Effect of ritonavir-induced cytochrome P450 3A4 inhibition on plasma fentanyl concentrations during patient-controlled epidural labor analgesia: a pharmacokinetic simulation.

BACKGROUND: Ritonavir inhibition of cytochrome P450 3A4 decreases the elimination clearance of fentanyl by 67%. We used a pharmacokinetic model developed from published data to simulate the effect of sample patient-controlled epidural labor analgesic regimens on plasma fentanyl concentrations in the absence and presence of ritonavir-induced cytochrome P450 3A4 inhibition. METHODS: Fentanyl absorption from the epidural space was modeled using tanks-in-series delay elements. Systemic fentanyl disposition was described using a three-compartment pharmacokinetic model. Parameters for epidural drug absorption were estimated by fitting the model to reported plasma fentanyl concentrations measured after epidural administration. The validity of the model was assessed by comparing predicted plasma concentrations after epidural administration to published data. The effect of ritonavir was modeled as a 67% decrease in fentanyl elimination clearance. Plasma fentanyl concentrations were simulated for six sample patient-controlled epidural labor analgesic regimens over 24 h using ritonavir and control models. Simulated data were analyzed to determine if plasma fentanyl concentrations producing a 50% decrease in minute ventilation (6.1 ng/mL) were achieved. RESULTS: Simulated plasma fentanyl concentrations in the ritonavir group were higher than those in the control group for all sample labor analgesic regimens. Maximum plasma fentanyl concentrations were 1.8 ng/mL and 3.4 ng/mL for the normal and ritonavir simulations, respectively, and did not reach concentrations associated with 50% decrease in minute ventilation. CONCLUSION: Our model predicts that even with maximal clinical dosing regimens of epidural fentanyl over 24 h, ritonavir-induced cytochrome P450 3A4 inhibition is unlikely to produce plasma fentanyl concentrations associated with a decrease in minute ventilation.

Essays on Job Search and Labor Market Dynamics

This dissertation consists of three separate essays on job search and labor market dynamics. In the first essay, “The Impact of Labor Market Conditions on Job Creation: Evidence from Firm Level Data”, I study how much changes in labor market conditions reduce employment fluctuations over the business cycle. Changes in labor market conditions make hiring more expensive during expansions and cheaper during recessions, creating counter-cyclical incentives for job creation. I estimate firm level elasticities of labor demand with respect to changes in labor market conditions, considering two margins: changes in labor market tightness and changes in wages. Using employer-employee matched data from Brazil, I find that all firms are more sensitive to changes in wages rather than labor market tightness, and there is substantial heterogeneity in labor demand elasticity across regions. Based on these results, I demonstrate that changes in labor market conditions reduce the variance of employment growth over the business cycle by 20% in a median region, and this effect is equally driven by changes along each margin. Moreover, I show that the magnitude of the effect of labor market conditions on employment growth can be significantly affected by economic policy. In particular, I document that the rapid growth of the national minimum wages in Brazil in 1997-2010 amplified the impact of the change in labor market conditions during local expansions and diminished this impact during local recessions.

In the second essay, “A Framework for Estimating Persistence of Local Labor

Demand Shocks”, I propose a decomposition which allows me to study the persistence of local labor demand shocks. Persistence of labor demand shocks varies across industries, and the incidence of shocks in a region depends on the regional industrial composition. As a result, less diverse regions are more likely to experience deeper shocks, but not necessarily more long lasting shocks. Building on this idea, I propose a decomposition of local labor demand shocks into idiosyncratic location shocks and nationwide industry shocks and estimate the variance and the persistence of these shocks using the Quarterly Census of Employment and Wages (QCEW) in 1990-2013.

In the third essay, “Conditional Choice Probability Estimation of Continuous- Time Job Search Models”, co-authored with Peter Arcidiacono and Arnaud Maurel, we propose a novel, computationally feasible method of estimating non-stationary job search models. Non-stationary job search models arise in many applications, where policy change can be anticipated by the workers. The most prominent example of such policy is the expiration of unemployment benefits. However, estimating these models still poses a considerable computational challenge, because of the need to solve a differential equation numerically at each step of the optimization routine. We overcome this challenge by adopting conditional choice probability methods, widely used in dynamic discrete choice literature, to job search models and show how the hazard rate out of unemployment and the distribution of the accepted wages, which can be estimated in many datasets, can be used to infer the value of unemployment. We demonstrate how to apply our method by analyzing the effect of the unemployment benefit expiration on duration of unemployment using the data from the Survey of Income and Program Participation (SIPP) in 1996-2007.

Intergenerational effects of parental substance-related convictions and adult drug treatment court participation on children's school performance.

This study examined the intergenerational effects of parental conviction of a substance-related charge on children's academic performance and, conditional on a conviction, whether completion of an adult drug treatment court (DTC) program was associated with improved school performance. State administrative data from North Carolina courts, birth records, and school records were linked for 2005-2012. Math and reading end-of-grade test scores and absenteeism were examined for 5 groups of children, those with parents who: were not convicted on any criminal charge, were convicted on a substance-related charge and not referred by a court to a DTC, were referred to a DTC but did not enroll, enrolled in a DTC but did not complete, and completed a DTC program. Accounting for demographic and socioeconomic factors, the school performance of children whose parents were convicted of a substance-related offense was worse than that of children whose parents were not convicted on any charge. These differences were statistically significant but substantially reduced after controlling for socioeconomic characteristics; for example, mother's educational attainment. We found no evidence that parent participation in an adult DTC program led to improved school performance of their children. While the children of convicted parents fared worse on average, much--but not all--of this difference was attributed to socioeconomic factors, with the result that parental conviction remained a risk factor for poorer school performance. Even though adult DTCs have been shown to have other benefits, we could detect no intergenerational benefit in improved school performance of their children.

Communication practices in physician decision-making for an unstable critically ill patient with end-stage cancer.

BACKGROUND: Shared decision-making has become the standard of care for most medical treatments. However, little is known about physician communication practices in the decision making for unstable critically ill patients with known end-stage disease. OBJECTIVE: To describe communication practices of physicians making treatment decisions for unstable critically ill patients with end-stage cancer, using the framework of shared decision-making. DESIGN: Analysis of audiotaped encounters between physicians and a standardized patient, in a high-fidelity simulation scenario, to identify best practice communication behaviors. The simulation depicted a 78-year-old man with metastatic gastric cancer, life-threatening hypoxia, and stable preferences to avoid intensive care unit (ICU) admission and intubation. Blinded coders assessed the encounters for verbal communication behaviors associated with handling emotions and discussion of end-of-life goals. We calculated a score for skill at handling emotions (0-6) and at discussing end of life goals (0-16). SUBJECTS: Twenty-seven hospital-based physicians. RESULTS: Independent variables included physician demographics and communication behaviors. We used treatment decisions (ICU admission and initiation of palliation) as a proxy for accurate identification of patient preferences. Eight physicians admitted the patient to the ICU, and 16 initiated palliation. Physicians varied, but on average demonstrated low skill at handling emotions (mean, 0.7) and moderate skill at discussing end-of-life goals (mean, 7.4). We found that skill at discussing end-of-life goals was associated with initiation of palliation (p = 0.04). CONCLUSIONS: It is possible to analyze the decision making of physicians managing unstable critically ill patients with end-stage cancer using the framework of shared decision-making.

Do diabetic veterans use the Internet? Self-reported usage, skills, and interest in using My HealtheVet Web portal.

OBJECTIVE: The Veterans Health Administration has developed My HealtheVet (MHV), a Web-based portal that links veterans to their care in the veteran affairs (VA) system. The objective of this study was to measure diabetic veterans' access to and use of the Internet, and their interest in using MHV to help manage their diabetes. MATERIALS AND METHODS: Cross-sectional mailed survey of 201 patients with type 2 diabetes and hemoglobin A(1c) > 8.0% receiving primary care at any of five primary care clinic sites affiliated with a VA tertiary care facility. Main measures included Internet usage, access, and attitudes; computer skills; interest in using the Internet; awareness of and attitudes toward MHV; demographics; and socioeconomic status. RESULTS: A majority of respondents reported having access to the Internet at home. Nearly half of all respondents had searched online for information about diabetes, including some who did not have home Internet access. More than a third obtained "some" or "a lot" of their health-related information online. Forty-one percent reported being "very interested" in using MHV to help track their home blood glucose readings, a third of whom did not have home Internet access. Factors associated with being "very interested" were as follows: having access to the Internet at home (p < 0.001), "a lot/some" trust in the Internet as a source of health information (p = 0.002), lower age (p = 0.03), and some college (p = 0.04). Neither race (p = 0.44) nor income (p = 0.25) was significantly associated with interest in MHV. CONCLUSIONS: This study found that a diverse sample of older VA patients with sub-optimally controlled diabetes had a level of familiarity with and access to the Internet comparable to an age-matched national sample. In addition, there was a high degree of interest in using the Internet to help manage their diabetes.

Prenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy.

BACKGROUND: Conflicting results have been reported among studies of protease inhibitor (PI) use during pregnancy and preterm birth. Uncontrolled confounding by indication may explain some of the differences among studies. METHODS: In total, 777 human immunodeficiency virus (HIV)-infected pregnant women in a prospective cohort who were not receiving antiretroviral (ARV) treatment at conception were studied. Births <37 weeks gestation were reviewed, and deliveries due to spontaneous labor and/or rupture of membranes were identified. Risk of preterm birth and low birth weight (<2500 g) were evaluated by using multivariable logistic regression. RESULTS: Of the study population, 558 (72%) received combination ARV with PI during pregnancy, and a total of 130 preterm births were observed. In adjusted analyses, combination ARV with PI was not significantly associated with spontaneous preterm birth, compared to ARV without PI (odds ratio [OR], 1.22; 95% confidence interval [CI], 0.70-2.12). Sensitivity analyses that included women who received ARV prior to pregnancy also did not identify a significant association (OR, 1.34; 95% CI, 0.84-2.16). Low birth weight results were similar. CONCLUSIONS: No evidence of an association between use of combination ARV with PI during pregnancy and preterm birth was found. Our study supports current guidelines that promote consideration of combination ARV for all HIV-infected pregnant women.

Risk communication in clinical trials: a cognitive experiment and a survey.

BACKGROUND: A Royal Statistical Society Working Party recently recommended that "Greater use should be made of numerical, as opposed to verbal, descriptions of risk" in first-in-man clinical trials. This echoed the view of many clinicians and psychologists about risk communication. As the clinical trial industry expands rapidly across the globe, it is important to understand risk communication in Asian countries. METHODS: We conducted a cognitive experiment about participation in a hypothetical clinical trial of a pain relief medication and a survey in cancer and arthritis patients in Singapore. In part 1 of the experiment, the patients received information about the risk of side effects in one of three formats (frequency, percentage and verbal descriptor) and in one of two sequences (from least to most severe and from most to least severe), and were asked about their willingness to participate. In part 2, the patients received information about the risk in all three formats, in the same sequence, and were again asked about their willingness to participate. A survey of preference for risk presentation methods and usage of verbal descriptors immediately followed. RESULTS: Willingness to participate and the likelihood of changing one's decision were not affected by the risk presentation methods. Most patients indicated a preference for the frequency format, but patients with primary school or no formal education were indifferent. While the patients used the verbal descriptors "very common", "common" and "very rare" in ways similar to the European Commission's Guidelines, their usage of the descriptors "uncommon" and "rare" was substantially different from the EU's. CONCLUSION: In this sample of Asian cancer and arthritis patients, risk presentation format had no impact on willingness to participate in a clinical trial. However, there is a clear preference for the frequency format. The lay use of verbal descriptors was substantially different from the EU's.

So different, yet so similar: meta-analysis and policy modeling of willingness to participate in clinical trials among Brazilians and Indians.

BACKGROUND: With the global expansion of clinical trials and the expectations of the rise of the emerging economies known as BRICs (Brazil, Russia, India and China), the understanding of factors that affect the willingness to participate in clinical trials of patients from those countries assumes a central role in the future of health research. METHODS: We conducted a systematic review and meta-analysis (SRMA) of willingness to participate in clinical trials among Brazilian patients and then we compared it with Indian patients (with results of another SRMA previously conducted by our group) through a system dynamics model. RESULTS: Five studies were included in the SRMA of Brazilian patients. Our main findings are 1) the major motivation for Brazilian patients to participate in clinical trials is altruism, 2) monetary reimbursement is the least important factor motivating Brazilian patients, 3) the major barrier for Brazilian patients to not participate in clinical trials is the fear of side effects, and 4) Brazilian patients are more likely willing to participate in clinical trials than Indians. CONCLUSION: Our study provides important insights for investigators and sponsors for planning trials in Brazil (and India) in the future. Ignoring these results may lead to unnecessary fund/time spending. More studies are needed to validate our results and for better understanding of this poorly studied theme.

Musculoskeletal symptoms among female garment factory workers in Sri Lanka.

OBJECTIVES: To assess the prevalence of musculoskeletal symptoms and their association with sociodemographic risk factors among female garment factory workers in Sri Lanka. METHODS: 1058 randomly selected female garment factory workers employed in the free trade zone of Kogalla, Sri Lanka were recruited to complete two interviewer-administered questionnaires assessing musculoskeletal symptoms and health behaviors. DISCUSSION: Musculoskeletal complaints among female garment workers in the FTZ of Kogalla are less common than expected. Sociocultural factors may have resulted in underreporting and similarly contribute to the low rates of healthcare utilization by these women. RESULTS: 164 (15.5%) of workers reported musculoskeletal symptoms occurring more than 3 times or lasting a week or more during the previous 12-month period. Back (57.3%) and knee (31.7%) were the most common sites of pain. Although most symptomatic women reported that their problems interfered with work and leisure activities, very few missed work as a result of their pain. Prevalence correlated positively with increased age and industry tenure of less than 12 months. Job type, body mass index, and education were not significant predictors of musculoskeletal symptoms.

Who tests, who doesn't, and why? Uptake of mobile HIV counseling and testing in the Kilimanjaro Region of Tanzania.

BACKGROUND: Optimally, expanded HIV testing programs should reduce barriers to testing while attracting new and high-risk testers. We assessed barriers to testing and HIV risk among clients participating in mobile voluntary counseling and testing (MVCT) campaigns in four rural villages in the Kilimanjaro Region of Tanzania. METHODS: Between December 2007 and April 2008, 878 MVCT participants and 506 randomly selected community residents who did not access MVCT were surveyed. Gender-specific logistic regression models were used to describe differences in socioeconomic characteristics, HIV exposure risk, testing histories, HIV related stigma, and attitudes toward testing between MVCT participants and community residents who did not access MVCT. Gender-specific logistic regression models were used to describe differences in socioeconomic characteristics, HIV exposure risk, testing histories, HIV related stigma, and attitudes toward testing, between the two groups. RESULTS: MVCT clients reported greater HIV exposure risk (OR 1.20 [1.04 to 1.38] for males; OR 1.11 [1.03 to 1.19] for females). Female MVCT clients were more likely to report low household expenditures (OR 1.47 [1.04 to 2.05]), male clients reported higher rates of unstable income sources (OR 1.99 [1.22 to 3.24]). First-time testers were more likely than non-testers to cite distance to testing sites as a reason for not having previously tested (OR 2.17 [1.05 to 4.48] for males; OR 5.95 [2.85 to 12.45] for females). HIV-related stigma, fears of testing or test disclosure, and not being able to leave work were strongly associated with non-participation in MVCT (ORs from 0.11 to 0.84). CONCLUSIONS: MVCT attracted clients with increased exposure risk and fewer economic resources; HIV related stigma and testing-related fears remained barriers to testing. MVCT did not disproportionately attract either first-time or frequent repeat testers. Educational campaigns to reduce stigma and fears of testing could improve the effectiveness of MVCT in attracting new and high-risk populations.

Environmental management for malaria control: knowledge and practices in Mvomero, Tanzania.

Environmental conditions play an important role in the transmission of malaria; therefore, regulating these conditions can help to reduce disease burden. Environmental management practices for disease control can be implemented at the community level to complement other malaria control methods. This study assesses current knowledge and practices related to mosquito ecology and environmental management for malaria control in a rural, agricultural region of Tanzania. Household surveys were conducted with 408 randomly selected respondents from 10 villages and qualitative data were collected through focus group discussions and in-depth interviews. Results show that respondents are well aware of the links between mosquitoes, the environment, and malaria. Most respondents stated that cleaning the environment around the home, clearing vegetation around the home, or draining stagnant water can reduce mosquito populations, and 63% of respondents reported performing at least one of these techniques to protect themselves from malaria. It is clear that many respondents believe that these environmental management practices are effective malaria control methods, but the actual efficacy of these techniques for controlling populations of vectors or reducing malaria prevalence in the varying ecological habitats in Mvomero is unknown. Further research should be conducted to determine the effects of different environmental management practices on both mosquito populations and malaria transmission in this region, and increased participation in effective techniques should be promoted.

Victims of infanticide and conspecific bite wounding in a female-dominant primate: a long-term study.

The aggression animals receive from conspecifics varies between individuals across their lifetime. As poignantly evidenced by infanticide, for example, aggression can have dramatic fitness consequences. Nevertheless, we understand little about the sources of variation in received aggression, particularly in females. Using a female-dominant species renowned for aggressivity in both sexes, we tested for potential social, demographic, and genetic patterns in the frequency with which animals were wounded by conspecifics. Our study included 243 captive, ring-tailed lemurs (Lemur catta), followed from infancy to adulthood over a 35-year time span. We extracted injury, social, and life-history information from colony records and calculated neutral heterozygosity for a subset of animals, as an estimate of genetic diversity. Focusing on victims rather than aggressors, we used General Linear Models to explain bite-wound patterns at different life stages. In infancy, maternal age best predicted wounds received, as infants born to young mothers were the most frequent infanticide victims. In adulthood, sex best predicted wounds received, as males were three times more likely than females to be seriously injured. No relation emerged between wounds received and the other variables studied. Beyond the generally expected costs of adult male intrasexual aggression, we suggest possible additive costs associated with female-dominant societies - those suffered by young mothers engaged in aggressive disputes and those suffered by adult males aggressively targeted by both sexes. We propose that infanticide in lemurs may be a costly by-product of aggressively mediated, female social dominance. Accordingly, the benefits of female behavioral 'masculinization' accrued to females through priority of access to resources, may be partially offset by early costs in reproductive success. Understanding the factors that influence lifetime patterns of conspecific wounding is critical to evaluating the fitness costs associated with social living; however, these costs may vary substantially between societies.

Development of a decision aid to inform patients' and families' renal replacement therapy selection decisions.

BACKGROUND: Few educational resources have been developed to inform patients' renal replacement therapy (RRT) selection decisions. Patients progressing toward end stage renal disease (ESRD) must decide among multiple treatment options with varying characteristics. Complex information about treatments must be adequately conveyed to patients with different educational backgrounds and informational needs. Decisions about treatment options also require family input, as families often participate in patients' treatment and support patients' decisions. We describe the development, design, and preliminary evaluation of an informational, evidence-based, and patient-and family-centered decision aid for patients with ESRD and varying levels of health literacy, health numeracy, and cognitive function. METHODS: We designed a decision aid comprising a complementary video and informational handbook. We based our development process on data previously obtained from qualitative focus groups and systematic literature reviews. We simultaneously developed the video and handbook in "stages." For the video, stages included (1) directed interviews with culturally appropriate patients and families and preliminary script development, (2) video production, and (3) screening the video with patients and their families. For the handbook, stages comprised (1) preliminary content design, (2) a mixed-methods pilot study among diverse patients to assess comprehension of handbook material, and (3) screening the handbook with patients and their families. RESULTS: The video and handbook both addressed potential benefits and trade-offs of treatment selections. The 50-minute video consisted of demographically diverse patients and their families describing their positive and negative experiences with selecting a treatment option. The video also incorporated health professionals' testimonials regarding various considerations that might influence patients' and families' treatment selections. The handbook was comprised of written words, pictures of patients and health care providers, and diagrams describing the findings and quality of scientific studies comparing treatments. The handbook text was written at a 4th to 6th grade reading level. Pilot study results demonstrated that a majority of patients could understand information presented in the handbook. Patient and families screening the nearly completed video and handbook reviewed the materials favorably. CONCLUSIONS: This rigorously designed decision aid may help patients and families make informed decisions about their treatment options for RRT that are well aligned with their values.

The professionalism disconnect: do entering residents identify yet participate in unprofessional behaviors?

BACKGROUND: Professionalism has been an important tenet of medical education, yet defining it is a challenge. Perceptions of professional behavior may vary by individual, medical specialty, demographic group and institution. Understanding these differences should help institutions better clarify professionalism expectations and provide standards with which to evaluate resident behavior. METHODS: Duke University Hospital and Vidant Medical Center/East Carolina University surveyed entering PGY1 residents. Residents were queried on two issues: their perception of the professionalism of 46 specific behaviors related to training and patient care; and their own participation in those specified behaviors. The study reports data analyses for gender and institution based upon survey results in 2009 and 2010. The study received approval by the Institutional Review Boards of both institutions. RESULTS: 76% (375) of 495 PGY1 residents surveyed in 2009 and 2010 responded. A majority of responders rated all 46 specified behaviors as unprofessional, and a majority had either observed or participated in each behavior. For all 46 behaviors, a greater percentage of women rated the behaviors as unprofessional. Men were more likely than women to have participated in behaviors. There were several significant differences in both the perceptions of specified behaviors and in self-reported observation of and/or involvement in those behaviors between institutions.Respondents indicated the most important professionalism issues relevant to medical practice include: respect for colleagues/patients, relationships with pharmaceutical companies, balancing home/work life, and admitting mistakes. They reported that professionalism can best be assessed by peers, patients, observation of non-medical work and timeliness/detail of paperwork. CONCLUSION: Defining professionalism in measurable terms is a challenge yet critical in order for it to be taught and assessed. Recognition of the differences by gender and institution should allow for tailored teaching and assessment of professionalism so that it is most meaningful. A shared understanding of what constitutes professional behavior is an important first step.