A stochastic modeling of early HIV-1 population dynamics.

In a recent paper, Tuckwell and Le Corfec [J. Theor. Biol. 195 (1998) 450-463] applied the multi-dimensional diffusion process to model early human immunodeficiency virus type-1 (HIV-1) population dynamics. The purpose of this paper is to assess certain features and consequences of their model in the context of Tan and Wu's stochastic approach [Math. Biosci. 147 (1998) 173-205].

Regional brain volume abnormalities and long-term cognitive outcome in preterm infants.

CONTEXT: Preterm infants have a high prevalence of long-term cognitive and behavioral disturbances. However, it is not known whether the stresses associated with premature birth disrupt regionally specific brain maturation or whether abnormalities in brain structure contribute to cognitive deficits. OBJECTIVE: To determine whether regional brain volumes differ between term and preterm children and to examine the association of regional brain volumes in prematurely born children with long-term cognitive outcomes. DESIGN AND SETTING: Case-control study conducted in 1998 and 1999 at 2 US university medical schools. PARTICIPANTS: A consecutive sample of 25 eight-year-old preterm children recruited from a longitudinal follow-up study of preterm infants and 39 term control children who were recruited from the community and who were comparable with the preterm children in age, sex, maternal education, and minority status. MAIN OUTCOME MEASURES: Volumes of cortical subdivisions, ventricular system, cerebellum, basal ganglia, corpus callosum, amygdala, and hippocampus, derived from structural magnetic resonance imaging scans and compared between preterm and term children; correlations of regional brain volumes with cognitive measures (at age 8 years) and perinatal variables among preterm children. RESULTS: Regional cortical volumes were significantly smaller in the preterm children, most prominently in sensorimotor regions (difference: left, 14.6%; right, 14.3% [P<.001 for both]) but also in premotor (left, 11.2%; right, 12.6% [P<.001 for both]), midtemporal (left, 7.4% [P =.01]; right, 10.2% [P<.001]), parieto-occipital (left, 7.9% [P =.01]; right, 7.4% [P =.005]), and subgenual (left, 8.9% [P =.03]; right, 11.7% [P =.01]) cortices. Preterm children's brain volumes were significantly larger (by 105. 7%-271.6%) in the occipital and temporal horns of the ventricles (P<. 001 for all) and smaller in the cerebellum (6.7%; P =.02), basal ganglia (11.4%-13.8%; P

Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo.

OBJECTIVE: To determine the upper gastrointestinal (GI) tolerability of celecoxib, naproxen, and placebo in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: An analysis of 5, 12-week, randomized, double blind, parallel group, placebo controlled clinical trials was conducted. In these trials, patients were randomized to: naproxen 500 mg bid (n = 1,099), placebo (n = 1,136), celecoxib 50 mg bid (n = 690) (subtherapeutic dose), celecoxib 100 mg (n = 1,131) or 200 mg bid (n = 1,125) (therapeutic dose), or celecoxib 400 mg bid (n = 434) (supratherapeutic dosage). The incidence and time until moderate to severe abdominal pain, dyspepsia, nausea, and any of the aforementioned 3 upper GI symptoms (composite endpoint) were determined using time-to-event analysis. RESULTS: The cumulative incidences of moderate to severe abdominal pain, dyspepsia, or nausea (composite endpoint) were: naproxen 500 mg (12.0%; 95% CI 9.9%-14.0%), celecoxib 50 mg bid (7.1%; 95% CI 5.0%-9.2%), celecoxib 100 mg bid (7.8%; 95% CI 6.0%-9.5%), celecoxib 200 mg bid (8.1%; 95% CI 6.4%-9.9%), celecoxib 400 mg bid (6.0%; 95% CI 3.6%-8.4%), and placebo (8.5%; 95% CI 6.5%-10.8%). After controlling for independent predictors of the composite endpoint, relative risks (RR) for the various treatments relative to naproxen 500 mg bid were: celecoxib 50 mg (RR 0.54; 95% CI 0.37-0.77; p < 0.001), celecoxib 100 mg (RR 0.60; 95% CI 0.45-0.80; p < 0.001), celecoxib 200 mg bid (RR 0.63; 95% CI 0.47-0.83; p = 0.001), celecoxib 400 mg bid (RR 0.56; 95% CI 0.35-0.89; p = 0.015), and placebo (RR 0.63; 95% CI 0.47-0.85; p = 0.002). After controlling for independent predictors of the composite endpoint, celecoxib treatment group patients did not differ from placebo patients when reporting the composite endpoint, with p values ranging from 0.40 to 0.96. CONCLUSION: The upper GI tolerability of celecoxib is superior to naproxen. A dose-response relationship between celecoxib and upper GI symptoms was not apparent.

Outcome of children in the indomethacin intraventricular hemorrhage prevention trial.

BACKGROUND: For preterm infants, intraventricular hemorrhage (IVH) may be associated with adverse neurodevelopmental outcome. We have demonstrated that early low-dose indomethacin treatment is associated with a decrease in both the incidence and severity of IVH in very low birth weight preterm infants. In addition, we hypothesized that the early administration of low-dose indomethacin would not be associated with an increase in the incidence of neurodevelopmental handicap at 4.5 years of age in our study children. METHODS: To test this hypothesis, we provided neurodevelopmental follow-up for the 384 very low birth weight survivors of the Multicenter Randomized Indomethacin IVH Prevention Trial. Three hundred thirty-seven children (88%) were evaluated at 54 months' corrected age, and underwent neurodevelopmental examinations, including the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R), the Peabody Picture Vocabulary Test-Revised (PPVT-R), and standard neurologic examinations. RESULTS: Of the 337 study children, 170 had been randomized to early low-dose indomethacin therapy and 167 children had received placebo. Twelve (7%) of the 165 indomethacin children and 11 (7%) of the 158 placebo children who underwent neurologic examinations were found to have cerebral palsy. For the 233 English-monolingual children for whom cognitive outcome data follow, the mean gestational age was significantly younger for the children who received indomethacin than for those who received placebo. In addition, although there were no differences in the WPPSI-R or the PPVT-R scores between the 2 groups, analysis of the WPPSI-R full-scale IQ by function range demonstrated significantly less mental retardation among those children randomized to early low-dose indomethacin (for the indomethacin study children, 9% had an IQ <70, 12% had an IQ of 70-80, and 79% had an IQ >80, compared with the placebo group, for whom 17% had an IQ <70, 18% had an IQ of 70-80, and 65% had an IQ >80). Indomethacin children also experienced significantly less difficulty with vocabulary skills as assessed by the PPVT-R when compared with placebo children. CONCLUSIONS: These data suggest that, for preterm neonates, the early administration of low-dose indomethacin therapy is not associated with adverse neurodevelopmental function at 54 months' corrected age.

Blood pressure exceeding national guidelines among women after stroke.

BACKGROUND AND PURPOSE: After a transient ischemic attack or stroke, the risk for recurrence may be reduced by treatment of hypertension. The purpose of this study was to determine how commonly blood pressure exceeds national guidelines among patients who have had one of these events. METHODS: Subjects were 644 women participating in a randomized trial of estrogen for secondary stroke prevention. We measured blood pressure 1 month after the stroke or TIA while patients were under the care of their personal physicians. Among 536 patients, a second measure was made at an average of 2.9 years after the first. RESULTS: The mean age of participants was 71 years, and 73% reported a history of hypertension. At baseline, only 44% (280/644) of the women had blood pressure values within national guidelines (<140/90 mm Hg). With separate guidelines used for diabetics (<130/85 mm Hg) and nondiabetics (<140/90 mm Hg), the proportions of women within the guidelines were 27% and 44%, respectively. Overall, 39% of patients were within the diabetes-adjusted guidelines. Among patients whose blood pressure exceeded 140/90 mm Hg at first examination, 55% were still in excess at follow-up. Features associated with severe hypertension at first examination (>160/100 mm Hg) were history of hypertension, education less than college, and higher cognitive functioning. CONCLUSIONS: Blood pressure values in excess of national guidelines are common after stroke and TIA, especially among diabetic patients. Efforts to lower blood pressure control may enhance secondary prevention.

The stroke prognosis instrument II (SPI-II) : A clinical prediction instrument for patients with transient ischemia and nondisabling ischemic stroke.

BACKGROUND AND PURPOSE: In 1991 we developed the Stroke Prognosis Instrument (SPI-I) to stratify patients with transient ischemic attack or ischemic stroke by prognosis for stroke or death in 2 years. In this article we validate and improve SPI-I (creating SPI-II). METHODS: To validate SPI-I, we applied it to 4 test cohorts and calculated pooled outcome rates. To create SPI-II, we incorporated new predictive variables identified in 1 of the test cohorts and validated it in the other 3 cohorts. RESULTS: For SPI-I, pooled rates (all 4 test cohorts) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 24%, respectively (P<0.01, log-rank test). SPI-II was created by adding congestive heart failure and prior stroke to SPI-I. Each patient's risk group was determined by the total score for 7 factors: congestive heart failure (3 points); diabetes (3 points); prior stroke (3 points); age >70 years (2 points); stroke for the index event (not transient ischemic attack) (2 points); hypertension (1 point); and coronary artery disease (1 point). Risk groups I, II, and III comprised patients with 0 to 3, 4 to 7, and 8 to 15 points, respectively. For SPI-I, pooled rates (3 cohorts excluding the SPI-II development cohort) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 23%, respectively. For SPI-II, pooled rates were 10%, 19%, and 31%, respectively. In receiver operator characteristic analysis, the area under the curve was 0.59 (95% CI, 0.57 to 0.60) for SPI-I and 0.63 (95% CI, 0.62 to 0.65) for SPI-II, confirming the better performance of the latter. CONCLUSIONS: Compared with SPI-I, SPI-II achieves greater discrimination in outcome rates among risk groups. SPI-II is ready for use in research design and may have a role in patient counseling.

Evaluation of therapeutic strategies: a new method for balancing risk and benefit.

OBJECTIVE: A patient-specific drug safety-efficacy index was developed that combined objective clinical trial information about dose-related efficacy and toxicity with subjective perspectives on efficacy-toxicity trades. METHODS: Patient preferences were systematically assessed using the probability tradeoff technique (PTT). Toxicity ranges over which a drug's efficacy exceeded the patient's minimally acceptable efficacy represented ranges of "surplus efficacy." These can be related to the dose interval in which a drug delivers this surplus efficacy. Seventy surplus efficacy functions (for 7 hypothetical drugs and 10 hypothetical preference curves) were simulated. RESULTS: The analysis showed that index values change markedly by dose and patient preference, suggesting that different patients will benefit from different drugs depending on the dose prescribed and each patient's subjective assessment of the efficacy/toxicity tradeoff. In most situations, drugs achieve positive surplus efficacy only over limited dose ranges. The model was sensitive to different preference curves and discriminated well among drugs with different efficacy or safety profiles. CONCLUSION: This index provides a new, systematic approach to choosing a specific therapeutic intervention and dosage, when known risks and benefits are reconciled against patient-specific preferences among an array of therapeutic alternatives.

The etiology and outcome of cerebral ventriculomegaly at term in very low birth weight preterm infants.

BACKGROUND: Despite improvements in survival data, the incidence of neurodevelopmental handicaps in preterm infants remains high. To prevent these handicaps, one must understand the pathophysiology behind them. For preterm infants, cerebral ventriculomegaly (VM) may be associated with adverse neurodevelopmental outcome. We hypothesized that although the causes of VM are multiple, the incidence of handicap at 4.5 years of age in preterm infants with this ultrasonographic finding at term would be high. METHODS: To test this hypothesis, we provided neurodevelopmental follow-up for all 440 very low birth weight survivors of the Multicenter Randomized Indomethacin Intraventricular Hemorrhage (IVH) Prevention Trial. A total of 384 children (87%) were evaluated at 54 months' corrected age (CA), and 257 subjects were living in English-speaking, monolingual households and are included in the following data analysis. RESULTS: Moderate to severe low pressure VM at term was documented in 11 (4%) of the English-speaking, monolingual survivors. High grade IVH and bronchopulmonary dysplasia (BPD) were both risk factors for the development of VM. Of 11 (45%) children with VM, 5 suffered grades 3 to 4 IVH, compared with 2/246 (1%) children without VM who experienced grades 3 to 4 IVH. Similarly, 9/11 (82%) children with VM had BPD, compared with 120/246 (49%) children without VM who had BPD. Logistic regression analysis was performed using birth weight, gestational age, gender, Apgar score at 5 minutes, BPD, sepsis, moderate to severe VM, periventricular leukomalacia, grade of IVH, and maternal education to predict IQ <70. Although maternal education was an important and independent predictor of adverse cognitive outcome, in this series of very low birth weight prematurely born children, VM was the most important predictor of IQ <70 (OR: 19.0; 95% CI: 4.5, 80.6). Of children with VM, 6/11 (55%) had an IQ <70, compared with 31/246 (13%) of children without VM. Children with VM had significantly lower verbal and performance scores compared with children without VM. CONCLUSIONS: These data suggest that, for preterm neonates, VM at term is a consequence of the vulnerability of the developing brain. Furthermore, its presence is an important and independent predictor of adverse cognitive and motor development at 4.5 years' CA.

Early-onset intraventricular hemorrhage in preterm neonates: incidence of neurodevelopmental handicap.

The neurodevelopmental outcome of very low birth weight infants experiencing early-onset intraventricular hemorrhage (IVH) occurring within the first 6 postnatal hours was compared with that of their peers without early-onset IVH at 3 years corrected age. The 440 surviving preterm infants (birth weight 600 to 1,250 g) who had been enrolled in a multicenter, prospectively randomized, controlled trial evaluating the efficacy of postnatal indomethacin to prevent IVH were evaluated with the Stanford-Binet Intelligence Scale and neurological examinations at 3 years corrected age. All study infants had echoencephalography between 5 and 11 hours of life, and testing is reported for all children residing in English monolingual households at 3 years corrected age (i.e., from the obstetric due date). Fifty five of the 73 (75%) infants with IVH within the first 5 to 11 hours survived to 3 years of age, compared with 385 of the 432 (89%) children without early-onset hemorrhage who were alive at 3 years corrected age (P<.001). Eleven of the 29 (38%) English monolingual children with early-onset IVH had Stanford-Binet intelligence quotient scores of less than 70, compared with 47 of the 249 (19%) children without early IVH (P = .03). Similarly, 7 of 28 (25%) early IVH children were found to have cerebral palsy, compared with 20 of 241 (8%) children without early IVH (P = .01). These data suggest that infants who experience the early onset of IVH are at high risk for both cognitive and motor handicaps at 3 years corrected age.

Stratified randomization for clinical trials.

Trialists argue about the usefulness of stratified randomization. For investigators designing trials and readers who use them, the argument has created uncertainty regarding the importance of stratification. In this paper, we review stratified randomization to summarize its purpose, indications, accomplishments, and alternatives. In order to identify research papers, we performed a Medline search for 1966-1997. The search yielded 33 articles that included original research on stratification or included stratification as the major focus. Additional resources included textbooks. Stratified randomization prevents imbalance between treatment groups for known factors that influence prognosis or treatment responsiveness. As a result, stratification may prevent type I error and improve power for small trials (<400 patients), but only when the stratification factors have a large effect on prognosis. Stratification has an important effect on sample size for active control equivalence trials, but not for superiority trials. Theoretical benefits include facilitation of subgroup analysis and interim analysis. The maximum desirable number of strata is unknown, but experts argue for keeping it small. Stratified randomization is important only for small trials in which treatment outcome may be affected by known clinical factors that have a large effect on prognosis, large trials when interim analyses are planned with small numbers of patients, and trials designed to show the equivalence of two therapies. Once the decision to stratify is made, investigators need to chose factors carefully and account for them in the analysis.

Association of chronic sublethal hypoxia with ventriculomegaly in the developing rat brain.

Bronchopulmonary dysplasia remains a major cause of neurodevelopmental handicap in preterm infants. Because bronchopulmonary dysplasia may be associated with prolonged hypoxemia without obvious changes in systemic blood pressure, we developed an animal model of chronic sublethal hypoxia to test the hypothesis that this insult results in significant alterations in corticogenesis in the developing brain. Three groups of newborn rats were placed in a chamber with FIO2 9.5% on postnatal day 3 (P3). One group was sacrificed at P13; a second group was sacrificed at P33, and the third group was removed at P33 and reared in normoxia until sacrifice at P63. Control rats were those raised in room air for the corresponding periods of time. Rats were transcardially perfused and the brains were embedded in celloidin and prepared for morphometric analysis using standard stereology methods. Although experimental rat pups in the third group demonstrated 'catch-up' of body weight following return to normoxia, these studies demonstrated both failure of brain growth (p<0.01) and progressive cerebral ventriculomegaly (p<0.01). Decreased subcortical white matter (p<0. 05) and corpus callosum size (p<0.01) were noted at P63 in pups reared under conditions of chronic hypoxia. Decreases in cortical volume (p<0.05) were noted at all three experimental time points for hypoxic-reared pups when compared to control animals. These data suggest that chronic sublethal hypoxia may lead to severe impairments in corticogenesis in an animal model of developing brain.

Prospective individual matching: covariate balance and power in a comparative study.

In phase II to phase IV studies, randomization has gained widespread acceptance as a methodologic tool for the allocation of patients to treatment. However, randomization is not always feasible. At times, the treatment intervention occurs universally throughout one or more units (for example, a hospital unit), while the control therapy is the only intervention provided in other units. Patients may arrive randomly at a unit, based solely on availability of the unit to accept new subjects. Thus, the treatment assignment process is out of the investigator's control and not subject to selection bias. We describe a prospective individual matching procedure through which one can achieve balanced allocation of subjects to treatment groups in this comparative study setting. In this paper, we compare balance of baseline covariates and power for this design, in which the subject is selected at random and assigned to a treatment group, and the traditional randomized block design, in which the treatment is chosen at random and assigned to a subject. We show that the prospective individual matching procedure compares favourably to the traditional randomized blocked design with respect to both baseline covariate comparability and statistical power.

Comparison of urine collection methods for evaluating urinary nuclear matrix protein, NMP22, as a tumor marker.

PURPOSE: The nuclear matrix protein, NMP22, has been shown to be a useful tumor marker for identifying patients with a high likelihood of rapid recurrence of transitional cell carcinoma of the urinary tract after surgical treatment. Currently measurement of NMP22 involves 3 urine voids collected during a 24-hour period, which are pooled and assayed as a single sample. This study was performed to determine whether any single void would yield similar results to the pooled 3-void sample. MATERIALS AND METHODS: A total of 2,018 urine samples (3 voids per sample) was included in the study. All analyses were performed using the nonparametric Wilcoxon signed rank test for matched pairs. RESULTS: Analysis showed that the NMP22 level of a single void collected between midnight and noon was similar to the NMP22 level of the pooled 3-void sample. Receiver operating characteristics curves of the midnight-to-noon single void and the pooled 3-void sample were similar for predicting recurrence postoperatively in patients with urinary tract transitional cell carcinoma. CONCLUSIONS: One void collected between midnight and noon compares favorably with the current 3-void collection method for determining NMP22 levels in urine.

Fluoxetine has no marked effect on tic symptoms in patients with Tourette's syndrome: a double-blind placebo-controlled study.

To evaluate the efficacy of fluoxetine in the treatment of tics and obsessive-compulsive symptoms in patients with Tourette's syndrome (TS), 14 subjects (8-33 years old) with TS participated in a 20-week, fixed-dose (20 mg daily), double-blind, placebo-controlled crossover trial of fluoxetine monotherapy. Five subjects met criteria for obsessive-compulsive disorder (OCD), 6 additional subjects had obsessive-compulsive features, and 3 subjects had TS without obsessive-compulsive symptoms. There was no improvement in tics after 8 weeks of treatment with fluoxetine (p = 0.58). In contrast, fluoxetine treatment was associated with a significant reduction in obsessive-compulsive symptoms for the group of 6 subjects initially randomized to fluoxetine (p = 0.04). Crossover analysis showed that fluoxetine had no marked effect on tics (n = 10, p = 0.30, but produced a modest decrease in obsessive-compulsive symptoms (n = 8, p = 0.06). Order effects and carry-over effects were not significant. Withdrawal to placebo was associated with a 55% increase in obsessive-compulsive symptoms (p = 0.05), but there was no effect on tics. The most common side effect was transient behavioral activation, which occurred in about half of the subjects and was more common in children. Fluoxetine may be useful for the treatment of obsessive-compulsive symptoms in some patients with TS, but does not appear to be effective for tics.

Antecedents of cerebral palsy in a multicenter trial of indomethacin for intraventricular hemorrhage.

OBJECTIVES: To determine if cerebral palsy (CP) rates were lower in the active treatment group compared with the control group, as improved survival rates of very low-birth-weight infants are postulated to be the cause of the increased incidence of CP in preterm infants, to evaluate relationships between multiple prenatal, perinatal, and postnatal variables and CP to understand better its antecedents in very low-birth-weight infants in the era of surfactant replacement therapy, and to determine the usefulness of a cranial ultrasonographic (US) scan in predicting CP. DESIGN: Inception cohort follow-up study as part of a randomized controlled trial of low-dose indomethacin sodium for the prevention of intraventricular hemorrhage. SETTING: Neonatal intensive care units at 3 medical centers. PATIENTS: Infants with birth weights between 600 and 1250 g were eligible, and 505 infants were enrolled in the original study. Of these infants, 440 (87%) survived; neurologic examinations were completed on 381 infants (86%) at 36 months corrected age. MAIN OUTCOME MEASURES: Statistical analyses were performed to identify the antecedents of CP, including the results of frequent cranial US scans obtained throughout the newborn period. RESULTS: Cerebral palsy was found in 36 (9.5%) of 381 infants at 36 months corrected age (range, 33-39 months corrected age). Univariate analysis identified chorioamnionitis, treatment with surfactant, bronchopulmonary dysplasia, and abnormal cranial US findings as antecedents of CP. Periventricular leukomalacia and ventriculomegaly were associated with the highest detection rates for CP (37% and 30%, respectively) with acceptable false-positive rates. Multivariate analysis identified bronchopulmonary dysplasia and an abnormal cranial US scan showing grade 3 to 4 intraventricular hemorrhage, periventricular leukomalacia, or ventriculomegaly as independent predictors of CP. Odds ratios for the detection of CP using cranial US findings tabulated by hospital day were in the range of 7 to 26 beginning on day 2. CONCLUSION: The results suggest that cranial US findings are useful predictors of CP during a patient's stay in the hospital.

Neurodevelopmental outcome at 36 months' corrected age of preterm infants in the Multicenter Indomethacin Intraventricular Hemorrhage Prevention Trial.

OBJECTIVES: Low-dose indomethacin has been shown to prevent intraventricular hemorrhage (IVH) in very low birth weight neonates, and long-term neurodevelopmental follow-up data are needed to validate this intervention. We hypothesized that the early administration of low-dose indomethacin would not be associated with adverse cognitive outcome at 36 months' corrected age (CA). METHODS: We enrolled 431 neonates of 600 to 1250 g birth weight with no IVH at 6 to 12 hours in a randomized, prospective trial to determine whether low-dose indomethacin would prevent IVH. A priori, neurodevelopmental follow-up examinations, including the Stanford-Binet Intelligence Scale and Peabody Picture Vocabulary Test-Revised, and standard neurologic examinations were planned at 36 months' CA. RESULTS: Three hundred eighty-four of the 431 infants survived (192 [92%] of 209 infants receiving indomethacin versus 192 [86%] of 222 infants receiving saline), and 343 (89%) children were examined at 36 months' CA. Thirteen (8%) of the 166 infants who received indomethacin and 14 (8%) of 167 infants receiving the placebo were found to have cerebral palsy. There were no differences in the incidence of deafness or blindness between the two groups. For the 248 English-monolingual children for whom IQ data follow, the mean gestational age was significantly younger for the infants who received indomethacin than for those who received the placebo. None of the 115 infants who received indomethacin was found to have ventriculomegaly on cranial ultrasound at term, compared with 5 of 110 infants who received the placebo. The mean +/- SD Stanford-Binet IQ score for the 126 English-monolingual children who had received indomethacin was 89.6 +/- 18.92, compared with 85.0 +/- 20.79 for the 122 English-monolingual children who had received the placebo. Although maternal education was strongly correlated with Stanford-Binet IQ at 36 months' CA, there was no difference in educational levels between mothers of the infants receiving indomethacin and the placebo. CONCLUSIONS: Indomethacin administered at 6 to 12 hours as prophylaxis against IVH in very low birth weight infants does not result in adverse cognitive or motor outcomes at 36 months' CA.