Longitudinal Randomized Clinical Trial Research Articles

Efficacy and safety of a non-immersive virtual reality-based neuropsychological intervention for cognitive stimulation and relaxation in patients with critical illness: study protocol of a randomized clinical trial (RGS-ICU)

BackgroundExperiencing a critical illness may be a stressful life event that is also associated with cognitive dysfunction during and after the intensive care unit (ICU) stay. A deep-tech solution based on non-immersive virtual reality, gamification and motion capture called Rehabilitation Gaming System for Intensive Care Units (RGS-ICU) has been developed that includes both cognitive stimulation and relaxation protocols specifically designed for patients with critical illness. This study aims to evaluate whether the cognitive and relaxation protocols of the RGS-ICU platform are 1) effective in improving neuropsychological outcomes during and after ICU stay and 2) safe for patients with critical illness.MethodsThis is a study protocol for a multicenter longitudinal randomized clinical trial. At least 80 patients with critical illness will be included: 40 experimental subjects and 40 control subjects. Patients in the experimental group will receive daily 20-min sessions of cognitive stimulation and relaxation with the RGS-ICU platform adjuvant to standard ICU care in their own rooms during the ICU stay and until discharge from the ICU or up to a maximum of 28 days after randomization, provided they are alert and calm. Patients in the experimental group will be constantly monitored as part of standard ICU care to ensure the safety of the intervention and that no avoidable adverse events occur. Patients in the control group will receive standard ICU care. The primary outcome is objective cognition 12 months after ICU discharge, assessed with a composite index including measures of attention, working memory, learning/memory, executive function and processing speed. The secondary outcome is the safety of the intervention, assessed by considering the number of sessions terminated early due to unsafe events in physiological parameters. Other outcomes are comfort experienced during the ICU stay, and subjective cognition, mental health (anxiety, depression and post-traumatic stress disorder), functionality and health-related quality of life 12 months after ICU discharge.DiscussionThe expected results are 1) better neuropsychological outcomes during and after the ICU stay in patients in the experimental group compared to patients in the control group and 2) that the cognitive and relaxation protocols of the RGS-ICU platform are safe for patients with critical illness.Trial registrationClinicaltrials.gov NCT06267911. Registered on February 20, 2024.

Small sample adjustment for inference without assuming orthogonality in a mixed model for repeated measures analysis

ABSTRACT The mixed model for repeated measures (MMRM) analysis is sometimes used as a primary statistical analysis for a longitudinal randomized clinical trial. When the MMRM analysis is implemented in ordinary statistical software, the standard error of the treatment effect is estimated by assuming orthogonality between the fixed effects and covariance parameters, based on the characteristics of the normal distribution. However, orthogonality does not hold unless the normality assumption of the error distribution holds, and/or the missing data are derived from the missing completely at random structure. Therefore, assuming orthogonality in the MMRM analysis is not preferable. However, without the assumption of orthogonality, the small-sample bias in the standard error of the treatment effect is significant. Nonetheless, there is no method to improve small-sample performance. Furthermore, there is no software that can easily implement inferences on treatment effects without assuming orthogonality. Hence, we propose two small-sample adjustment methods inflating standard errors that are reasonable in ideal situations and achieve empirical conservatism even in general situations. We also provide an R package to implement these inference processes. The simulation results show that one of the proposed small-sample adjustment methods performs particularly well in terms of underestimation bias of standard errors; consequently, the proposed method is recommended. When using the MMRM analysis, our proposed method is recommended if the sample size is not large and between-group heteroscedasticity is expected.

Effectiveness of the myPlan Teen App, a Digital Healthy Relationship and Safety Planning Intervention With Adolescent Aged 15–17 Years

PurposeTo determine the effectiveness of myPlan Teen app compared to usual care on the use of helpful safety behaviors, dating violence victimization and perpetration, depression, and suicide behavior. MethodsA longitudinal randomized clinical trial with 617 adolescents randomized to myPlan Teen or usual care. Participants in both groups completed surveys using validated measures at baseline, 3, 6-, and 12-months post-baseline. The study analysis examined the difference between the intervention and control groups in change over time in outcomes. ResultsmyPlan Teen significantly increased the use and helpfulness of safety behaviors among adolescents compared to the control group. Intervention users also significantly reduced the perpetration of physical and sexual violence and suicide behaviors. Although both groups experienced decreases in victimization and depression over the 12 months, the differences were not significantly different by group. DiscussionmyPlan Teen, a digitally delivered intervention, is one of the few interventions targeting dating violence in adolescence that has proven effective.

Cognitive intra-individual variability as an outcome or moderator of speed of processing training in aging adults with HIV-associated neurocognitive disorder: A secondary data analysis of a 2-year longitudinal randomized clinical trial

ObjectiveCognitive intra-individual variability (IIV), dispersion of cognitive performance across cognitive domains, indicates diminished cognitive control resulting from brain pathology or aging. For people with HIV-Associated Neurocognitive Disorder (HAND), cognitive IIV may interfere with and/or be improved by cognitive training. In this current secondary data analysis, we explored whether cognitive IIV functions as an outcome or moderator variable in speed of processing (SOP) training in middle-aged and older people living with HIV (PLWH). MethodIn this randomized clinical trial, 216 PLWH with HAND or borderline HAND were randomized to either: 1) 10 h of SOP training; 2) 20 h of SOP training, or 3) 10 h of Internet Navigation Control Training. Participants completed a seven-domain cognitive battery at baseline, posttest after training, and years 1 and 2 follow up; from this, the coefficient of variation (CoV) served as the cognitive IIV dispersion score. Participants also completed a gold-standard measure of SOP (i.e., Useful Field of View Test (UFOV®), a targeted cognitive outcomes of the SOP training paradigm) at each time point. ResultsUsing linear mixed-effect models, no strong pattern of SOP training effects were detected on cognitive IIV. However, a three-way interaction tests between time, group, and baseline cognitive IIV CoV suggested potential moderation effects. Stratified analyses showed differential treatment effects between the lower cognitive IIV and higher cognitive IIV group. ConclusionsAlthough SOP training did not improve cognitive IIV, cognitive IIV may be a modifier of SOP training. Implications for future research and other types of training are provided.

Efficacy of the combination of myofunctional therapy (lip exercises) and activator high-pull headgear in the closure of interlabial gap in long-face skeletal class II patients with lip incompetence: A 6–8-month longitudinal randomized clinical trial

ABSTRACT Background: Lip incompetence is an important issue in orthodontics. No study has evaluated the effects of the combination of headgear + lip exercises on lip incompetence. Therefore, this study was conducted. Materials and Methods: This was a longitudinal randomized clinical trial on 29 subjects (16 controls and 13 experimental subjects). Both groups were treated with standardized activator high-pull headgear (and followed up monthly) for 6–8 months. In the experimental group, patients were also instructed to practice certain lip exercises 3 sessions a day, 5 times per session. Pre-/post-treatment interlabial gap, upper lip length and vermilion height, lower lip length and vermilion height, nasolabial angle, and profile convexity angle were measured clinically and photographically, immediately before treatment and after it. Data were analyzed using paired/unpaired t-tests (α = 0.025) and partial correlation coefficient controlling for the intervention type (α = 0.05). Results: Lip exercise plus activator headgear significantly changed/improved all parameters (P ≤ 0.006) over the 6–8-month course of treatment. Activator headgear alone changed/improved only 4 parameters: interlabial gap, upper and lower lip lengths, the lower lip vermilion height, and profile convexity (P ≤ 0.008). Compared to the control (activator headgear alone), in the experimental group, the changes observed in the interlabial gap closure (P = 0.011), upper lip lengthening (P = 0.002), and upper lip vermilion lengthening (P = 0.017) were significantly greater. Convexity angle corrections were more successful in cooperative patients (R = 0.469, P = 0.012). Cases with smaller pretreatment nasolabial angles may experience more changes in this angle after treatment (R = 0.581, P = 0.001). Conclusion: The addition of lip exercises to activator high-pull headgear can boost activator headgear’s efficacy in treating lip incompetence.

Unconditional Cash Transfers and Maternal Assessments of Children's Health, Nutrition, and Sleep

Children experiencing poverty are more likely to experience worse health outcomes, including injury, chronic illness, worse nutrition, and poorer sleep. The extent to which poverty reduction improves these outcomes is unknown. To evaluate the effect of a 3-year, monthly unconditional cash transfer on health, nutrition, sleep, and health care utilization among children experiencing poverty who were healthy at birth. This longitudinal randomized clinical trial recruited 1000 mother-infant dyads between May 2018 and June 2019. Dyads were recruited from postpartum wards in 12 hospitals in 4 US cities: New York, New York; Omaha, Nebraska; New Orleans, Louisiana; and Minneapolis/St Paul, Minnesota. Eligibility criteria included an annual income less than the federal poverty line, legal age for consent, English or Spanish speaking, residing in the state of recruitment, and an infant admitted to the well-baby nursery who will be discharged to the mother's custody. Data analysis was conducted from July 2022 to August 2023. Mothers were randomly assigned to receive either a high-cash gift ($333/mo, or $3996/y) or a low-cash gift ($20/mo, or $240/y) for the first several years of their child's life. Primary preregistered outcomes reported here include an index of child health and medical care and child sleep disturbances. Secondary preregistered outcomes reported include children's consumption of healthy and unhealthy foods. A total of 1000 mother-infant dyads were enrolled, with 400 randomized to the high-cash gift group and 600 to the low-cash gift group. Participants were majority Black (42%) and Hispanic (41%); 857 mothers participated in all 3 waves of data collection. We found no statistically detectable differences between the high-cash and low-cash gift groups in maternal assessments of children's health (effect size [ES] range, 0.01-0.08; SE range, 0.02-0.07), sleep (ES range, 0.01-0.10; SE, 0.07), or health care utilization (ES range, 0.01-0.11; SE range, 0.03-0.07). However, mothers in the high-cash gift group reported higher child consumption of fresh produce at child age 2 years, the only time point it was measured (ES, 0.17; SE, 0.07; P = .03). In this study, unconditional cash transfers to mothers experiencing poverty did not improve reports of their child's health, sleep, or health care utilization. However, stable income support of this magnitude improved toddlers' consumption of fresh produce. Healthy newborns tend to grow into healthy toddlers, and the impacts of poverty reduction on children's health and sleep may not be fully borne out until later in life. ClinicalTrials.gov Identifier: NCT03593356.

Anti-vascular endothelial growth factor therapy in retinopathy of prematurity: An updated literature review.

Laser photocoagulation can still be considered the gold standard for treatment for retinopathy of prematurity (ROP). However, anti-vascular endothelial growth factor (anti-VEGF) therapy has increasingly become an important option that plays a significant role in the treatment of ROP. Major clinical trials have been published regarding the anti-VEGF use in ROP, along with multiple other studies looking into the different agents, doses, techniques, and possible complications. Anti-VEGF therapies can be considered as a safe and effective option for managing ROP. More longitudinal randomized clinical trials are necessary to evaluate the preferred treatment agent, the appropriate dose, best follow-up protocol, and the long-term ocular and systemic outcomes following treatment.

The glaucoma intensive treatment study: interim results from an ongoing longitudinal randomized clinical trial.

The aim of the study was to determine the perimetric rate of glaucoma progression in the ongoing Glaucoma Intensive Treatment Study (GITS) after 3 years of follow-up. This is a randomized, two-centre, prospective open-labelled treatment trial for open-angle glaucoma (OAG). The participants of this study were treatment-naive patients with newly diagnosed OAG, aged 46-78 years, with early to moderate glaucomatous visual field loss scheduled to be followed for 5 years within the study. Patients were randomized to initial treatment with either topicalmonotherapy or with an intensive approach using drugs from three different classes, plus 360° laser trabeculoplasty. Changes in treatment were allowed. Standard automated perimetry and tonometry were performed and side-effects documented. All results are presented using intention-to-treat analysis. A total of 242 patients were randomized. After 3 years of follow-up, eight patients were lost to follow-up, six of whom were deceased. The median untreated baseline intraocular pressure (IOP) was 24 mmHg in both arms. The median IOP was almost constant over the 3 years of follow-up: ≈17 mmHg in the mono-arm and ≈14 mmHg in the multi-treatment arm. Treatment was intensified in 42% of the mono-treated patients and in 7% of the multi-treated patients. Treatment was reduced in 13% of the multi-treated patients. The median perimetric rate of progression was -0.5%/year in the mono-treated group and -0.1%/year in the multi-treated group (p = 0.03). The rate of disease progression was significantly slower in the multi-treated patients than in the mono-treated patients. Further follow-up will show whether this difference is sustained over time.

Using a microprocessor knee (C-Leg) with appropriate foot transitioned individuals with dysvascular transfemoral amputations to higher performance levels: a longitudinal randomized clinical trial

BackgroundIndividuals with transfemoral amputations who are considered to be limited community ambulators are classified as Medicare functional classification (MFCL) level K2. These individuals are usually prescribed a non-microprocessor controlled knee (NMPK) with an appropriate foot for simple walking functions. However, existing research suggests that these individuals can benefit from using a microprocessor controlled knee (MPK) and appropriate foot for their ambulation, but cannot obtain one due to insurance policy restrictions. With a steady increase in older adults with amputations due to vascular conditions, it is critical to evaluate whether advanced prostheses can provide better safety and performance capabilities to maintain and improve quality of life in individuals who are predominantly designated MFCL level K2. To decipher this we conducted a 13 month longitudinal clinical trial to determine the benefits of using a C-Leg and 1M10 foot in individuals at K2 level with transfemoral amputation due to vascular disease. This longitudinal clinical trial incorporated recommendations prescribed by the lower limb prosthesis workgroup to design a study that can add evidence to improve reimbursement policy through clinical outcomes using an MPK in K2 level individuals with transfemoral amputation who were using an NMPK for everyday use.MethodsTen individuals (mean age: 63 ± 9 years) with unilateral transfemoral amputation due to vascular conditions designated as MFCL K2 participated in this longitudinal crossover randomized clinical trial. Baseline outcomes were collected with their current prosthesis. Participants were then randomized to one of two groups, either an intervention with the MPK with a standardized 1M10 foot or their predicate NMPK with a standardized 1M10 foot. On completion of the first intervention, participants crossed over to the next group to complete the study. Each intervention lasted for 6 months (3 months of acclimation and 3 months of take-home trial to monitor home use). At the end of each intervention, clinical outcomes and self-reported outcomes were collected to compare with their baseline performance. A generalized linear model ANOVA was used to compare the performance of each intervention with respect to their own baseline.ResultsStatistically significant and clinically meaningful improvements were observed in gait performance, safety, and participant-reported measures when using the MPK C-Leg + 1M10 foot. Most participants were able to achieve higher clinical scores in gait speed, balance, self-reported mobility, and fall safety, while using the MPK + 1M10 combination. The improvement in scores were within range of scores achieved by individuals with K3 functional level as reported in previous studies.ConclusionsIndividuals with transfemoral amputation from dysvascular conditions designated MFCL level K2 benefited from using an MPK + appropriate foot. The inference and evidence from this longitudinal clinical trial will add to the knowledgebase related to reimbursement policy-making.Trial registration This study is registered on clinical trials.gov with the study title “Functional outcomes in dysvascular transfemoral amputees” and the associated ClinicalTrials.gov Identifier: NCT01537211. The trial was retroactively registered on February 7, 2012 after the first participant was enrolled.

An Innovative Patient-Centered Virtual Reality Intervention for Pediatric TBI Cognitive Rehabilitation: Preliminary Efficacy

To describe a pilot longitudinal randomized clinical trial (RCT) to examine the feasibility, safety, and preliminary efficacy of a novel patient-centered VR-based interactive cognitive training (VICT) program for rehabilitation of three core EFs: inhibitory control, working memory, and cognitive flexibility among children with TBI.

Evaluation of Race as a Predictor of Fear of Falling in Black Older Adults

Fear of falling (FOF) is a common issue and health concern reported by adults 65 years of age and older.There is mixed evidence about potential disparity in fall incident rates due to race and FOF, and it is unclear if and under what circumstance falls rates and risks differ by racial ethnicity. The purpose of this study is to determine if race predicts fear of falling in older adults at greater risk for falls; and to examine the relationship between activities of daily living (ADL) and mobility performance measures with FOF. A cross-sectional observational study was used to examine predictors of FOF among community dwelling-older adults using data from two longitudinal randomized clinical trials (RCT). Participants (N=259) had a mean age of 75.7 ±7.4, 78.8% female, 80.64% Black, and 77.03% White or Other, with ≥ 1 fall in the last 12 months. Subjects completed a demographic profile; the Tinetti and Short Falls Efficacy Scale to assess FOF; and activities of daily living (ADL) and mobility performance scales to assess function. The chi square analysis revealed Black older adults were two times more likely to report FOF (OR = 2.17, 95% CI = 1.14, 4.15; p=.05) in comparison to White older adults. The regression analysis demonstrated that race is a significant factor to predict FOF (OR = .67, 95% CI = 1.21, 3.24; p=.05); and the descriptive analysis revealed significantly worse ADL and mobility function scores within the high FOF group.

Convergence Insufficiency Neuro-mechanism in Adult Population Study Randomized Clinical Trial: Clinical Outcome Results.

These data confirm the effectiveness of office-based vergence/accommodative therapy for improving the near point of convergence and positive fusional vergence in young adults with symptomatic convergence insufficiency within a double-masked longitudinal randomized clinical trial. This study aimed to report changes in clinical signs and symptoms of convergence insufficiency from a randomized clinical trial evaluating the effectiveness of office-based vergence/accommodative therapy for young adults with symptomatic convergence insufficiency. In this double-masked, randomized clinical trial, convergence insufficiency patients (n = 50; average age, 21 ± 3 years; range, 18 to 32 years) were randomized to either office-based vergence/accommodative therapy or office-based placebo therapy. Improvements in (1) near point of convergence, (2) positive fusional vergence, and (3) self-reported symptoms (Convergence Insufficiency Symptom Survey [CISS] score) were evaluated after twelve 1-hour sessions of treatment within the office comparing the results from the vergence/accommodative therapy and the placebo therapy groups. The mean near point of convergence improved by 6.0 and 3.1 cm in the vergence/accommodative and placebo therapy groups, respectively (mean difference of -2.9 cm; 95% confidence interval [CI], -4.6 to -1.0 cm; P < .01). The mean positive fusional vergence increased by 17.3 and 7.4Δ in the vergence/accommodative and placebo therapy groups, respectively (mean difference of 9.9Δ; 95% CI, 4.9 to 16.0Δ; P < .001). The mean CISS score improved by 12.4 and 10.1 points in the vergence/accommodative and placebo therapy groups, respectively (mean difference of 2.3 points; 95% CI, -8.3 to +4.6 points; P = .56). Our results demonstrate that office-based vergence/accommodative therapy is effective for improving the near point of convergence and positive fusional vergence in young adults with symptomatic convergence insufficiency. However, given that both treatment groups had a similar reduction in self-reported symptoms, we recommend that the CISS be revised if it is to be used as an outcome measure in future studies of convergence insufficiency.

A note on the bias of standard errors when orthogonality of mean and variance parameters is not satisfied in the mixed model for repeated measures analysis.

The mixed effect models for repeated measures (MMRM) analysis is sometimes used as a primary analysis in longitudinal randomized clinical trials. The SE for the treatment effect in the MMRM analysis is usually estimated by assuming the orthogonality of the fixed effect and variance-covariance parameters, which is the orthogonality property of a multivariate normal distribution, because of default settings of most standard statistical software. However, this property might be lost when analysis models are misspecified and/or data include missing values with the mechanism of being missing at random. In this study, we investigated the effect of the assumption of the orthogonality property on the estimation of the SE for the MMRM analysis. From simulation and case studies, it was shown that the SE with the assumption of orthogonality property had nonnegligible bias, especially when the analysis models assuming heteroscedasticity between treatment groups were applied. We also introduce the SAS code for the MMRM analysis without assuming the orthogonality property. Assuming the orthogonality property in the MMRM analysis would lead to invalid statistical inference, and it is necessary to be careful when applying the MMRM analysis with most standard software.

Test-Retest Reliability of Functional Magnetic Resonance Imaging Activation for a Vergence Eye Movement Task.

Vergence eye movements are the inward and outward rotation of the eyes responsible for binocular coordination. While studies have mapped and investigated the neural substrates of vergence, it is not well understood whether vergence eye movements evoke the blood oxygen level-dependent signal reliably in separate experimental visits. The test-retest reliability of stimulus-induced vergence eye movement tasks during a functional magnetic resonance imaging (fMRI) experiment is important for future randomized clinical trials (RCTs). In this study, we established region of interest (ROI) masks for the vergence neural circuit. Twenty-seven binocularly normal young adults participated in two functional imaging sessions measured on different days on the same 3T Siemens scanner. The fMRI experiments used a block design of sustained visual fixation and rest blocks interleaved between task blocks that stimulated eight or four vergence eye movements. The test-retest reliability of task-activation was assessed using the intraclass correlation coefficient (ICC), and that of spatial extent was assessed using the Dice coefficient. Functional activation during the vergence eye movement task of eight movements compared to rest was repeatable within the primary visual cortex (ICC = 0.8), parietal eye fields (ICC = 0.6), supplementary eye field (ICC = 0.5), frontal eye fields (ICC = 0.5), and oculomotor vermis (ICC = 0.6). The results demonstrate significant test-retest reliability in the ROIs of the vergence neural substrates for functional activation magnitude and spatial extent using the stimulus protocol of a task block stimulating eight vergence eye movements compared to sustained fixation. These ROIs can be used in future longitudinal RCTs to study patient populations with vergence dysfunctions.

Single-stage advanced versus rotated flaps in the treatment of gingival recessions: A 5-year longitudinal randomized clinical trial.

The objective of the present study was to compare the efficacy of single-stage laterally positioned flap (LPF) and coronally advanced flap (CAF) techniques in the treatment of localized maxillary gingival recession (GR) defects, 1 and 5years after surgical procedures. Thirty-six patients with Miller Class I GR defects were randomly assigned to be treated by either CAF (n=18) or LPF (n=18). Recession height (RECH), width of keratinized tissue (WKT), probing depth (PD), vertical clinical attachment level (VAL), visual plaque score (VPS), and bleeding on probing (BOP) were assessed and compared. Clinical recordings were performed at baseline, 1 and 5years later. The differences between initial clinical recordings and after 1 and 5years were subjected to statistical analysis. Both flap designs effectively improved RECH and VAL on GR defects. The LPF resulted in significantly more gains in KTW and root coverage (RC) after 5years. LPF and CAF procedures may be used for the treatment of GR, however, LPF results in greater longitudinal stability of RC and increased WKT in the treated areas.

Effects of an attachment-based intervention in infancy on children’s autonomic regulation during middle childhood

The present study used a longitudinal randomized clinical trial to test whether an early intervention has causal effects on children’s autonomic nervous system regulation. When children were infants, parents involved with Child Protective Services received Attachment and Biobehavioral Catch-up (ABC; N = 43), an intervention that promotes sensitive parenting, or a control intervention (N = 53). When children were 9 years old, children whose parents had received ABC exhibited higher respiratory sinus arrhythmia and lower heart rate at rest and during a parent-child interaction than children in the control group. Intervention effects were not detected for children’s average skin conductance levels or for indices of autonomic reactivity. Results suggest that a parenting-focused early intervention impacted the development of children’s autonomic regulation.

Information-anchored sensitivity analysis: theory and application.

SummaryAnalysis of longitudinal randomized clinical trials is frequently complicated because patients deviate from the protocol. Where such deviations are relevant for the estimand, we are typically required to make an untestable assumption about post‐deviation behaviour to perform our primary analysis and to estimate the treatment effect. In such settings, it is now widely recognized that we should follow this with sensitivity analyses to explore the robustness of our inferences to alternative assumptions about post‐deviation behaviour. Although there has been much work on how to conduct such sensitivity analyses, little attention has been given to the appropriate loss of information due to missing data within sensitivity analysis. We argue that more attention needs to be given to this issue, showing that it is quite possible for sensitivity analysis to decrease and increase the information about the treatment effect. To address this critical issue, we introduce the concept of information‐anchored sensitivity analysis. By this we mean sensitivity analyses in which the proportion of information about the treatment estimate lost because of missing data is the same as the proportion of information about the treatment estimate lost because of missing data in the primary analysis. We argue that this forms a transparent, practical starting point for interpretation of sensitivity analysis. We then derive results showing that, for longitudinal continuous data, a broad class of controlled and reference‐based sensitivity analyses performed by multiple imputation are information anchored. We illustrate the theory with simulations and an analysis of a peer review trial and then discuss our work in the context of other recent work in this area. Our results give a theoretical basis for the use of controlled multiple‐imputation procedures for sensitivity analysis.

Longitudinal Randomized Controlled Trial of Advance Care Planning for Teens: Religiousness and End of Life Treatment Preferences

Purpose: One pilot study among HIV positive adolescents indicated spirituality, as measured by the FACIT-SP, was not associated with the decision to use intensive life-prolonging treatments. Yet adult studies indicate the opposite (Phelps, 2009), particularly for African-Americans (Johnston, et al., 2005). The purpose of this study is to examine the relationship between religiousness in adolescents living with HIV and their end of life treatment preferences in a longitudinal randomized clinical trial of an advance care planning intervention. Hypothesis: high religiousness at baseline will interact with an advance care planning intervention to increase the likelihood of choosing to continue all treatments across end of life situations at 3 month post-intervention follow-up. Methods: Adolescents ( 14, <21 years of age, N1⁄4107) were randomized to either the FAmily-CEntered Advance Care Planning intervention or to the Healthy Living Control condition. Religiousness was assessed at baseline through the Brief Multidimensional Measurement of Religiousness/Spirituality (BMMRS; Fetzer Institute/NIA 1999). The Statement of Treatment Preferences measured treatment preferences in three HIV related bad outcome situations (SOTP; Hammes & Briggs, 2008) at 3 month post-intervention. Analysis included 85 adolescents who completed 3 month follow-up, using latent profile analysis (LPA) of models of religiousness. The logistic procedure for analysis of maximum likelihood estimates was then used to test for direct intervention effects and intervention interactionwith latent profiles of religiousness on preference outcomes. Fisher’s exact test for binary relationship and logistic model were then used. Results: Adolescents were: 51% female, 72% perinatally-acquired HIV; mean age 18 years old; 93% African-American or black; 27% advanced HIV. LPA yielded four profiles: Profile 1 and 3 were religious while Profile 2 and 4 were not. There was one significant relationship of continue treatment in Situation 1 and religious profile. Patients in Religious Profile 1 and Profile 3 (higher religiousness) were more likely to choose to continue all treatments in Situation 1 (prolonged hospital stay with multiple interventions) than patients in Religious Profile 2 and Profile 4 (low religiousness) (b1⁄43.00-0.731⁄42.27, p-value1⁄40.0137). The main effect of the advance care planning intervention was to significantly decrease the choice to continue all treatments in Situation 1 (Maximum likelihood estimate -2.3286, p1⁄40.0276). In the control group there was no interaction of religiousness with treatment preferences. There were no significant effects for age, gender, race or mode of transmission. Conclusions: The main effect of the intervention, to decrease the choice to continue all treatments in Situation 1, disappeared if the adolescent had strong religiousness. This is similar to adult studies that show religiousness as a mediator of end of life decisions. Religious HIV positive adolescents who were randomized to the intervention were willing to endure long hospitalizations compared to their nonreligious peers. Sources of Support:

Metabolic Programming: Effects of Early Nutrition on Growth, Metabolism and Body Composition.

High protein requirements of premature infants during the first weeks of postnatal life are a well-established fact. Those infants gain fat-free mass and protein rapidly during the first weeks of postnatal growth and require a much higher protein/energy ratio than term infants. Recommended protein intakes are 3.5-4.0 g/kg per day. For term infants, on the other hand, FAO and WHO have recently lowered recommended protein intakes to better reflect our current knowledge about the protein concentration in breast milk during the first 12 months of lactation. Longitudinal randomized clinical trials now confirm that term infants who are fed infant and follow-up formulas with protein concentrations >2.25 g/100 kcal (high protein formulas) during the first year of life grow faster than indicated by the WHO growth standards. Rapid weight gain during infancy is a predictor of childhood and adult obesity. Infants fed high protein quality formulas with protein concentrations of 1.6-2.2 g/100 kcal from 3 to 4 months onwards experience weight gain that is very close to that of breastfed infants. Biomarkers (insulin or IGF-1) of infants receiving low protein formulas differ from those of infants receiving high protein formulas. Six-year-old children who received low protein formulas in the first year of life had a lower risk of childhood obesity (BMI >95th percentile of WHO standards) compared with children who received high protein formulas as infants. BMI at 5 years of age is similar in children who were breastfed or received low protein formulas as infants. It is most important that the new low protein formulas are safe and adequate for all healthy term infants. Based on new protein technologies, the levels of essential and branched-chain amino acids in low protein formulas are now close to those in breast milk. Safety has been confirmed by following anthropometric parameters to 5-6 years of age and comparing these parameters with the WHO growth standards. Body composition measurements indicate similar protein accretion between 3 and 6 months of age in infants fed high or low protein formulas. Longitudinal data on body composition indicate that children who received a low protein formula until age 12 months gain less fat between 6 and 60 months than children who received a high protein formula. Breastfeeding and the use of low/high protein quality formulas in term infants who cannot be breastfed can help support appropriate metabolic programming during this critical period and reduce the risk of later obesity.

Locally efficient estimation of marginal treatment effects when outcomes are correlated: is the prize worth the chase?

Semiparametric methods have been developed to increase efficiency of inferences in randomized trials by incorporating baseline covariates. Locally efficient estimators of marginal treatment effects, which achieve minimum variance under an assumed model, are available for settings in which outcomes are independent. The value of the pursuit of locally efficient estimators in other settings, such as when outcomes are multivariate, is often debated. We derive and evaluate semiparametric locally efficient estimators of marginal mean treatment effects when outcomes are correlated; such outcomes occur in randomized studies with clustered or repeated-measures responses. The resulting estimating equations modify existing generalized estimating equations (GEE) by identifying the efficient score under a mean model for marginal effects when data contain baseline covariates. Locally efficient estimators are implemented for longitudinal data with continuous outcomes and clustered data with binary outcomes. Methods are illustrated through application to AIDS Clinical Trial Group Study 398, a longitudinal randomized clinical trial that compared the effects of various protease inhibitors in HIV-positive subjects who had experienced antiretroviral therapy failure. In addition, extensive simulation studies characterize settings in which locally efficient estimators result in efficiency gains over suboptimal estimators and assess their feasibility in practice.