An adaptive Simon Two-Stage Design for Phase 2 studies of targeted therapies

The field of specialized medicine and clinical development programs for targeted cancer therapies are rapidly expanding. The proposed Phase 2 design allows for preliminary determination of efficacy that may be restricted to a particular sub-population defined by biomarker status (presence/absence). The design is an adaptation of the Simon Two-Stage Design. We provide examples where the adaptation can result in substantial savings in sample size and thus potentially lead to greater efficiency in decision making during the drug development process.     

Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials

Context  The US Food and Drug Administration (FDA) has issued warnings that use of antidepressant medications poses a small but significantly increased risk of suicidal ideation/suicide attempt for children and adolescents. Objective  To assess the efficacy and risk of reported suicidal ideation/suicide attempt of antidepressants for treatment of pediatric major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and non-OCD anxiety disorders. Data Sources and Study Selection  PubMed (1988 to July 2006), relevant US and British regulatory agency reports, published abstracts of important scientific meetings (1998-2006), clinical trial registries, and information from authors. Studies were published and unpublished randomized, placebo-controlled, parallel-group trials of second-generation antidepressants (selective serotonin reuptake inhibitors, nefazodone, venlafaxine, and mirtazapine) in participants younger than 19 years with MDD, OCD, or non-OCD anxiety disorders. Data Extraction  Information was extracted on study characteristics, efficacy outcomes, and spontaneously reported suicidal ideation/suicide attempt. Data Synthesis  Twenty-seven trials of pediatric MDD (n = 15), OCD (n = 6), and non-OCD anxiety disorders (n = 6) were selected, and risk differences for response and for suicidal ideation/suicide attempt estimated by random-effects methods. Pooled risk differences in rates of primary study-defined measures of responder status significantly favored antidepressants for MDD (11.0%; [95% confidence interval {CI}, 7.1% to 14.9%]), OCD (19.8% [95% CI, 13.0% to 26.6%), and non-OCD anxiety disorders (37.1% [22.5% to 51.7%]), corresponding to a number needed to treat (NNT) of 10 (95% CI, 7 to 15), 6 (4 to 8), and 3 (2 to 5), respectively. While there was increased risk difference of suicidal ideation/suicide attempt across all trials and indications for drug vs placebo (0.7%; 95% CI, 0.1% to 1.3%) (number needed to harm, 143 [95% CI, 77 to 1000]), the pooled risk differences within each indication were not statistically significant: 0.9% (95% CI, –0.1% to 1.9%) for MDD, 0.5% (–1.2% to 2.2%) for OCD, and 0.7% (–0.4% to 1.8%) for non-OCD anxiety disorders. There were no completed suicides. Age-stratified analyses showed that for children younger than 12 years with MDD, only fluoxetine showed benefit over placebo. In MDD trials, efficacy was moderated by age, duration of depression, and number of sites in the treatment trial. Conclusions  Relative to placebo, antidepressants are efficacious for pediatric MDD, OCD, and non-OCD anxiety disorders, although the effects are strongest in non-OCD anxiety disorders, intermediate in OCD, and more modest in MDD. Benefits of antidepressants appear to be much greater than risks from suicidal ideation/suicide attempt across indications, although comparison of benefit to risk varies as a function of indication, age, chronicity, and study conditions.      

Diagnosing platelet delta-storage pool disease in children by flow cytometry

Bleeding problems are symptomatic of platelet delta-storage pool diseases (SPDs) such as Hermansky-Pudlak syndrome. Although at present no cure is available for delta-SPD, early diagnosis is of great importance for prophylactic and supportive treatment. This study tested the usefulness of a flow cytometric assay for platelet serotonin in children. The assay was used to diagnose delta-SPD in a 10-year-old girl. Platelet serotonin levels were significantly lower in the patient than in all healthy control subjects (10 children and 10 adults). The serotonin results were supported by traditional tests, which are transmission electron microscopy of whole mounts and adenosine triphosphate release by lumi-aggregometry. The flow cytometric serotonin assay is a major improvement to current pediatric diagnostics. The advantages of this test are small sample volume of fresh or fixed/frozen platelets, availability of objective results within 2 hours of obtaining the blood sample, and automated analysis by flow cytometry.     

The effect of age on memory for emotional faces

Prior studies of emotion suggest that young adults should have enhanced memory for negative faces and that this enhancement should be reduced in older adults. Several studies have not shown these effects but were conducted with procedures different from those used with other emotional stimuli. In this study, researchers examined age differences in recognition of faces with emotional or neutral expressions, using trial-unique stimuli, as is typically done with other types of emotional stimuli. They also assessed the influence of personality traits and mood on memory. Enhanced recognition for negative faces was found in young adults but not in older adults. Recognition of faces was not influenced by mood or personality traits in young adults, but lower levels of extraversion and better emotional sensitivity predicted better negative face memory in older adults. These results suggest that negative expressions enhance memory for faces in young adults, as negative valence enhances memory for words and scenes. This enhancement is absent in older adults, but memory for emotional faces is modulated in older adults by personality traits that are relevant to emotional processing.     

A Cardiovascular Health Intervention for Spanish Speakers: The Health Literacy and ESL Curriculum

Spanish speakers in the United States are in need of effective interventions that address both cardiovascular disease (CVD) and health literacy. However, the literature lacks interventions that have used and evaluated a strategies that focus on both, particularly at the community level. The aim of this study was to explore the effect of a health literacy curriculum on cardiovascular health behavior among Spanish speaking adults. It used a randomized controlled pre-posttest design. Participants included Hispanic adults with a low-to-intermediate level of English proficiency. The intervention group received the health literacy and English as a second language (ESL) Curriculum with CVD specific content, while the control group received a conventional ESL curriculum. Tools included the Spanish Cardiovascular Health Questionnaire (CSC), the test of functional health literacy in adults (TOFHLA), and the Combined English Language Skills Assessment. Analysis of change scores included independent sample t test and multiple linear regression. A total of 155 participants completed the study. There was a significant greater improvement for the intervention group in change of CSC score from pretest to posttest (P?=?0.049) compared to controls. The study also found significantly improved TOFHLA (P?=?0.011), however it did not find a relationship between changes in CVD behavior and health literacy or English proficiency. The Health Literacy and ESL Curriculum constitutes a valuable resource for addressing the cardiovascular health, literacy, and language needs of Spanish-speaking adults. Interventions that take a multilevel education and health approach may be more effective in addressing the needs of immigrants. Research should further explore the interactions between CVD behavior, health literacy, and English proficiency.     

Peer Reviewed: Starting School Healthy and Ready to Learn: Using Social Indicators to Improve School Readiness in Los Angeles County

Background

School readiness is an important public health outcome, determined by a set of interdependent health and developmental trajectories and influenced by a child''s family, school, and community environments. The same factors that influence school readiness also influence educational success and health throughout life.

Context

A California cigarette tax ballot initiative (Proposition 10) created new resources for children aged 0 to 5 years and their families statewide through county-level First 5 commissions, including First 5 LA in Los Angeles County. An opportunity to define and promote school readiness indicators was facilitated by collaborative relationships with a strong emphasis on data among First 5 LA, the Children''s Planning Council, and the Los Angeles County Public Health Department, and other child-serving organizations.

Methods

A workgroup developed school readiness goals and indicators based on recommendations of the National Education Goals Panel and five key domains of child well-being: 1) good health, 2) safety and survival, 3) economic well-being, 4) social and emotional well-being, and 5) education/workforce readiness.

Consequences

The Los Angeles County Board of Supervisors and First 5 LA Commission adopted the school readiness indicators. First 5 LA incorporated the indicators into the results-based accountability framework for its strategic plan and developed a community-oriented report designed to educate and spur school readiness-oriented action. The Los Angeles County Board of Supervisors approved a countywide consensus-building plan designed to engage key stakeholders in the use of the indicators for planning, evaluation, and community-building activities.

Interpretation

School readiness indicators in Los Angeles County represent an important step forward for public health practice, namely, the successful blending of an expanded role for assessment with the ecological model.     

Advance care planning for residents in aged care facilities: what is best practice and how can evidence-based guidelines be implemented?

Background Advance care planning in a residential care setting aims to assist residents to make decisions about future healthcare and to improve end-of-life care through medical and care staff knowing and respecting the wishes of the resident. The process enables individuals and others who are important to them, to reflect on what is important to the resident including their beliefs/values and preferences about care when they are dying. This paper describes a project conducted as part of the Joanna Briggs Institute Clinical Aged Care Fellowship Program implemented at the Manningham Centre in metropolitan Melbourne in a unit providing services for 46 low and high care residents. Objectives The objectives of the study were to document implementation of best practice in advance care planning in a residential aged care facility using a cycle of audit, feedback and re-audit cycle audit with a clinical audit software program, the Practical Application of Clinical Evidence System. The evidence-based guidelines found in 'Guidelines for a Palliative Approach in Residential Aged Care' were used to inform the process of clinical practice review and to develop a program to implement advance care planning. Results The pre-implementation audit results showed that advance care planning practice was not based on high level evidence as initial compliance with five audit criteria was 0%. The barriers to implementation that became apparent during the feedback stage included the challenge of creating a culture where advance care planning policy, protocols and guidelines could be implemented, and advance care planning discussions held, by adequately prepared health professionals and carers. Opportunities were made to equip the resident to discuss their wishes with family, friends and healthcare staff. Some residents made the decision to take steps to formally document those wishes and/or appoint a Medical Enduring Power of Attorney to act on behalf of the resident when they are unable to communicate wishes. The post-implementation audit showed a clear improvement as compliance ranged from 15-100% for the five audit criteria. Strong leadership by the project team was effective in engaging staff in this quality improvement program. Conclusion The outcomes of the project were extremely positive and demonstrate a genuine improvement in practice. All audit criteria indicate that the Manningham Centre is now positively working towards improved practice based on the best available evidence. It is hoped that as the expertise developed during this project is shared, other areas of gerontological practice will be similarly improved and more facilities caring for the older person will embrace evidence-based practice.