Risk and resiliency: The untold story of youth in military families

Background: Risky sexual behaviors have been shown to increase the risk of unintended pregnancy and sexually transmitted infections (STIs) among youth. Youth in military families may be especially at risk for engaging in risky sexual behaviors because they are exposed to factors that are unique to the military culture, such as multiple relocations and parental deployment. However, data on sexual behaviors among military-dependent youth are limited and few studies have examined how these factors influence the sexual behaviors among youth. Purpose: The purpose of this dissertation was to estimate the prevalence of risky sexual behaviors among military-dependent youth and to describe how military factors may influence their sexual behaviors. Methods: Youth, aged 15–19 years, who attended a military health facility in the southern United States between June 2011 and September 2011 were recruited to complete a short, paper-based survey (N= 208, males and females) and to participate in an in-depth interview (N = 25, females). For quantitative data, prevalence estimates were computed and chi-square analyses were conducted. Logistic regression analyses were also conducted, adjusting for age, gender, and parents' duty status. For qualitative data, thematic coding of transcribed interviews was performed. Common and unique themes were examined across participants' experiences. Results: Over half of the youth was sexually experienced (53.7%). Parental deployment and number of relocations were significantly associated with having had sex in the past 3 months; however no significant associations were found between these military factors and other sexual behaviors. Although some youth felt that being a military-dependent had negatively impacted their sexual decisions, most believed the military experience had little influence on their sexual decisions. Most youth in military families also perceived having higher parental expectations to avoid risky behaviors, in general, than youth in civilian families. Conclusions: The majority of military-dependent youth are sexually experienced; however, individual and parental factors may have a greater role in sexual initiation among youth than military stressors do. The findings highlight the need for implementation of evidence-based strategies to prevent teen pregnancy and STIs at military installations. Future studies with larger sample sizes are needed to further explore how youth may cope with these military factors and the impact of parental factors on the sexual behaviors of youth.^

Bayesian adaptive designs in early phase clinical trials

There are two practical challenges in the phase I clinical trial conduct: lack of transparency to physicians, and the late onset toxicity. In my dissertation, Bayesian approaches are used to address these two problems in clinical trial designs. The proposed simple optimal designs cast the dose finding problem as a decision making process for dose escalation and deescalation. The proposed designs minimize the incorrect decision error rate to find the maximum tolerated dose (MTD). For the late onset toxicity problem, a Bayesian adaptive dose-finding design for drug combination is proposed. The dose-toxicity relationship is modeled using the Finney model. The unobserved delayed toxicity outcomes are treated as missing data and Bayesian data augment is employed to handle the resulting missing data. Extensive simulation studies have been conducted to examine the operating characteristics of the proposed designs and demonstrated the designs' good performances in various practical scenarios.^

A comparison of adherence with minocycline treatment in Parkinson's disease and rheumatoid arthritis clinical trials

Background: Little is known about the effects on patient adherence when the same study drug is administered in the same dose in two populations with two different diseases in two different clinical trials. The Minocycline in Rheumatoid Arthritis (MIRA) trial and the NIH Exploratory Trials in Parkinson's disease (NET-PD) Futility Study I provide a unique opportunity to do the above and to compare methods measuring adherence. This study may increase understanding of the influence of disease and adverse events on patient adherence and will provide insights to investigators selecting adherence assessment methods in clinical trials of minocycline and other drugs in future.^ Methods: Minocycline adherence by pill count and the effect of adverse events was compared in the MIRA and NET-PD FS1 trials using multivariable linear regression. Within the MIRA trial, agreement between assay and pill count was compared. The association of adverse events with assay adherence was examined using multivariable logistic regression.^ Results: Adherence derived from pill count in the MIRA and NET-PD FS1 trials did not differ significantly. Adverse events potentially related to minocycline did not appear useful to predict minocycline adherence. In the MIRA trial, adherence measured by pill count appears higher than adherence measured by assay. Agreement between pill count and assay was poor (kappa statistic = 0.25).^ Limitations: Trial and disease are completely confounded and hence the independent effect of disease on adherence to minocycline treatment cannot be studied.^ Conclusion: Simple pill count may be preferred over assay in the minocycline clinical trials to measure adherence. Assays may be less sensitive in a clinical setting where appointments are not scheduled in relation to medication administration time, given assays depend on many pharmacokinetic and instrument-related factors. However, pill count can be manipulated by the patient. Another study suggested that self-report method is more sensitive than pill count method in differentiating adherence from non-adherence. An effect of medication-related adverse events on adherence could not be detected.^

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.^

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.^

Optimal, minimax, and Bayesian two-stage designs in two-dose phase II clinical trials

Background: For most cytotoxic and biologic anti-cancer agents, the response rate of the drug is commonly assumed to be non-decreasing with an increasing dose. However, an increasing dose does not always result in an appreciable increase in the response rate. This may especially be true at high doses for a biologic agent. Therefore, in a phase II trial the investigators may be interested in testing the anti-tumor activity of a drug at more than one (often two) doses, instead of only at the maximum tolerated dose (MTD). This way, when the lower dose appears equally effective, this dose can be recommended for further confirmatory testing in a phase III trial under potential long-term toxicity and cost considerations. A common approach to designing such a phase II trial has been to use an independent (e.g., Simon's two-stage) design at each dose ignoring the prior knowledge about the ordering of the response probabilities at the different doses. However, failure to account for this ordering constraint in estimating the response probabilities may result in an inefficient design. In this dissertation, we developed extensions of Simon's optimal and minimax two-stage designs, including both frequentist and Bayesian methods, for two doses that assume ordered response rates between doses. ^ Methods: Optimal and minimax two-stage designs are proposed for phase II clinical trials in settings where the true response rates at two dose levels are ordered. We borrow strength between doses using isotonic regression and control the joint and/or marginal error probabilities. Bayesian two-stage designs are also proposed under a stochastic ordering constraint. ^ Results: Compared to Simon's designs, when controlling the power and type I error at the same levels, the proposed frequentist and Bayesian designs reduce the maximum and expected sample sizes. Most of the proposed designs also increase the probability of early termination when the true response rates are poor. ^ Conclusion: Proposed frequentist and Bayesian designs are superior to Simon's designs in terms of operating characteristics (expected sample size and probability of early termination, when the response rates are poor) Thus, the proposed designs lead to more cost-efficient and ethical trials, and may consequently improve and expedite the drug discovery process. The proposed designs may be extended to designs of multiple group trials and drug combination trials.^

Clinical trials, informed consent, & emergency medicine: A systematic literature review

Background: In the United States, the Food and Drug Administration (FDA) regulates clinical trials. These regulations address good clinical practices as well as human subject protection (FDA, 2012). One of the most important legal and ethical concerns in clinical trials is informed consent. 21 CFR 50 governs human subjects research. Part 50.24 provides an emergency research exception to the informed consent requirement. Research was conducted to determine the appropriateness of this exception, whether the benefit justifies the exception, and its public health significance.^ Methods: A systematic literature review was conducted and articles were identified from peer-reviewed journals.^ Results: There is some variance in opinions regarding the appropriateness of the exception, but the literature reviewed found the study results of these trials justified the waiver.^ Conclusion: The exception to the informed consent requirement is likely appropriate and justified in emergency research when implemented within the specified guidelines.^

Organizational perspectives on the management and evaluation of large -scale multicenter controlled clinical trials: An exploratory study of participation in the beta -blocker heart attack trial

A review of literature related to appointment-keeping served as the basis for the development of an organizational paradigm for the study of appointment-keeping in the Beta-blocker Heart Attack Trial (BHAT). Features of the organizational environment, demographic characteristics of BHAT enrollees, organizational structure and processes and previous organizational performance variables were measured so as to provide exploratory information relating to the appointment-keeping behavior of 3,837 participants enrolled at thirty-two Clinical Centers. Results suggest that the social context of individual behavior is an important consideration for the understanding of patient compliance. In particular, the degree to which previous organizational performance--as measured by obtaining recruitment goals--and the ability to utilize resources had particularly strong bivariate associations with appointment-keeping. Implications for future theory development, research and practical implications were provided as was a suggestion for the development of multidisciplinary research efforts conducted within the context of Centers for the study and application of adherence behaviors. ^

A simulation study of the effects of small center enrollment in multi -center clinical trials

Multi-center clinical trials are very common in the development of new drugs and devices. One concern in such trials, is the effect of individual investigational sites enrolling small numbers of patients on the overall result. Can the presence of small centers cause an ineffective treatment to appear effective when treatment-by-center interaction is not statistically significant?^ In this research, simulations are used to study the effect that centers enrolling few patients may have on the analysis of clinical trial data. A multi-center clinical trial with 20 sites is simulated to investigate the effect of a new treatment in comparison to a placebo treatment. Twelve of these 20 investigational sites are considered small, each enrolling less than four patients per treatment group. Three clinical trials are simulated with sample sizes of 100, 170 and 300. The simulated data is generated with various characteristics, one in which treatment should be considered effective and another where treatment is not effective. Qualitative interactions are also produced within the small sites to further investigate the effect of small centers under various conditions.^ Standard analysis of variance methods and the "sometimes-pool" testing procedure are applied to the simulated data. One model investigates treatment and center effect and treatment-by-center interaction. Another model investigates treatment effect alone. These analyses are used to determine the power to detect treatment-by-center interactions, and the probability of type I error.^ We find it is difficult to detect treatment-by-center interactions when only a few investigational sites enrolling a limited number of patients participate in the interaction. However, we find no increased risk of type I error in these situations. In a pooled analysis, when the treatment is not effective, the probability of finding a significant treatment effect in the absence of significant treatment-by-center interaction is well within standard limits of type I error. ^

Oat Variety Trials, 2010 and 2011

Oat is the major spring-sown, small grain crop in Iowa. Spring-sown small grains can be used for grain and straw production, as a companion crop to establish hay and pastures, or as a source of early-season forage as hay or haylage. Because small grains generally mature before the end of July, a forage legume, cover crop, or green manure crop can follow oats, or animal manure can be spread on the field in which oats were grown.

On-farm Cooperator Trials 2011: Effect of Extended-duration Row Covers on Muskmelon and Winter Squash on Bacterial Wilt and Yield

Susceptible cucurbit crops are difficult to grow in Iowa because of bacterial wilt, caused by Erwinia tracheiphila. Striped and spotted cucumber beetles transmit bacterial wilt. Other insect pests such as squash vine borer and squash bugs may also have an economic impact on yield, particularly in squash.

Discursos, memorias y verdades : Algunas reflexiones acerca del juicio por delitos de lesa humanidad cometidos en la Norpatagonia

La realización del juicio oral y público a los responsables militares de los delitos de lesa humanidad, cometidos en la región del Comahue durante la última dictadura cívico-militar, estuvo caracterizado por una fuerte tensión en los discursos que lo constituyeron. Una tensión dada por cuatro diferentes relatos respecto de lo sucedido durante aquel período de la historia argentina, sobre los cuales, a su vez, se apoyan y construyen las distintas memorias colectivas que se reciben, transmiten, reproducen y reconstruyen con respecto a aquel período. En este artículo, describo cuáles fueron las características de este juicio realizado en la ciudad de Neuquén en 2008, y explico cómo se articularon esos relatos en las exposiciones de las partes en el debate oral. Finalmente, propongo una reflexión acerca de las formas en que la verdad histórica se articula con el derecho y la memoria

Psicología y delitos de lesa humanidad : Dispositivos de acompañamiento activo. Un aporte posible desde la psicología en los juicios por lesa humanidad

Con la puesta en marcha y desarrollo de los juicios por crímenes de lesa humanidad cometidos durante la última dictadura cívico-militar se inaugura un nuevo espacio de intervención para la psicología. El interés por ampliar y profundizar las posibilidades de trabajar en este campo impulsa a llevar adelante una tarea de investigación, conceptualización y desarrollo acerca de los aportes posibles de la psicología a las problemáticas que plantea el abordaje de las víctimas de los delitos de lesa humanidad en el marco de su tramitación judicial. Se analizará la evolución en el campo jurídico de las variables que permitieron el pasaje de la consideración de los delitos cometidos por el régimen militar a su calificación como delitos de lesa humanidad, condición fundamental que les confiere el carácter de imprescriptibilidad, lo cual habilita el relanzamiento de los juicios por estas causas y la consiguiente osibilidad de intervenir desde nuestra profesión. Para ello será necesario tener en cuenta tanto el análisis de las condiciones de inicio del campo de la salud mental y derechos humanos, como los requerimientos y posibilidades actuales del mismo. En este sentido, se presentará el diseño e implementación de un modelo de Dispositivo de acompañamiento activo dirigido a testigos-víctimas y querellantes en juicios por crímenes de lesa humanidad en contexto de acceso a la justicia

Discursos, memorias y verdades : Algunas reflexiones acerca del juicio por delitos de lesa humanidad cometidos en la Norpatagonia

La realización del juicio oral y público a los responsables militares de los delitos de lesa humanidad, cometidos en la región del Comahue durante la última dictadura cívico-militar, estuvo caracterizado por una fuerte tensión en los discursos que lo constituyeron. Una tensión dada por cuatro diferentes relatos respecto de lo sucedido durante aquel período de la historia argentina, sobre los cuales, a su vez, se apoyan y construyen las distintas memorias colectivas que se reciben, transmiten, reproducen y reconstruyen con respecto a aquel período. En este artículo, describo cuáles fueron las características de este juicio realizado en la ciudad de Neuquén en 2008, y explico cómo se articularon esos relatos en las exposiciones de las partes en el debate oral. Finalmente, propongo una reflexión acerca de las formas en que la verdad histórica se articula con el derecho y la memoria

Psicología y delitos de lesa humanidad : Dispositivos de acompañamiento activo. Un aporte posible desde la psicología en los juicios por lesa humanidad

Con la puesta en marcha y desarrollo de los juicios por crímenes de lesa humanidad cometidos durante la última dictadura cívico-militar se inaugura un nuevo espacio de intervención para la psicología. El interés por ampliar y profundizar las posibilidades de trabajar en este campo impulsa a llevar adelante una tarea de investigación, conceptualización y desarrollo acerca de los aportes posibles de la psicología a las problemáticas que plantea el abordaje de las víctimas de los delitos de lesa humanidad en el marco de su tramitación judicial. Se analizará la evolución en el campo jurídico de las variables que permitieron el pasaje de la consideración de los delitos cometidos por el régimen militar a su calificación como delitos de lesa humanidad, condición fundamental que les confiere el carácter de imprescriptibilidad, lo cual habilita el relanzamiento de los juicios por estas causas y la consiguiente osibilidad de intervenir desde nuestra profesión. Para ello será necesario tener en cuenta tanto el análisis de las condiciones de inicio del campo de la salud mental y derechos humanos, como los requerimientos y posibilidades actuales del mismo. En este sentido, se presentará el diseño e implementación de un modelo de Dispositivo de acompañamiento activo dirigido a testigos-víctimas y querellantes en juicios por crímenes de lesa humanidad en contexto de acceso a la justicia