Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial. OBJECTIVE: Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age. DESIGN/METHODS: A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups. RESULTS: Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non-central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5 degrees C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories. CONCLUSIONS: Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.

Intracranial EEG reveals a time- and frequency-specific role for the right inferior frontal gyrus and primary motor cortex in stopping initiated responses.

Inappropriate response tendencies may be stopped via a specific fronto/basal ganglia/primary motor cortical network. We sought to characterize the functional role of two regions in this putative stopping network, the right inferior frontal gyrus (IFG) and the primary motor cortex (M1), using electocorticography from subdural electrodes in four patients while they performed a stop-signal task. On each trial, a motor response was initiated, and on a minority of trials a stop signal instructed the patient to try to stop the response. For each patient, there was a greater right IFG response in the beta frequency band ( approximately 16 Hz) for successful versus unsuccessful stop trials. This finding adds to evidence for a functional network for stopping because changes in beta frequency activity have also been observed in the basal ganglia in association with behavioral stopping. In addition, the right IFG response occurred 100-250 ms after the stop signal, a time range consistent with a putative inhibitory control process rather than with stop-signal processing or feedback regarding success. A downstream target of inhibitory control is M1. In each patient, there was alpha/beta band desynchronization in M1 for stop trials. However, the degree of desynchronization in M1 was less for successfully than unsuccessfully stopped trials. This reduced desynchronization on successful stop trials could relate to increased GABA inhibition in M1. Together with other findings, the results suggest that behavioral stopping is implemented via synchronized activity in the beta frequency band in a right IFG/basal ganglia network, with downstream effects on M1.

CLINICAL TRIAL ENROLLMENT IN A MULTIDISCIPLINARY PROSTATE CANCER

Purpose: Clinical oncology trials are hampered by low accrual rates. Less than 5% of adult cancer patients are treated on a clinical trial. We aimed to evaluate clinical trial enrollment in our Multidisciplinary Prostate Cancer Clinic and to assess if a clinical trial initiative, introduced in 2006, increased our trial enrollment.Methods: Prostate cancer patients with non-metastatic disease who were seen in the clinic from 2004 to 2008 were included in the analysis. Men were categorized by whether they were seen before or after the clinical trial enrollment initiative started in 2006. The initiative included posting trial details in the clinic, educating patients about appropriate clinical trial options during the treatment recommendation discussion, and providing patients with documentation of trials offered to them. Univariate and multivariate (MVA) logistic regression analysis evaluated the impact of patient characteristics and the clinical trial initiative on clinical trial enrollment.Results: The majority of the 1,370 men were white (83%), and lived within the surrounding counties or state (69.4%). Median age was 64.2 years. Seventy-three point five percent enrolled in at least one trial and 28.5% enrolled in more than one trial. Sixty-seven percent enrolled in laboratory studies, 18% quality of life studies, 13% novel studies, and 3.7% procedural studies. On MVA, men seen in later years (p < 0.0001) were more likely to enroll in trials. The proportion of men enrolling increased from 38.9% to 84.3% (p<0.0001) after the clinical trial initiative. On MVA, older men (p < 0.0001) were less likely to enroll in clinical trials. There was a trend toward men in the high-risk group being more likely to participate in clinical trials (p = 0.056). There was a second trend for men of Hispanic, Asian, Native American and Indian decent being less likely to participate in clinical trials (p = 0.054).Conclusion: Clinical trial enrollment in the multidisciplinary clinic increased after introduction of a clinical trial initiative. Older men were less likely to enroll in trials. We speculate we achieved high enrollment rates because 1) specific trials are discussed at time of treatment recommendations, 2) we provide a letter documenting offered trials and 3) we introduce patients to the research team at the same clinic visit if they are interested in trial participation.

Systematic review of interventions designed to reduce screen time in children and adolescents

This descriptive systematic review describes intervention trials for children and youth that targeted screen time (ST) as a way to prevent or control obesity and measured ST, and at least one of the following: physical activity, dietary intake, and adiposity. Both “hands-on” (e.g., video games) and “hands free” (e.g., television viewing) ST were included. Published, completed intervention trials (k=12), not-yet-published, completed trials (k=6), and in-progress trials (k=11) were identified through searches of electronic databases, including trial registries and bibliographies of eligible study reports. Study characteristics of the 29 identified trials were coded and presented in evidence tables. Considerable attention was paid to the type of ST addressed, measures used, and the type of interventions. Based on the number of in-progress and not-yet-published trials, the number of completed, published reports will double in the next three years. Most of the studies were funded by federal sources. General populations, not restricted by race, gender, or weight status, were targets of most interventions with children ages 9-12 yeas as the modal age group. Most trials used randomized control trials in which the majority of control or comparison group received an intervention. The mean number of participants was 242.8 (SD=314.7) and interventions were delivered over an average of 10.5 months and consisted of approximately 16 sessions, with a total time of about eight hours. The majority of completed trials evaluate each of the four constructs, however, most studies have more than one measure to assess each construct (e.g., BMI and tricep skinfold thickness to evaluate adiposity) and rarely did studies use the same measures. This is likely why the majority of studies produced at least one significant intervention effect on each outcome that was assessed. The four major outcomes should be evaluated in all interventions attempting to reduce screen time in order to determine the mechanisms involved that may contribute to obesity. More importantly researchers should work together to determine the best measures to evaluate the four main constructs to allow studies to be compared. Another area for consensus is the definition of ST. ^

Identifying and removing barriers to cycling as a viable means of transportation in Houston, Texas

The citizens of Houston, Texas, spend much time commuting. It has repeatedly been named among the “Fattest Cities” by Men’s Fitness Magazine (The fittest and fattest cities in America – Men’s Fitness. ). Obesity is one of its major public health problems as Houstonians often do not engage in enough physical activity to help them maintain their ideal weights. The use of bicycles provides a healthy and ecological alternative to commuting by driving. However, because urban cyclists must often share the roads with motorized vehicles, cyclists are often exposed to high levels of emissions. As vulnerable users of the roadways, urban cyclists also face the threat of injury. Nevertheless, there are some programs that encourage the use of bicycles. Laws and ordinances not only reveal public policy relating to bicycling but are a means to develop policy which can encourage bicycling. ^

Body mass index trajectories and predictors among 3rd to 12th graders using growth curve mixture modeling the Child and Adolescent Trial for Cardiovascular Health (CATCH) study

This dissertation examined body mass index (BMI) growth trajectories and the effects of gender, ethnicity, dietary intake, and physical activity (PA) on BMI growth trajectories among 3rd to 12th graders (9-18 years of age). Growth curve model analysis was performed using data from The Child and Adolescent Trial for Cardiovascular Health (CATCH) study. The study population included 2909 students who were followed up from grades 3-12. The main outcome was BMI at grades 3, 4, 5, 8, and 12. ^ The results revealed that BMI growth differed across two distinct developmental periods of childhood and adolescence. Rate of BMI growth was faster in middle childhood (9-11 years old or 3rd - 5th grades) than in adolescence (11-18 years old or 5th - 12th grades). Students with higher BMI at 3rd grade (baseline) had faster rates of BMI growth. Three groups of students with distinct BMI growth trajectories were identified: high, average, and low. ^ Black and Hispanic children were more likely to be in the groups with higher baseline BMI and faster rates of BMI growth over time. The effects of gender or ethnicity on BMI growth differed across the three groups. The effects of ethnicity on BMI growth were weakened as the children aged. The effects of gender on BMI growth were attenuated in the groups with a large proportion of black and Hispanic children, i.e., “high” or “average” BMI trajectory group. After controlling for gender, ethnicity, and age at baseline, in the “high BMI trajectory”, rate of yearly BMI growth in middle childhood increased 0.102 for every 500 Kcals increase (p=0.049). No significant effects of percentage of energy from total fat and saturated fat on BMI growth were found. Baseline BMI increased 0.041 for every 30 minutes increased in moderate-to-vigorous PA (MVPA) in the “low BMI trajectory”, while Baseline BMI decreased 0.345 for every 30 minutes increased in vigorous PA (VPA) in the “high BMI trajectory”. ^ Childhood overweight and obesity interventions should start at the earliest possible ages, prior to 3rd grade and continue through grade school. Interventions should focus on all children, but specifically black and Hispanic children, who are more likely to be highest at-risk. Promoting VPA earlier in childhood is important for preventing overweight and obesity among children and adolescents. Interventions should target total energy intake, rather than only percentage of energy from total fat or saturated fat. ^

AN ILLNESS-DEATH PROCESS WITH TIME-DEPENDENT COVARIATES

A general model for the illness-death stochastic process with covariates has been developed for the analysis of survival data. This model incorporates important baseline and time-dependent covariates to make proper adjustment for the transition probabilities and survival probabilities. The follow-up period is subdivided into small intervals and a constant hazard is assumed for each interval. An approximation formula is derived to estimate the transition parameters when the exact transition time is unknown.^ The method developed is illustrated by using data from a study on the prevention of the recurrence of a myocardial infarction and subsequent mortality, the Beta-Blocker Heart Attack Trial (BHAT). This method provides an analytical approach which simultaneously includes provision for both fatal and nonfatal events in the model. According to this analysis, the effectiveness of the treatment can be compared between the Placebo and Propranolol treatment groups with respect to fatal and nonfatal events. ^

Comparison of methods for assessing in home night time crying in healthy infants

Background. Infant colic is a common condition that is thought to put infants at risk for Shaken Baby Syndrome, a particularly devastating form of child abuse. However, little research has been done on techniques parents can use to deal with infant colic. This pilot study was conducted to assess the equipment that will be used in a randomized control trial that will compare the results for two different techniques that parents can use to reduce crying in infants with colic. ^ Methods. A total of 11 healthy infants, between one and five months of age, were recruited into this pilot study. All infants had a dosimeter, actiwatch and maternal log placed into the home and a subset of infants (N=3) were also recorded by a video camera. The equipment recorded between 6pm and 6am for at least two and up to five nights. The maternal log and video log were compared with one another to determine if the maternal log provides an accurate representation of the infant's night-time activities (i.e. sleep, awake, crying, feeding). The maternal log was then compared to the dosimeter and actiwatch data to determine if the dosimeter/actiwatch accurately reproduce the maternal log. ^ Results. Data from 10 infants were included in the analyses. The maternal log and video log were in full or partial agreement 90% of the time. When comparing events noted by the mother, the maternal log and dosimeter data were in agreement 84% of the time, and the maternal log and actiwatch data were in agreement 87% of the time. In combination, the dosimeter and/or actiwatch data agreed with the maternal log 90% of the time. ^ Conclusions. Our preliminary analyses of these data suggest the dosimeter and actiwatch will be useful tool for defining infant sleep patterns relative to the maternal log. However further analysis will be required to develop threshold values that can be used to objectively define events in the proposed RCT. Such analyses will need to integrate data from multiple dosimeters and deal with the shifting baselines observed for both the dosimeter and actiwatch.^

The heart challenge: The effect of regular aerobic exercise on body fat distribution in third and fourth grade school children: A randomized clinical trial

The pattern of body fat distribution known as "centralized", and characterized by a predominance of subcutaneous fat on the trunk and a "pot belly", has been associated with an increased risk of chronic disease. These patterns of fat distribution, as well as the lifestyle habit variables associated with adult fatness and chronic morbidity clearly begin to develop during childhood, indicating the need for intervention and primary prevention of obesity, particularly the centralized form, during childhood or adolescence. The purpose of this study was to determine whether regular aerobic exercise could beneficially alter the distribution of body fat in 8 and 9 year old children. One hundred and eighty-eight participants were randomized into either a regular aerobic exercise treatment group or a standard physical education program control group. A variety of aerobic activities was used for intervention 5 days per week during physical education class for a period of 12 weeks. Fat distribution was measured by a number of the most commonly used indices, including ratios of body circumferences and skinfolds and indices derived from a principal components analysis. Change over time in average pulse rate was used to determine if intervention actually occurred. Approximately 10% of the students were remeasured, allowing the calculation of intra- and interexaminer measurement reliability estimates for all indices.^ This study group was comparable to the U.S. population, though the study children were slightly larger for certain measures. No effect of the exercise intervention was found. The most likely explanation for this was inadequacy of the intervention, as indicated by the lack of any change in average pulse rate with treatment. The results of the measurement reliability analysis are reported and indicate that body circumference ratios are more precise than skinfold ratios, particularly when multiple observers are used. Reliability estimates for the principal component indices were also high.^ It remains unclear whether the distribution of body fat can be altered with exercise. It is likely that this issue will remain undecided until one highly reliable, valid, and sensitive measure of fat distribution can be found. ^

Effect of patient accrual patterns on power and size of log-rank test for time-to-event outcome in clinical trials

The determination of size as well as power of a test is a vital part of a Clinical Trial Design. This research focuses on the simulation of clinical trial data with time-to-event as the primary outcome. It investigates the impact of different recruitment patterns, and time dependent hazard structures on size and power of the log-rank test. A non-homogeneous Poisson process is used to simulate entry times according to the different accrual patterns. A Weibull distribution is employed to simulate survival times according to the different hazard structures. The current study utilizes simulation methods to evaluate the effect of different recruitment patterns on size and power estimates of the log-rank test. The size of the log-rank test is estimated by simulating survival times with identical hazard rates between the treatment and the control arm of the study resulting in a hazard ratio of one. Powers of the log-rank test at specific values of hazard ratio (≠1) are estimated by simulating survival times with different, but proportional hazard rates for the two arms of the study. Different shapes (constant, decreasing, or increasing) of the hazard function of the Weibull distribution are also considered to assess the effect of hazard structure on the size and power of the log-rank test. ^

Health outcomes, quality improvement and cost-effectiveness of the Community Diabetes Education (CoDE) program: Results of a randomized controlled trial

The objectives of this dissertation were to evaluate health outcomes, quality improvement measures, and the long-term cost-effectiveness and impact on diabetes-related microvascular and macrovascular complications of a community health worker-led culturally tailored diabetes education and management intervention provided to uninsured Mexican Americans in an urban faith-based clinic. A prospective, randomized controlled repeated measures design was employed to compare the intervention effects between: (1) an intervention group (n=90) that participated in the Community Diabetes Education (CoDE) program along with usual medical care; and (2) a wait-listed comparison group (n=90) that received only usual medical care. Changes in hemoglobin A1c (HbA1c) and secondary outcomes (lipid status, blood pressure and body mass index) were assessed using linear mixed-models and an intention-to-treat approach. The CoDE group experienced greater reduction in HbA1c (-1.6%, p<.001) than the control group (-.9%, p<.001) over the 12 month study period. After adjusting for group-by-time interaction, antidiabetic medication use at baseline, changes made to the antidiabetic regime over the study period, duration of diabetes and baseline HbA1c, a statistically significant intervention effect on HbA1c (-.7%, p=.02) was observed for CoDE participants. Process and outcome quality measures were evaluated using multiple mixed-effects logistic regression models. Assessment of quality indicators revealed that the CoDE intervention group was significantly more likely to have received a dilated retinal examination than the control group, and 53% achieved a HbA1c below 7% compared with 38% of control group subjects. Long-term cost-effectiveness and impact on diabetes-related health outcomes were estimated through simulation modeling using the rigorously validated Archimedes Model. Over a 20 year time horizon, CoDE participants were forecasted to have less proliferative diabetic retinopathy, fewer foot ulcers, and reduced numbers of foot amputations than control group subjects who received usual medical care. An incremental cost-effectiveness ratio of $355 per quality-adjusted life-year gained was estimated for CoDE intervention participants over the same time period. The results from the three areas of program evaluation: impact on short-term health outcomes, quantification of improvement in quality of diabetes care, and projection of long-term cost-effectiveness and impact on diabetes-related health outcomes provide evidence that a community health worker can be a valuable resource to reduce diabetes disparities for uninsured Mexican Americans. This evidence supports formal integration of community health workers as members of the diabetes care team.^