Sex, drugs, and STIs: Syphilis infection and hepatitis B vaccine compliance among illicit drug users in Houston

Although the association between syphilis infection status and compliance with the hepatitis B virus vaccine has been the focus of investigation, there is a lack of data regarding the association between syphilis infection and HBV vaccine compliance. The author investigated the association between the exposure of syphilis infection and the outcome of HBV vaccine completion, defined as degree of constancy and accuracy with which a patient follows a prescribed regimen. A cohort design was employed using interview and serological data from the Drugs, AIDS, STDs, Hepatitis (DASH) Research Project; analysis was restricted to HIV and HBV seronegative (at baseline), illicit drug users residing in Harris County. Syphilis negative and syphilis positive infection status was determined from the serological data while covariates and outcome information were determined from the DASH Project Questionnaire; enrolled subjects (n=1160) were selected from the data. Association between exposure and outcome was assessed with logistic regression adjusted for data-based confounders. ^ A prevalence of 7% and 71% was found for syphilis and HBV vaccine compliance, respectively. When measuring the actual association between syphilis infection status and HBV vaccine compliance, an odds ratio of 1.49 (95% CI: 0.86, 2.72) was obtained. There was a non-significant association between these two variables. 78% of the study population was syphilis positive and completed the vaccine series compared to 70% of the population that was syphilis negative and received all three doses. This finding confirms that there is a difference between syphilis positive and negative drug users with respect to HBV vaccine compliance. The fact that differences were found in these drug users with respect to vaccine schedule supports the idea that sub-group differences may exist and thus merits further investigation. If these differences are confirmed, it is recommended that STI interventions identify community characteristics of their samples and target populations based on practices specific to that community. ^

The role of workplace absence as an organizational mechanism in predicting employee alcohol and drug disorders

Background. EAP programs for airline pilots in companies with a well developed recovery management program are known to reduce pilot absenteeism following treatment. Given the costs and safety consequences to society, it is important to identify pilots who may be experiencing an AOD disorder to get them into treatment. ^ Hypotheses. This study investigated the predictive power of workplace absenteeism in identifying alcohol or drug disorders (AOD). The first hypothesis was that higher absenteeism in a 12-month period is associated with higher risk that an employee is experiencing AOD. The second hypothesis was that AOD treatment would reduce subsequent absence rates and the costs of replacing pilots on missed flights. ^ Methods. A case control design using eight years (time period) of monthly archival absence data (53,000 pay records) was conducted with a sample of (N = 76) employees having an AOD diagnosis (cases) matched 1:4 with (N = 304) non-diagnosed employees (controls) of the same profession and company (male commercial airline pilots). Cases and controls were matched on the variables age, rank and date of hire. Absence rate was defined as sick time hours used over the sum of the minimum guarantee pay hours annualized using the months the pilot worked for the year. Conditional logistic regression was used to determine if absence predicts employees experiencing an AOD disorder, starting 3 years prior to the cases receiving the AOD diagnosis. A repeated measures ANOVA, t tests and rate ratios (with 95% confidence intervals) were conducted to determine differences between cases and controls in absence usage for 3 years pre and 5 years post treatment. Mean replacement costs were calculated for sick leave usage 3 years pre and 5 years post treatment to estimate the cost of sick leave from the perspective of the company. ^ Results. Sick leave, as measured by absence rate, predicted the risk of being diagnosed with an AOD disorder (OR 1.10, 95% CI = 1.06, 1.15) during the 12 months prior to receiving the diagnosis. Mean absence rates for diagnosed employees increased over the three years before treatment, particularly in the year before treatment, whereas the controls’ did not (three years, x = 6.80 vs. 5.52; two years, x = 7.81 vs. 6.30, and one year, x = 11.00cases vs. 5.51controls. In the first year post treatment compared to the year prior to treatment, rate ratios indicated a significant (60%) post treatment reduction in absence rates (OR = 0.40, CI = 0.28, 0.57). Absence rates for cases remained lower than controls for the first three years after completion of treatment. Upon discharge from the FAA and company’s three year AOD monitoring program, case’s absence rates increased slightly during the fourth year (controls, x = 0.09, SD = 0.14, cases, x = 0.12, SD = 0.21). However, the following year, their mean absence rates were again below those of the controls (controls, x = 0.08, SD = 0.12, cases, x¯ = 0.06, SD = 0.07). Significant reductions in costs associated with replacing pilots calling in sick, were found to be 60% less, between the year of diagnosis for the cases and the first year after returning to work. A reduction in replacement costs continued over the next two years for the treated employees. ^ Conclusions. This research demonstrates the potential for workplace absences as an active organizational surveillance mechanism to assist managers and supervisors in identifying employees who may be experiencing or at risk of experiencing an alcohol/drug disorder. Currently, many workplaces use only performance problems and ignore the employee’s absence record. A referral to an EAP or alcohol/drug evaluation based on the employee’s absence/sick leave record as incorporated into company policy can provide another useful indicator that may also carry less stigma, thus reducing barriers to seeking help. This research also confirms two conclusions heretofore based only on cross-sectional studies: (1) higher absence rates are associated with employees experiencing an AOD disorder; (2) treatment is associated with lower costs for replacing absent pilots. Due to the uniqueness of the employee population studied (commercial airline pilots) and the organizational documentation of absence, the generalizability of this study to other professions and occupations should be considered limited. ^ Transition to Practice. The odds ratios for the relationship between absence rates and an AOD diagnosis are precise; the OR for year of diagnosis indicates the likelihood of being diagnosed increases 10% for every hour change in sick leave taken. In practice, however, a pilot uses approximately 20 hours of sick leave for one trip, because the replacement will have to be paid the guaranteed minimum of 20 hour. Thus, the rate based on hourly changes is precise but not practical. ^ To provide the organization with practical recommendations the yearly mean absence rates were used. A pilot flies on average, 90 hours a month, 1080 annually. Cases used almost twice the mean rate of sick time the year prior to diagnosis (T-1) compared to controls (cases, x = .11, controls, x = .06). Cases are expected to use on average 119 hours annually (total annual hours*mean annual absence rate), while controls will use 60 hours. The cases’ 60 hours could translate to 3 trips of 20 hours each. Management could use a standard of 80 hours or more of sick time claimed in a year as the threshold for unacceptable absence, a 25% increase over the controls (a cost to the company of approximately of $4000). At the 80-hour mark, the Chief Pilot would be able to call the pilot in for a routine check as to the nature of the pilot’s excessive absence. This management action would be based on a company standard, rather than a behavioral or performance issue. Using absence data in this fashion would make it an active surveillance mechanism. ^

Bayesian adaptive designs for drug combinations in early phase clinical trials

Treating patients with combined agents is a growing trend in cancer clinical trials. Evaluating the synergism of multiple drugs is often the primary motivation for such drug-combination studies. Focusing on the drug combination study in the early phase clinical trials, our research is composed of three parts: (1) We conduct a comprehensive comparison of four dose-finding designs in the two-dimensional toxicity probability space and propose using the Bayesian model averaging method to overcome the arbitrariness of the model specification and enhance the robustness of the design; (2) Motivated by a recent drug-combination trial at MD Anderson Cancer Center with a continuous-dose standard of care agent and a discrete-dose investigational agent, we propose a two-stage Bayesian adaptive dose-finding design based on an extended continual reassessment method; (3) By combining phase I and phase II clinical trials, we propose an extension of a single agent dose-finding design. We model the time-to-event toxicity and efficacy to direct dose finding in two-dimensional drug-combination studies. We conduct extensive simulation studies to examine the operating characteristics of the aforementioned designs and demonstrate the designs' good performances in various practical scenarios.^

Use of Echogenic Immunoliposomes for Delivery of both Drug and Stem Cells for Inhibition of Atheroma Progression

Use of Echogenic Immunoliposomes for Delivery of both Drug and Stem Cells for Inhibition of Atheroma Progression By Ali K. Naji B.S. Advisor: Dr. Melvin E. Klegerman PhD Background and significance: Echogenic liposomes can be used as drug and cell delivery vehicles that reduce atheroma progression. Vascular endothelial growth factor (VEGF) is a signal protein that induces vasculogenesis and angiogenesis. VEGF functionally induces migration and proliferation of endothelial cells and increases intracellular vascular permeability. VEGF activates angiogenic transduction factors through VEGF tyrosine kinase domains in high-affinity receptors of endothelial cells. Bevacizumab is a humanized monoclonal antibody specific for VEGF-A which was developed as an anti-tumor agent. Often, anti-VEGF agents result in regression of existing microvessels, inhibiting tumor growth and possibly causing tumor shrinkage with time. During atheroma progression neovasculation in the arterial adventitia is mediated by VEGF. Therefore, bevacizumab may be effective in inhibiting atheroma progression. Stem cells show an ability to inhibit atheroma progression. We have previously demonstrated that monocyte derived CD-34+ stem cells that can be delivered to atheroma by bifunctional-ELIP ( BF-ELIP) targeted to Intercellular Adhesion Molecule-1 (ICAM-1) and CD-34. Adhesion molecules such as ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) are expressed by endothelial cells under inflammatory conditions. Ultrasound enhanced liposomal targeting provides a method for stem cell delivery into atheroma and encapsulated drug release. This project is designed to examine the ability of echogenic liposomes to deliver bevacizumab and stem cells to inhibit atheroma progression and neovasculation with and without ultrasound in vitro and optimize the ultrasound parameters for delivery of bevacizumab and stem cells to atheroma. V Hypotheses: Previous studies showed that endothelial cell VEGF expression may relate to atherosclerosis progression and atheroma formation in the cardiovascular system. Bevacizumab-loaded ELIP will inhibit endothelial cell VEGF expression in vitro. Bevacizumab activity can be enhanced by pulsed Doppler ultrasound treatment of BEV-ELIP. I will also test the hypothesis that the transwell culture system can serve as an in vitro model for study of US-enhanced targeted delivery of stem cells to atheroma. Monocyte preparations will serve as a source of CD34+ stem cells. Specific Aims: Induce VEGF expression using PKA and PKC activation factors to endothelial cell cultures and use western blot and ELISA techniques to detect the expressed VEGF.  Characterize the relationship between endothelial cell proliferation and VEGF expression to develop a specific EC culture based system to demonstrate BEV-ELIP activity as an anti-VEGF agent. Design a cell-based assay for in vitro assessment of ultrasound-enhanced bevacizumab release from echogenic liposomes.  Demonstrate ultrasound delivery enhancement of stem cells by applying different types of liposomes on transwell EC culture using fluorescently labeled monocytes and detect the effect on migration and attachment rate of these echogenic liposomes with and without ultrasound in vitro.

Modified 3+3 design for phase I clinical trials

Phase I clinical trial is mainly designed to determine the maximum tolerated dose (MTD) of a new drug. Optimization of phase I trial design is crucial to minimize the number of enrolled patients exposed to unsafe dose levels and to provide reliable information to the later phases of clinical trials. Although it has been criticized about its inefficient MTD estimation, nowadays the traditional 3+3 method remains dominant in practice due to its simplicity and conservative estimation. There are many new designs that have been proven to generate more credible MTD estimation, such as the Continual Reassessment Method (CRM). Despite its accepted better performance, the CRM design is still not widely used in real trials. There are several factors that contribute to the difficulties of CRM adaption in practice. First, CRM is not widely accepted by the regulatory agencies such as FDA in terms of safety. It is considered to be less conservative and tend to expose more patients above the MTD level than the traditional design. Second, CRM is relatively complex and not intuitive for the clinicians to fully understand. Third, the CRM method take much more time and need statistical experts and computer programs throughout the trial. The current situation is that the clinicians still tend to follow the trial process that they are comfortable with. This situation is not likely to change in the near future. Based on this situation, we have the motivation to improve the accuracy of MTD selection while follow the procedure of the traditional design to maintain simplicity. We found that in 3+3 method, the dose transition and the MTD determination are relatively independent. Thus we proposed to separate the two stages. The dose transition rule remained the same as 3+3 method. After getting the toxicity information from the dose transition stage, we combined the isotonic transformation to ensure the monotonic increasing order before selecting the optimal MTD. To compare the operating characteristics of the proposed isotonic method and the other designs, we carried out 10,000 simulation trials under different dose setting scenarios to compare the design characteristics of the isotonic modified method with standard 3+3 method, CRM, biased coin design (BC) and k-in-a-row design (KIAW). The isotonic modified method improved MTD estimation of the standard 3+3 in 39 out of 40 scenarios. The improvement is much greater when the target is 0.3 other than 0.25. The modified design is also competitive when comparing with other selected methods. A CRM method performed better in general but was not as stable as the isotonic method throughout the different dose settings. The results demonstrated that our proposed isotonic modified method is not only easily conducted using the same procedure as 3+3 but also outperforms the conventional 3+3 design. It can also be applied to determine MTD for any given TTL. These features make the isotonic modified method of practical value in phase I clinical trials.^