Detailed analysis of sequence changes occurring during vlsE antigenic variation in the mouse model of Borrelia burgdorferi infection.

Lyme disease Borrelia can infect humans and animals for months to years, despite the presence of an active host immune response. The vls antigenic variation system, which expresses the surface-exposed lipoprotein VlsE, plays a major role in B. burgdorferi immune evasion. Gene conversion between vls silent cassettes and the vlsE expression site occurs at high frequency during mammalian infection, resulting in sequence variation in the VlsE product. In this study, we examined vlsE sequence variation in B. burgdorferi B31 during mouse infection by analyzing 1,399 clones isolated from bladder, heart, joint, ear, and skin tissues of mice infected for 4 to 365 days. The median number of codon changes increased progressively in C3H/HeN mice from 4 to 28 days post infection, and no clones retained the parental vlsE sequence at 28 days. In contrast, the decrease in the number of clones with the parental vlsE sequence and the increase in the number of sequence changes occurred more gradually in severe combined immunodeficiency (SCID) mice. Clones containing a stop codon were isolated, indicating that continuous expression of full-length VlsE is not required for survival in vivo; also, these clones continued to undergo vlsE recombination. Analysis of clones with apparent single recombination events indicated that recombinations into vlsE are nonselective with regard to the silent cassette utilized, as well as the length and location of the recombination event. Sequence changes as small as one base pair were common. Fifteen percent of recovered vlsE variants contained "template-independent" sequence changes, which clustered in the variable regions of vlsE. We hypothesize that the increased frequency and complexity of vlsE sequence changes observed in clones recovered from immunocompetent mice (as compared with SCID mice) is due to rapid clearance of relatively invariant clones by variable region-specific anti-VlsE antibody responses.

Detailed analysis of sequence changes occurring during vlsE antigenic variation in the mouse model of Borrelia burgdorferi infection.

Lyme disease Borrelia can infect humans and animals for months to years, despite the presence of an active host immune response. The vls antigenic variation system, which expresses the surface-exposed lipoprotein VlsE, plays a major role in B. burgdorferi immune evasion. Gene conversion between vls silent cassettes and the vlsE expression site occurs at high frequency during mammalian infection, resulting in sequence variation in the VlsE product. In this study, we examined vlsE sequence variation in B. burgdorferi B31 during mouse infection by analyzing 1,399 clones isolated from bladder, heart, joint, ear, and skin tissues of mice infected for 4 to 365 days. The median number of codon changes increased progressively in C3H/HeN mice from 4 to 28 days post infection, and no clones retained the parental vlsE sequence at 28 days. In contrast, the decrease in the number of clones with the parental vlsE sequence and the increase in the number of sequence changes occurred more gradually in severe combined immunodeficiency (SCID) mice. Clones containing a stop codon were isolated, indicating that continuous expression of full-length VlsE is not required for survival in vivo; also, these clones continued to undergo vlsE recombination. Analysis of clones with apparent single recombination events indicated that recombinations into vlsE are nonselective with regard to the silent cassette utilized, as well as the length and location of the recombination event. Sequence changes as small as one base pair were common. Fifteen percent of recovered vlsE variants contained "template-independent" sequence changes, which clustered in the variable regions of vlsE. We hypothesize that the increased frequency and complexity of vlsE sequence changes observed in clones recovered from immunocompetent mice (as compared with SCID mice) is due to rapid clearance of relatively invariant clones by variable region-specific anti-VlsE antibody responses.

Choosing and Maintaining Programs for Sex Education in Schools: The CHAMPSS Model

Background: Despite effective solutions to reduce teen birth rates, Texas teen birth rates are among the highest in the nation. School districts can impact youth sexual behavior through implementation of evidence-based programs (EBPs); however, teen pregnancy prevention is a complex and controversial issue for school districts. Subsequently, very few districts in Texas implement EBPs for pregnancy prevention. Additionally, school districts receive little guidance on the process for finding, adopting, and implementing EBPs. Purpose: The purpose of this report is to present the CHoosing And Maintaining Programs for Sex education in Schools (CHAMPSS) Model, a practical and realistic framework to help districts find, adopt, and implement EBPs. Methods: Model development occurred in four phases using the core processes of Intervention Mapping: 1) knowledge acquisition, 2) knowledge engineering, 3) model representation, and 4) knowledge development. Results: The CHAMPSS Model provides seven steps, tailored for school-based settings, which encompass phases of assessment, preparation, implementation, and maintenance: Prioritize, Asses, Select, Approve, Prepare, Implement, and Maintain. Advocacy and eliciting support for adolescent sexual health are also core elements of the model. Conclusion: This systematic framework may help schools increase adoption, implementation, and maintenance for EBPs.

Physician's adherence to the standard protocol for diabetes treatment in Brooke Army Medical Center (BAMC)

The level of compliance with clinical practice guidelines for patients with Type II Diabetes Mellitus was evaluated in 157 patients treated at BAMC from 1 January 2006 to 1 January 2007. This retrospective analysis was conducted reviewing data from medical records and following the VA/DOD protocols that health care providers are expected to follow at this facility. Data collected included patient’s age and gender, presence or absence of complications of diabetes, physical examination findings, glycemic and lipid control, eye care, foot care, kidney function, and self-management and education. Subjects were selected performing systematic random sampling, and included both male and female patients, from a variety of ages and ethnic groups. The Diabetes complications screened for included glycemic and lipid complications, retinopathy, cardiovascular complications, peripheral circulation complications, and nephropathy. The results revealed that 19.10% had no complications and that the most common complications were: cardiovascular (49.68%), glycemic and lipid control (10.82%), retinopathy and peripheral circulation (8.28% each), and nephropathy (2.54%). Only 2.54% of the records reviewed did not include information on complications. Strictly following the Department of Defense guidelines, six treatment modules were evaluated independently and together to get a final percentage of adherence to the clinical practice guidelines. It was established that the level of adherence was going to be graded as follows: Extremely deficient: 0-15%; very poor: 16-30%; Poor and in need of improvement: 31-45%. Acceptable: 46-60%; Good: 61-80%, and Excellent: 81-100%. The results indicated that the percentage of physicians' adherence to each protocol was as follows: 88.31%, 89.93%, 90.63%, 89.42%, 89.42% and 89.64%. When the results were pooled, the level of adherence to the clinical practice guidelines was 89.55%, proving my hypothesis that Brooke Army Medical Center physicians have excellent adherence to the standard protocols for Diabetes Type II to treat their patients. ^

Assessing residents' readiness to screen for domestic violence: Utilizing the transtheoretical model - stages of change, decisional balance and self-efficacy

Domestic violence is a major public health problem, yet most physicians do not effectively identify patients at risk. Medical students and residents are not routinely educated on this topic and little is known about the factors that influence their decisions to include screening for domestic violence in their subsequent practice. In order to assess the readiness of primary care residents to screen all patients for domestic violence, this study utilized a survey incorporating constructs from the Transtheoretical Model, including Stages of Change, Decisional Balance (Pros and Cons) and Self-Efficacy. The survey was distributed to residents at the University of Texas Health Science Center Medical School in Houston in: Internal Medicine, Medicine/Pediatrics, Pediatrics, Family Medicine, and Obstetrics and Gynecology. Data from the survey was analyzed to test the hypothesis that residents in the earlier Stages of Change report more costs and fewer benefits with regards to screening for domestic violence, and that those in the later stages exhibit higher Self-Efficacy scores. The findings from this study were consistent with the model in that benefits to screening (Pros) and Self-Efficacy were correlated with later Stages of Change, however reporting fewer costs (Cons) was not. Very few residents were ready to screen all of their patients.^

Comparison of compliance and immune response of drug users on the standard and accelerated hepatitis B vaccine schedules - Houston, Texas

Despite the availability of hepatitis B vaccine for over two decades, drug users and other high-risk adult populations have experienced low vaccine coverage. Poor compliance has limited efforts to reduce transmission of hepatitis B infection in this population. Evidence suggests that immunological response in drug users is impaired compared to the general population, both in terms of lower seroprotection rates and antibodies levels.^ The current study investigated the effectiveness of the multi-dose hepatitis B vaccine and compared the effect of the standard and accelerated vaccine schedules in a not-in-treatment, drug-using adult population in the city of Houston, USA.^ A population of drug-users from two communities in Houston, susceptible to hepatitis B, was sampled by outreach workers and referral methodology. Subjects were randomized either to the standard hepatitis vaccine schedule (0, 1-, 6-month) or to an accelerated schedule (0, 1-, 2-month). Antibody levels were detected through laboratory analyses at various time-points. The participants were followed for two years and seroconversion rates were calculated to determine immune response.^ A four percent difference in the overall compliance rate was observed between the standard (73%) and accelerated schedules (77%). Logistic regression analyses showed that drug users living on the streets were twice as likely to not complete all three vaccine doses (p=0.028), and current speedball use was also associated with non-completion (p=0.002). Completion of all three vaccinations in the multivariate analysis was also correlated with older age. Drug users on the accelerated schedule were 26% more likely to achieve completion, although this factor was marginally significant (p=0.085).^ Cumulative adequate protective response was gained by 65% of the HBV susceptible subgroup by 12-months and was identical for both the standard and accelerated schedules. Excess protective response (>=100 mIU/mL) occurred with greater frequency at the later period for the standard schedule (36% at 12-months compared to 14% at six months), while the greater proportion of excess protective response for the accelerated schedule occurred earlier (34% at 6 months compared to 18% at 12-months). Seroconversion at the adequate protective response level of 10 mIU/mL was reached by the accelerated schedule group at a quicker rate (62% vs. 49%), and with a higher mean titer (104.8 vs. 64.3 mIU/mL), when measured at six months. Multivariate analyses indicated a 63% increased risk of non-response for older age and confirmed the existence of an accelerating decline in immune response to vaccination manifesting after 40 years (p=0.001). Injecting more than daily was also highly associated with the risk of non-response (p=0.016).^ The substantial increase in the seroprotection rate at six months may be worth the trade-off against the faster antibody titer decrease and is recommended for enhancing compliance and seroconversion. Utilization of the accelerated schedule with the primary objective of increasing compliance and seroconversion rates during the six months after the first dose may confer early protective immunity and reduce the HBV vulnerability of drug users who continue, or have recently initiated, increased high risk drug use and sexual behaviors.^

A simulation study of the standard design, the rolling six design, the CRM, and the modified CRM in Phase I clinical trials

The Phase I clinical trial is considered the "first in human" study in medical research to examine the toxicity of a new agent. It determines the maximum tolerable dose (MTD) of a new agent, i.e., the highest dose in which toxicity is still acceptable. Several phase I clinical trial designs have been proposed in the past 30 years. The well known standard method, so called the 3+3 design, is widely accepted by clinicians since it is the easiest to implement and it does not need a statistical calculation. Continual reassessment method (CRM), a design uses Bayesian method, has been rising in popularity in the last two decades. Several variants of the CRM design have also been suggested in numerous statistical literatures. Rolling six is a new method introduced in pediatric oncology in 2008, which claims to shorten the trial duration as compared to the 3+3 design. The goal of the present research was to simulate clinical trials and compare these phase I clinical trial designs. Patient population was created by discrete event simulation (DES) method. The characteristics of the patients were generated by several distributions with the parameters derived from a historical phase I clinical trial data review. Patients were then selected and enrolled in clinical trials, each of which uses the 3+3 design, the rolling six, or the CRM design. Five scenarios of dose-toxicity relationship were used to compare the performance of the phase I clinical trial designs. One thousand trials were simulated per phase I clinical trial design per dose-toxicity scenario. The results showed the rolling six design was not superior to the 3+3 design in terms of trial duration. The time to trial completion was comparable between the rolling six and the 3+3 design. However, they both shorten the duration as compared to the two CRM designs. Both CRMs were superior to the 3+3 design and the rolling six in accuracy of MTD estimation. The 3+3 design and rolling six tended to assign more patients to undesired lower dose levels. The toxicities were slightly greater in the CRMs.^

Behavioral decision making and the levels of change: An application of the transtheoretical model to prenatal smoking in low -income women

Despite continued research and public health efforts to reduce smoking during pregnancy, prenatal cessation rates in the United States have decreased and the incidence of low birth weight has increased from 1985 to 1991. Lower socioeconomic status women who are at increased risk for poor pregnancy outcomes may be resistant to current intervention efforts during pregnancy. The purpose of this dissertation was to investigate the determinants of continued smoking and quitting among low-income pregnant women.^ Using data from cross-sectional surveys of 323 low-income pregnant smokers, the first study developed and tested measures of the pros and cons of smoking during pregnancy. The original decisional balance measure for smoking was compared with a new measure that added items thought to be more salient to the target population. Confirmatory factor analysis using structural equation modeling showed neither the original nor new measure fit the data adequately. Using behavioral science theory, content from interviews with the population, and statistical evidence, two 7-item scales representing the pros and cons were developed from a portion (n = 215) of the sample and successfully cross-validated on the remainder of the sample (n = 108). Logistic regression found only pros were significantly associated with continued smoking. In a discriminant function analysis, stage of change was significantly associated with pros and cons of smoking.^ The second study examined the structural relationships between psychosocial constructs representing some of the levels of and the pros and cons of smoking. The cross-sectional design mandates that statements made regarding prediction do not prove causation or directionality from the data or methods analysis. Structural equation modeling found the following: more stressors and family criticism were significantly more predictive of negative affect than social support; a bi-directional relationship was found between negative affect and current nicotine addiction; and negative affect, addiction, stressors, and family criticism were significant predictors of pros of smoking.^ The findings imply reversing the trend of decreasing smoking cessation during pregnancy may require supplementing current interventions for this population of pregnant smokers with programs addressing nicotine addiction, negative affect, and other psychosocial factors such as family functioning and stressors. ^