were as follows: CLo = 13.2 +/- 2.4 L/h, CLmax = 25.0 +/- 3.6 L/h, time of half-maximal increase in CL (T50) = 41.1 +/- 8.2 h, gamma (Hill coefficient) = 3.8 +/- 0.6, and volume of distribution (Vd) = 137 +/- 30.2 L. Disease progression indices and patient demographics were evaluated as covariates, and no significant correlation was found. Means (+/- SD) of plasma protein binding differed between healthy individuals (72% +/- 4%) and ARDS patients (46% +/- 11%) (p < 0.001). The pharmacokinetics of MP in ARDS patients has not been described previously.

In uncontrolled studies, noninvasive positive pressure ventilation (NPPV) was found useful in avoiding endotracheal intubation in patients with acute respiratory failure (ARF) caused by severe community-acquired pneumonia (CAP). We conducted a prospective, randomized study comparing standard treatment plus NPPV delivered through a face mask to standard treatment alone in patients with severe CAP and ARF. Patients fitting the American Thoracic Society criteria for severe CAP were included in presence of ARF (refractory hypoxemia and/or hypercapnia with acidosis). Exclusion criteria were: severe hemodynamic instability, requirement for emergent cardiopulmonary resuscitation, home mechanical ventilation or oxygen long-term supplementation, concomitant severe disease with a low expectation of life, inability to expectorate or contraindications to the use of the mask. Fifty-six consecutive patients (28 in each arm) were enrolled, and the two groups were similar at study entry. The use of NPPV was well tolerated, safe, and associated with a significant reduction in respiratory rate, need for endotracheal intubation (21% versus 50%; p = 0.03), and duration of intensive care unit (ICU) stay (1.8 +/- 0.7 d versus 6 +/- 1.8 d; p = 0.04). The two groups had a similar intensity of nursing care workload, time interval from study entry to endotracheal intubation, duration of hospitalization, and hospital mortality. Among patients with chronic obstructive pulmonary disease (COPD), those randomized to NPPV had a lower intensity of nursing care workload (p = 0.04) and improved 2-mo survival (88.9% versus 37.5%; p = 0.05). We conclude that in selected patients with ARF caused by severe CAP, NPPV was associated with a significant reduction in the rate of endotracheal intubation and duration of ICU stay. A 2-mo survival advantage was seen in patients with COPD.

Ineffective lung repair in patients with unresolving acute respiratory distress syndrome (ARDS) is accompanied by progressive fibroproliferation, inability to improve lung injury score (LIS), progressive multiple organ dysfunction syndrome (MODS), and an unfavorable outcome. Our aim was to investigate the relationship between fibrogenesis, pulmonary and extrapulmonary organ dysfunction, and outcome during the natural course of ARDS and in response to prolonged methylprednisolone treatment. We investigated 29 patients with ARDS. We obtained serial measurements of plasma and BAL procollagen aminoterminal propeptide type I (PINP) and type III (PIIINP) levels and components of the lung injury score (LIS) and MODS score. A reduction in LIS greater than one point from day 1 to day 7 of ARDS divided patients in improvers (group 1, n = 7) and nonimprovers (n = 22). Nonimprovers included those who were recruited (day 9 +/- 3 of ARDS) into a prospective, randomized, double-blind, placebo-controlled trial investigating prolonged methylprednisolone therapy in unresolving ARDS (group 2, n = 17), and those who died (all by day 10 of ARDS) prior to meeting eligibility criteria for the randomized trial (group 3, n = 5). On day 1 of ARDS, plasma PINP or PIIINP levels were elevated in all patients. By day 7 of ARDS, mean plasma PINP or PIIINP levels were unchanged in group 1 but increased significantly in group 2 (p = 0. 0002) and group 3 (p = 0.03). On day 7, patients with plasma PINP levels less than 100 ng/ml were 2.5 times more likely to survive (95% CI: 0.855-7.314), and patients with plasma PIIINP levels greater than 25 ng/ml were nine times more likely to die (95% CI: 1. 418-55.556). In group 2, patients taking placebo (n = 6) had no change in plasma PINP or PIIINP levels over time, while patients treated with methylprednisolone (n = 11) had a rapid and sustained reduction in mean plasma and bronchoalveolar lavage (BAL) PINP and PIIINP levels. By day 3 of treatment, mean plasma PINP and PIIINP levels (ng/ml) decreased from 100 +/- 9 to 45 +/- 8 (p = 0.0001) and 31 +/- 3 to 12 +/- 3 (p = 0.0008), respectively. After 8 to 15 d of methylprednisolone, mean BAL PINP and PIIINP levels (ng/ml) decreased from 63 +/- 25 to 6 +/- 23 (p = 0.002) and 42 +/- 5 to 10 +/- 3 (p = 0.003), respectively. Estimated partial correlation coefficients indicated that as plasma PINP and PIIINP levels decreased over the first 7 d of methylprednisolone treatment, positive end-expiratory pressure, creatinine, bilirubin, and temperature also decreased, while PaO2:FIO2 increased. In early ARDS, plasma PINP and PIIINP levels are elevated and continue to increase over time in those not improving. Among nonimprovers, those randomized to prolonged methylprednisolone treatment had a rapid and significant reduction in plasma and BAL aminoterminal propeptide levels and similar changes in lung injury and MODS scores. These findings provide additional evidence of an association between biological efficacy and physiologic response during prolonged methylprednisolone treatment of unresolving ARDS.

Objective To identify reasons for non-use of modern family planning in Rwanda, to examine specific barriers to contraception, and to explore psychosocial factors influencing modern contraceptive use. Methods In total, 637 in-union, parous, and non-pregnant women aged 21–49 years participated in a cross-sectional community-based survey in 5 districts. In-depth interviews (IDIs) were conducted with 54 women and 27 male partners. Multivariate logistic regression examined correlates of current non-use. IDI transcripts were analyzed independently and compared thematically with survey findings. Results Overall, 50% of survey respondents were using a modern method. Fertility- and partner-related variables were key correlates of non-use. The most commonly reported reasons for non-use were related to perceived fecundity. Men were mostly supportive of contraceptive use and had an important role in a woman’s decision to use contraception. Women’s IDIs revealed misperceptions about fertility leading to gaps in contraceptive coverage, particularly postpartum. Those IDIs also highlighted how provider practices, including screening for pregnancy through direct observation of menses, may hamper contraceptive use. Conclusion Programmatic recommendations include increasing information efforts aimed at men; developing effective messages about postpartum risk of pregnancy and training providers on postpartum contraceptive eligibility and needs; and reinforcing use of alternative pregnancy-screening methods.

Background The explicit use of theory in research helps expand the knowledge base. Theories and models have been used extensively in HIV-prevention research and in interventions for preventing sexually transmitted infections (STIs). The health behavior field uses many theories or models of change. However, educational interventions addressing contraception often have no stated theoretical base. Objectives Review randomized controlled trials (RCTs) that tested a theoretical approach to inform contraceptive choice; encourage contraceptive use; or promote adherence to, or continuation of, a contraceptive regimen. Search methods Through June 2013, we searched computerized databases for trials that tested a theory-based intervention for improving contraceptive use (MEDLINE, POPLINE, CENTRAL, PsycINFO, ClinicalTrials.gov, and ICTRP). Previous searches also included EMBASE. For the initial review, we wrote to investigators to find other trials. Selection criteria Trials tested a theory-based intervention for improving contraceptive use. We excluded trials focused on high-risk groups and preventing sexually transmitted infections or HIV. Interventions addressed the use of one or more contraceptive methods for contraception. The reports provided evidence that the intervention was based on a specific theory or model. The primary outcomes were pregnancy, contraceptive choice or use, and contraceptive adherence or continuation. Data collection and analysis The primary author evaluated abstracts for eligibility. Two authors extracted data from included studies. For the dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) with 95% CI was calculated using a fixed-effect model. Cluster randomized trials used various methods of accounting for the clustering, such as multilevel modeling. Most reports did not provide information to calculate the effective sample size. Therefore, we presented the results as reported by the investigators. No meta-analysis was conducted due to differences in interventions and outcome measures. Main results We included three new trials for a total of 17. Ten randomly assigned individuals and seven were cluster-randomized. Eight trials showed some intervention effect. Two of 12 trials with pregnancy or birth data showed some effect. A theory-based group was less likely than the comparison group to have a second birth (OR 0.41; 95% CI 0.17 to 1.00) or to report a pregnancy (OR 0.24 (95% CI 0.10 to 0.56); OR 0.27 (95% CI 0.11 to 0.66)). The theoretical bases were social cognitive theory (SCT) and another social cognition model. Of 12 trials with data on contraceptive use (non-condom), six showed some effect. A theory-based group was more likely to consistently use oral contraceptives (OR 1.41; 95% CI 1.06 to 1.87), hormonal contraceptives (reported relative risk (RR) 1.30; 95% CI 1.06 to 1.58) or dual methods (reported RR 1.36; 95% CI 1.01 to 1.85); to use an effective contraceptive method (reported effect size 1.76; OR 2.04 (95% CI 1.47 to 2.83)) or use more habitual contraception (reported P < 0.05); and were less likely to use ineffective contraception (OR 0.56; 95% CI 0.31 to 0.98). Theories and models included the Health Belief Model (HBM), SCT, SCT plus another theory, other social cognition, and motivational interviewing (MI). For condom use, a theory-based group had favorable results in 5 of 11 trials. The main differences were reporting more consistent condom use (reported RR 1.57; 95% CI 1.28 to 1.94) and more condom use during last sex (reported results: risk ratio 1.47 (95% CI 1.12 to 1.93); effect size 1.68; OR 2.12 (95% CI 1.24 to 3.56); OR 1.45 (95% CI 1.03 to 2.03)). The theories were SCT, SCT plus another theory, and HBM. Nearly all trials provided multiple sessions or contacts. SCT provided the basis for seven trials focused on adolescents, of which five reported some effectiveness. Two others based on other social cognition models had favorable results with adolescents. Of six trials including adult women, five provided individual sessions. Some effect was seen in two using MI and one using the HBM. Two based on the Transtheoretical Model did not show any effect. Authors' conclusions Eight trials provided evidence of high or moderate quality. Family planning researchers and practitioners could adapt the effective interventions, although most provided group sessions for adolescents. Three were conducted outside the USA. Clinics and low-resource settings need high-quality evidence on changing behavior. Thorough use of single theories would help in identifying what works, as would better reporting on research design and intervention implementation.

Decreased heart rate variability (HRV) occurs with physical and psychological disorders and is a predictor of cardiac and all-cause mortality. This study was the first of which we are aware to examine and report the relationship between military sexual trauma (MST) and HRV measures. In a historical cohort study of female veterans with (n = 27) and without (n = 99) MST who received Holter and electrocardiogram evaluation at a Veteran Affairs medical center during 2007-2010, we examined the relationship between MST and the standard deviation of all R-R intervals (SDNN) and the square root of the mean of the sum of the squares of differences between adjacent R-R intervals (RMSSD). Female veterans with MST were younger, p = .002, frequently had a probable posttraumatic stress disorder diagnosis, 80% versus 15%, p =.0001, and had lower SDNN, p = .0001, and RMSSD, p = .001, than those without MST. The SDNN and RMSSD of a 25-year-old female veteran with MST were comparable to that of female veterans aged 69 to 81 years without MST. Further research is needed to evaluate relationships between MST and HRV measures.

Guidelines recommend multiple types of cytologic and tissue samplings in the diagnosis of lung cancer by bronchoscopy, but differences of opinion exist as to the relative value of bronchial brushings and endobronchial or transbronchial biopsies. Our objective was to determine concordance of these procedures by a test of symmetry in a historical cohort referred to the pulmonary diagnostic laboratory.From 1988 to 2001, patients with pathologic confirmation of primary lung cancer were examined by standard bronchoscopic techniques of that period. An electronic medical record system was used, with statistical analysis of symmetry between brushings and biopsies establishing the diagnosis.Of 968 patients, 98% had bronchoscopy for 624 central and 322 peripheral suspect lesions. Bronchial brushings from 915 patients confirmed pulmonary malignancy in 811 (89%) patients. Endobronchial or transbronchial biopsies from 739 patients showed lung cancer in 603 (82%) cases. Bronchial washings in 16 patients and transthoracic needle biopsies in 30 patients established diagnosis. Transbronchial needle aspiration of mediastinal nodes identified metastases in 94 patients. Only 14 patients required a surgical procedure for diagnosis, but 188 received surgical excision as primary treatment. Statistical evaluation used only patients with both bronchial brushings and endobronchial or transbronchial biopsies. Analysis by a test of symmetry showed a significant difference (P0.0001).Positive, suspicious, and negative specimens were consistent, with bronchial brushings being more sensitive with a lower false-negative rate than endobronchial or transbronchial biopsies. Multiple techniques are recommended for bronchoscopic confirmation of lung cancer, but bronchial brushings should be collected initially, as technical or patient limitations might preclude diagnostic tissue biopsies.

Three groups of age- and weight-matched men (aged 40 to 70 years) without diabetes were studied: controls (n = 10), plasma triglycerides (TG) less than 180 mg/dL and no cardiovascular disease (CVD); HTG-CVD (n = 11), hypertriglyceridemic (HTG) (TG240 mg/dL) without CVD; and HTG+CVD (n = 10), HTG (TG240 mg/dL) with documented CVD. HTG+CVD subjects had higher fasting and post-oral glucose tolerance test insulin levels than the other two groups, respectively. Very-low-density lipoprotein (VLDL)+chylomicrons (CMs), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and three high-density lipoprotein (HDL) subfractions (HDL-L, HDL-M, and HDL-D, from least to most dense) were isolated by gradient ultracentrifugation. Fasting lipoproteins were similar in HTG groups, except for higher VLDL lipid to apolipoprotein (apo) B ratios (P.04) in the HTG+CVD group. Subjects were fed a high-fat mixed meal, and lipoprotein composition was determined at 3, 6, 9, and 12 hours postprandially. Postprandial responses of the core lipids (TG and cholesterol esters [CE]) in all of the lipoprotein subfractions were similar in the two HTG groups at each time point. However, both controls and HTG-CVD subjects had increases in HDL-M phospholipid (PL) at 9 and 12 hours with no change in HDL-D PL. The HTG+CVD group, on the other hand, had no increase in HDL-M PL and had a substantial reduction in HDL-D PL. These changes resulted in significant increases in HDL-M and HDL-D PL to apo A-I ratios in both controls and HTG-CVD subjects between 6 and 12 hours, whereas there was no increase seen in the HTG+CVD group. The HTG-CVD group also had a significantly greater increase in the VLDL+CM PL to apo B ratio (P = .038) at 3 hours than the HTG+CVD group. This diminished amount of surface lipid per VLDL particle may account for the late decrease in the HDL-D PL to apo A-I ratio seen in HTG+CVD patients. There were no other postprandial lipid or apolipoprotein differences between the two HTG groups. We conclude therefore that the major postprandial lipoprotein abnormality in these HTG+CVD patients was a failure to increase the PL content per particle in VLDL+CM, HDL-M, and HDL-D. This abnormality could prevent the usual increase in reverse cholesterol transport seen in postprandial plasma and therefore contribute to their increased incidence of CVD. The greater insulin resistance seen in these patients also appears to contribute significantly to their CVD.

The objective of this randomized controlled trial was to assess the effects of a 1-year behavioral contract intervention on immunosuppressant therapy (IST) adherence and healthcare utilizations and costs among adult renal transplant recipients (RTRs). The sample included adult RTRs who were at least 1 year posttransplant, taking tacrolimus or cyclosporine and served by a specialty pharmacy. Pharmacy refill records were used to measure adherence and monthly questionnaires were used to measure healthcare utilizations. Direct medical costs were estimated using the 2009 Medicare Expenditure Panel Survey. Adherence was analyzed using the GLM procedure and the MIXED procedure of SAS. Rate ratios and 95% confidence intervals were estimated to quantify the rate of utilizing healthcare services relative to treatment assignment. One hundred fifty RTRs were enrolled in the study. Intervention group RTRs (n = 76) had higher adherence than control group RTRs (n = 74) over the study period (p < 0.01). And 76.1% of the intervention group compared with 42.7% of the control group was not hospitalized during the 1-year study period (RR = 1.785; 95% CI: 1.314, 2.425), resulting in cost savings. Thus, evidence supports using behavioral contracts as an effective adherence intervention that may improve healthcare outcomes and lower costs.

BACKGROUND: Current guidelines for the correct peak expiratory flow (PEF) maneuver include standing. In the hospital setting, PEF values are often ordered to assess response to asthma therapy for exacerbations. We have observed that the PEF is sometimes performed with the patient in bed. METHODS: Healthy adults performed the PEF maneuver in random order, standing, lying back at an 45° angle on pillows, and sitting, slumped forward 10° with legs extended. PEF was recorded for 3 attempts in each of the 3 positions. RESULTS: We enrolled 94 subjects (39 male, 55 female, mean age 24 y) in 2011. Mean PEF in the standing position (669 42 L/min) was significantly higher than in the lying back (621 42 L/min) (P < .001) and sitting (615 42 L/min) positions in males (P < .001), and, similarly, in females, standing produced a significantly higher mean PEF (462 42 L/min) than the lying back (422 42 L/min) (P < .001) and sitting (447 42 L/ min) positions (P < .05). CONCLUSIONS: Clinicians should ensure that PEF is obtained with patients out of bed and in the standing position. Key words: peak expiratory flow; asthma; correct maneuver. [Respir Care 2013;58(3):494–497. © 2013 Daedalus Enterprises]

Background: Ventilator-associated pneumonia, a leading cause of sepsis in patients with acute respiratory failure, is difficult to distinguish clinically from other processes affecting patients receiving mechanical ventilation. We conducted a prospective study of patients with suspected ventilator-associated pneumonia to identify the causes of fever and densities on chest radiographs and to evaluate the diagnostic yield and efficiency of tests used alone and in combination. Methods: The 50 patients entered into the study underwent a systematic diagnostic protocol designed to identify all potential causes of fever and pulmonary densities. Diagnoses responsible for fever were established by strict diagnostic criteria for 45 of the 50 patients. The prevalence of specific conditions and diagnostic yield of individual tests were used to formulate a simplified diagnostic protocol. Results: The diagnostic protocol identified 78 causes of fever (median 2 per patient). Infections were the leading causes of fever and pulmonary densities. Of the 45 patients with fever, 37 had one or more infections identified (67 sources). Most infections (84 percent) were one of four types: pneumonia, sinusitis, catheter-related infection, or urinary tract infection. Ventilator-associated pneumonia occurred in only 42 percent. All but nine infections (87 percent) were directly or indirectly related to insertion of a catheter or a tube. Concomitant infections were frequent (62 percent), particularly in patients with sinusitis (100 percent), catheter-related infections (93 percent), and pneumonia (74 percent). Of concomitant infections, 60 percent were caused by a different pathogen. Noninfectious causes of fever were more common in the 22 patients with adult respiratory distress syndrome. Histologically proved pulmonary fibroproliferation was the only cause of fever in 25 percent of patients with adult respiratory distress syndrome. Radiographic densities were caused by an infection in only 20 patients (19 pneumonia, 1 empyema). In more than 50 percent of the 25 patients without adult respiratory distress syndrome, congestive heart failure, and atelectasis were the sole causes of pulmonary densities, and fever always originated from an extrapulmonary site of infection. Used in combination, bronchoscopy with protected sampling, computed tomographic scan of the sinuses, and cultures of maxillary sinus aspirate, central intravenous or arterial lines, urine, and blood identified 58 of the 78 sources of fever (74 percent). Conclusions: The observations in this study document the complex nature of acute respiratory failure and fever and underscore the need for accuracy in diagnosis. The frequent occurrence of multiple infectious and noninfeetious processes justifies a systematic search for source of fever, using a comprehensive diagnostic protocol. A simplified diagnostic protocol was devised based on the diagnostic value of individual tests.

The inconclusive results of past trials and recent findings of partial protection of Tenofovir 1% gel underscore the need to better understand product adherence in microbicide trials. This study aimed to identify factors predicting couples’ ability to sustain topical gel and condom use during clinical trial participation. We enrolled 100 Indian participants of a randomized, controlled safety trial of Tenofovir 1% gel (CT cohort) and 100 similar women who were ineligible or declined trial participation (NCT cohort). Compared to the NCT cohort, CT women reported higher baseline condom use, more positive attitudes towards condoms and higher levels of protection efficacy. While NCT condom use remained low, CT condom use increased dramatically during the study. Reported gel consistency was higher than condom consistency. Individual and couple-related factors predicted condom consistency and interest in future gel use, but not gel consistency. Findings could inform trial recruitment strategies and product introduction.

Research suggests that the HIV/AIDS epidemic has spread to monogamous women in India. Gender inequalities prevent women from asserting control over the circumstances that increase their vulnerability to infection. Men control most of the sexual decision-making. The present study explores views on use of microbicides by men and circumstances in which they might find microbicide use with their wives acceptable. Progressive in-depth interviews were conducted among 15 consenting men from Pune, India. Men felt that women with identifiable HIV risk, such as being a sex worker, having an HIV infected husbands or being educated; were more likely to use microbicides. Most high-risk men would permit or force their wives to use microbicides and had a higher intention to use microbicides compared with low-risk men probably due to perceived susceptibility. The majority of men with previous experience of microbicide use mentioned that privacy was important for gel use. Most low-risk men believed that they would be angry with covert gel use by their wives. They felt that covert use was impossible since their wives were under their control and they would notice the gel due to a change in their sexual experience. Low-risk men also opined that husband’s permission was not required if he was HIV-infected or having extra-marital sex. Some men stressed the need for exercising sexual control while women inserted gel before sex. Men’s risk-perception, knowledge about their safety concerns, as well as their behavior may affect acceptability of gel use, hence men’s involvement and cooperation is imperative for microbicide gel use by women in India.

Objective To study the safety of 3-4 diaminopyridine (DAP) in patients with motor neuron diseases and to examine its efficacy in reducing muscle fatigue and weakness and in improving objective parameters of muscle function. Design Assessments of safety included a questionnaire of symptoms, clinical examination, blood testing, and electrocardiography at each visit; efficacy was assessed by subjective scores of fatigue and weakness; an Amyotrophic Lateral Sclerosis Functional Rating Scale and functional ability scores, including timed verbal scores; manual muscle testing; grip dynamometry; pulmonary function tests; timed functional tests; and electrophysiological studies. Participants Thirteen subjects with amyotrophic lateral sclerosis and seven subjects with only a lower motor neuron syndrome. Main outcomes Assess tolerability of DAP and determine if there was symptomatic improvement of muscle fatigue. SECONDARY OUTCOME: To determine the effects of DAP on objective parameters of muscle function. Results The drug was well tolerated with only four subjects reporting tingling of lips and fingers during the active drug period. The subjective scores for fatigue and weakness showed a mild improvement after 4 weeks on DAP compared with placebo. A significant benefit of DAP was also demonstrated in the timed verbal scores. Conclusion 3-4 DAP appeared to be safe and produced subjective benefit in motor neuron diseases. The drug could be added for symptomatic treatment in these diseases. Larger studies are necessary to demonstrate efficacy.

PURPOSE This study was undertaken to investigate the pharmacodynamic relationship between etoposide drug levels on 21-day oral treatment courses and hematologic toxicities in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Thirty-two patients with stage IIIB or IV NSCLC were treated with oral etoposide 50 mg/m2/d for 21 consecutive days in combination with cisplatin 100 mg/m2 on day 1. Treatment was repeated every 28 days for up to six courses. Patients had not received previous chemotherapy and had a performance status of 0 to 2. Patients were monitored weekly while on treatment for compliance with oral etoposide and toxicity, including complete blood cell counts, and a blood sample before the daily etoposide dose (drug trough levels). Etoposide concentrations were measured in the plasma by high-performance liquid chromatography (HPLC). RESULTS Three patients achieved a complete response (CR) and 10 patients a partial response for an objective response rate of 41% (95% confidence interval, 24% to 58%). The median survival was 4 months (range, 1 to 23). Neutropenia was dose-limiting, and two patients died of neutropenic sepsis. Pharmacodynamic correlations for drug concentrations and hematologic toxicities were available for 27 patients and a total of 76 treatment courses, and correlations were significant for graded hematologic toxicity and nadir counts of leukocytes, neutrophils, hemoglobin, and platelets. The grade of infection (77 courses) was also related to drug levels. Using data from 27 initial courses, a pharmacodynamic model was developed to estimate the nadir leukocyte or neutrophil count (WBCn, ANCn) based on the pretreatment count (WBCp, ANCp) and the etoposide concentration (Ec) as follows: WBCn = 0.35 (1 + WBCp x e-1.12 x Ec) and ANCn = 0.32 (1 + ANCp x e-2.47 x Ec). CONCLUSION Etoposide concentrations are related to the resulting hematologic toxicities. It is possible to predict nadir counts in the first course by a pharmacodynamic model. The above equations need to be validated prospectively and may be useful in future studies of prolonged oral etoposide.