MR Fingerprinting of Adult Brain Tumors: Initial Experience.

BACKGROUND AND PURPOSE: MR fingerprinting allows rapid simultaneous quantification of T1 and T2 relaxation times. This study assessed the utility of MR fingerprinting in differentiating common types of adult intra-axial brain tumors. MATERIALS AND METHODS: MR fingerprinting acquisition was performed in 31 patients with untreated intra-axial brain tumors: 17 glioblastomas, 6 World Health Organization grade II lower grade gliomas, and 8 metastases. T1, T2 of the solid tumor, immediate peritumoral white matter, and contralateral white matter were summarized within each ROI. Statistical comparisons on mean, SD, skewness, and kurtosis were performed by using the univariate Wilcoxon rank sum test across various tumor types. Bonferroni correction was used to correct for multiple-comparison testing. Multivariable logistic regression analysis was performed for discrimination between glioblastomas and metastases, and area under the receiver operator curve was calculated. RESULTS: Mean T2 values could differentiate solid tumor regions of lower grade gliomas from metastases (mean, 172 ± 53 ms, and 105 ± 27 ms, respectively; P = .004, significant after Bonferroni correction). The mean T1 of peritumoral white matter surrounding lower grade gliomas differed from peritumoral white matter around glioblastomas (mean, 1066 ± 218 ms, and 1578 ± 331 ms, respectively; P = .004, significant after Bonferroni correction). Logistic regression analysis revealed that the mean T2 of solid tumor offered the best separation between glioblastomas and metastases with an area under the curve of 0.86 (95% CI, 0.69-1.00; P < .0001). CONCLUSIONS: MR fingerprinting allows rapid simultaneous T1 and T2 measurement in brain tumors and surrounding tissues. MR fingerprinting-based relaxometry can identify quantitative differences between solid tumor regions of lower grade gliomas and metastases and between peritumoral regions of glioblastomas and lower grade gliomas.

Qualitative and quantitative performance of ¹8F-FDG-PET/MRI versus ¹8F-FDG-PET/CT in patients with head and neck cancer.

BACKGROUND AND PURPOSE: MR imaging and PET/CT are integrated in the work-up of head and neck cancer patients. The hybrid imaging technology (18)F-FDG-PET/MR imaging combining morphological and functional information might be attractive in this patient population. The aim of the study was to compare whole-body (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT in patients with head and neck cancer, both qualitatively in terms of lymph node and distant metastases detection and quantitatively in terms of standardized uptake values measured in (18)F-FDG-avid lesions. MATERIALS AND METHODS: Fourteen patients with head and neck cancer underwent both whole-body PET/CT and PET/MR imaging after a single injection of (18)F-FDG. Two groups of readers counted the number of lesions on PET/CT and PET/MR imaging scans. A consensus reading was performed in those cases in which the groups disagreed. Quantitative standardized uptake value measurements were performed by placing spheric ROIs over the lesions in 3 different planes. Weighted and unweighted κ statistics, correlation analysis, and the Wilcoxon signed rank test were used for statistical analysis. RESULTS: κ statistics for the number of head and neck lesion lesions counted (pooled across regions) revealed interreader agreement between groups 1 and 2 of 0.47 and 0.56, respectively. Intrareader agreement was 0.67 and 0.63. The consensus reading provided an intrareader agreement of 0.63. For the presence or absence of metastasis, interreader agreement was 0.85 and 0.70. The consensus reading provided an intrareader agreement of 0.72. The correlations between the maximum standardized uptake value in (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT for primary tumors and lymph node and metastatic lesions were very high (Spearman r = 1.00, 0.93, and 0.92, respectively). CONCLUSIONS: In patients with head and neck cancer, (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT provide comparable results in the detection of lymph node and distant metastases. Standardized uptake values derived from (18)F-FDG-PET/MR imaging can be used reliably in this patient population.

Optimization of the Expansion and Differentiation of Rabbit Chondrocytes In Vitro.

OBJECTIVE: To develop a tissue culture expansion method for rabbit chondrocytes that promotes robust expansion while preserving chondrogenic potential. DESIGN: Rabbit chondrocytes isolated from articular or auricular chondrocytes were assessed for chondrogenic differentiation potential versus population doubling using different expansion and differentiation conditions. Expansion conditions included serum alone, serum plus basic fibroblast growth factor 2 (FGF-2), and serum plus insulin-like growth factor 1 (IGF-1) and FGF-2. Differentiation conditions consisted of defined medium with and without bone morphogenetic protein 2 (BMP-2). RESULTS: Nonsupplemented chondrocytes showed limited expandability, whereas supplementation with FGF-2 allowed articular chondrocytes to be expanded past 10 population doublings (PDs) and allowed auricular chondrocytes to expand past 15 population doublings. Differentiation, as measured by glycosaminoglycan production in aggregate cultures, was minimal in articular chondrocytes without BMP-2 supplementation and diminished to less than 50% maximal in auricular chondrocytes by PD 20. However, when FGF-2 was used during expansion and BMP-2 used during differentiation, both articular and auricular chondrocytes retained greater than 50% maximal differentiation for more than 25 PDs. The addition of IGF-1 to FGF-2 during expansion decreased chondrogenicity of auricular chondrocytes exposed to BMP-2, whereas for articular chondrocytes, chondrogenic expression increased. CONCLUSION: These results demonstrate that FGF-2, for expansion, and BMP-2, for differentiation, dramatically increase the functional expansion of auricular and articular chondrocytes and provide a methodology to expand sufficient numbers of chondrocytes for tissue engineering applications.

Improved weight attainment of extremely low-gestational-age infants with bronchopulmonary dysplasia.

OBJECTIVE: To determine whether changes in neonatal practice and morbidity since 2000 have improved the growth attainment of infants with bronchopulmonary dysplasia (BPD). STUDY DESIGN: We compared the respective z-scores of the weight, length and head circumference of extremely low-gestational-age infants (aged <28 weeks) with BPD at birth, 40 weeks and 20 months corrected age (CA) during two time periods, namely period I, 1996-1999 (n=117) and period II, 2000-2003 (n=105), and examined the effects of significant changes in neonatal practice, morbidities and neurosensory outcome on 20-month growth outcomes. RESULT: During the most recent period (2000-2003), there was a significant increase in mean weight z-scores (-1.60 vs -1.22) and decrease in rates of subnormal weight (40 vs 21%), P<0.05 at 20 months CA but not in those of length or head circumference. Significant predictors of the 20-month weight z-score included time period (period I vs II), duration of ventilator dependence and 20-month neurosensory abnormality (all P<0.05). CONCLUSION: Despite an improvement in weight since 2000, poor growth attainment remains a major problem among infants with BPD.

Murine models of chronic Pseudomonas aeruginosa lung infection.

The animal model of chronic bronchopulmonary infection using agarose beads laden with Pseudomonas aeruginosa is frequently utilized in cystic fibrosis research, though it is challenging to perform it in mice. This paper reports the most successful methods for the creation of this model. Transtracheal insertion of a 22 G 1" over-the-needle intravenous catheter to preferentially inoculate the right mainstem bronchus using tribromoethanol anaesthesia administered i.p. was better for a successful surgical outcome compared, respectively, to the use of a 27 G (1/2)" needle, bilateral inoculation or an anaesthetic cocktail of xylazine, acepromazine and ketamine administered i.p. Bilateral infection was associated with higher mortality, greater weight loss and higher levels of bronchoalveolar cytokine concentration, compared to mice infected primarily in the right lung. Mucoid clinical strain PA M57-15 was preferred since mucoid clinical strain PA 2192 led to comparatively more severe lesions and higher mortality. Using the same operator for a given task reduced the variability inherent in this model, illustrated using outcome measures such as gross lung pathology. The response of mice inoculated with P. aeruginosa-laden agarose beads was characterized by bronchopulmonary inflammation, high production of cytokines, and significant weight loss; whereas the response to infection with free-living bacteria was characterized by pneumonia, lower production of cytokines and weight loss. The use of free P. aeruginosa pre-mixed with sterile agarose beads may be considered as an alternative to the use of P. aeruginosa-laden agarose beads, since the histopathological features were similar, though further characterization is needed to evaluate its utility as an adequate model of cystic fibrosis.

Reliability of multicenter pediatric echocardiographic measurements of left ventricular structure and function: the prospective P(2)C(2) HIV study.

BACKGROUND: To assess the reliability of pediatric echocardiographic measurements, we compared local measurements with those made at a central facility. METHODS AND RESULTS: The comparison was based on the first echocardiographic recording obtained on 735 children of HIV-infected mothers at 10 clinical sites focusing on measurements of left ventricular (LV) dimension, wall thicknesses, and fractional shortening. The recordings were measured locally and then remeasured at a central facility. The highest agreement expressed as an intraclass correlation coefficient (ICC=0.97) was noted for LV dimension, with much lower agreement for posterior wall thickness (ICC=0.65), fractional shortening (ICC=0.64), and septal wall thickness (ICC=0.50). The mean dimension was 0.03 cm smaller in central measurements (95% prediction interval [PI], -0.32 to 0.25 cm) for which 95% PI reflects the magnitude of differences between local and central measurements. Mean posterior wall thickness was 0.02 cm larger in central measurements (95% PI, -0.18 to 0.22 cm). Mean fractional shortening was 1% smaller in central measurements. However, the 95% PI was -10% to 8%, indicating that a fractional shortening of 32% measured centrally could be anywhere between 22% and 40% when measured locally. Central measurements of mean septal thickness were approximately 0.1 cm thicker than local ones (95% PI, -0.18 to 0.34 cm). Centrally measured wall thickness was more closely related to mortality and possibly was more valid than local measurements. CONCLUSIONS: Although LV dimension was reliably measured, local measurements of LV wall thickness and fractional shortening differed from central measurements.

Relation of measures of sleep-disordered breathing to neuropsychological functioning.

Sleep-disordered breathing (SDB) has been associated with neuropsychological (NP) deficits. The extent to which such effects are attributable to unmeasured confounders or selection biases, or are manifest across a range of SDB is unclear. The relationship of SDB with a broad range of NP functions was examined in 100 volunteers with a spectrum of SDB and without underlying comorbidity. Factor analysis suggested that the NP tests could be summarized as four constructs: declarative memory, signal discrimination, working memory, and set shifting. These factors plus vigilance were dependent variables. Independent variables were age, the respiratory disturbance index (RDI), a sleepiness score, the arousal index, and sleep-associated hypoxemia. Factors "declarative memory" (measuring 25% of the common variance, alpha = 0.95), "signal discrimination" (10% variance, alpha = 0.70), and "working memory" (9% variance, alpha = 0.52) were each significantly, linearly predicted by hypoxemia and/or the RDI, with no evidence for significant threshold effects. SDB measures accounted for 4-6% of the variance in NP constructs. In contrast, sleepiness best predicted vigilance. Thus, adverse exposures (hypoxemia or RDI) during sleep may negatively influence NP functions in a dose-response relationship, and, other than vigilance, these effects may not be directly attributable to sleepiness.

Respiratory diseases in the first year of life in children born to HIV-1-infected women.

Our objective was to describe the respiratory complications, clinical findings, and chest radiographic changes in the first year of life in infected and uninfected children born to HIV-1-infected women. We prospectively followed a cohort of 600 infants born to HIV-1-infected women from birth to 12 months in a multicenter study. Of these, 93 infants (15.5%) were HIV-1-infected, 463 were uninfected, and 44 were of unknown status prior to death or loss to follow-up. The cumulative incidence ( +/- SE) of an initial pneumonia episode at 12 months was 24.1 +/- 4.7% in HIV-1-infected children compared to 1.4 +/- 0.6% in HIV-1-uninfected children (P < 0.001). The rate of Pneumocystis carinii pneumonia (PCP) was 9.5 per 100 child-years. The HIV-1 RNA load was not higher in the group that developed pneumonia in the first year vs. those who did not. Children who developed lower respiratory tract infections or PCP had increased rates of decline of CD4 cell counts during the first 6 months of life. Lower maternal CD4 cell counts were associated with higher rates of pneumonia, and upper and lower respiratory tract infections. The rates of upper respiratory tract infection and bronchiolitis/reactive airway disease in infected children were not significantly different than in uninfected children. At 12 months, significantly more HIV-1-infected than uninfected children had tachypnea and chest radiographs with nodular and reticular densities. There was no relationship between cytomegalovirus infection in the first year of life and radiographic changes or occurrences of pneumonia. In conclusion, despite a low incidence of PCP, rates of pneumonia remain high in HIV-infected children in the first year of life. The incidence of pneumonia in uninfected infants born to HIV-1-infected mothers is low. Chest X-ray abnormalities and tachypnea suggest that subacute disease is present in infected infants. Further follow-up is warranted to determine its nature.

Analysis of change in the presence of informative censoring: application to a longitudinal clinical trial of progressive renal disease.

The rate of change in a continuous variable, measured serially over time, is often used as an outcome in longitudinal studies or clinical trials. When patients terminate the study before the scheduled end of the study, there is a potential for bias in estimation of rate of change using standard methods which ignore the missing data mechanism. These methods include the use of unweighted generalized estimating equations methods and likelihood-based methods assuming an ignorable missing data mechanism. We present a model for analysis of informatively censored data, based on an extension of the two-stage linear random effects model, where each subject's random intercept and slope are allowed to be associated with an underlying time to event. The joint distribution of the continuous responses and the time-to-event variable are then estimated via maximum likelihood using the EM algorithm, and using the bootstrap to calculate standard errors. We illustrate this methodology and compare it to simpler approaches and usual maximum likelihood using data from a multi-centre study of the effects of diet and blood pressure control on progression of renal disease, the Modification of Diet in Renal Disease (MDRD) Study. Sensitivity analyses and simulations are used to evaluate the performance of this methodology in the context of the MDRD data, under various scenarios where the drop-out mechanism is ignorable as well as non-ignorable.

Placental lesions associated with abnormal growth in twins.

Abnormal growth in one or both twins may contribute to the increased morbidity and mortality observed in twin gestation. Our objective in this retrospective study of all twin pregnancies delivered at our hospital (n = 240) over a 2-year period was to study the relationship between placental lesions and abnormal growth. Standardized placental examinations were performed in 192 cases (80%), which constituted the study population. Two growth abnormalities were studied: discordant growth as defined by > 15% difference in birth weight and small-for-gestational-age (SGA) birth as defined by birth weight less-than the 10th percentile for gestational age. The majority of twin pregnancies with either discordant growth (41/57 cases) or SGA birth (26/35 cases) had dichorionic placentas. In monochorionic placentas studied by injection there was no significant relationship between vascular anastomoses and discordant growth. Placental weight for small discordant and SGA twins was equivalent or increased relative to infant weight, a pattern not suggestive of maternal vascular underperfusion. Eight lesions, five considered to represent chronic placental disease and three considered to represent intrauterine adaptation, were studied as possible predictors of abnormal growth. The overall prevalence of these lesions in twin placentas was less than that seen in singleton births. Concordance between twin placentas for most lesions was higher than would be expected, based on their prevalence in singleton placentas. Two lesions were associated with discordant growth in both univariate and multivariate analyses: peripheral cord insertion (OR 3.6, 95% CI 1.7-7.6) and avascular villi (AV; OR 3.2, 95% CI 1.0-10.3). Three placental lesions were associated with SGA infants at the univariate level: peripheral cord insertion, avascular villi, and maternal vascular underperfusion. Only peripheral cord insertion (OR 9.8, 95% CI 4.1-23.4) and AV (OR 3.7, CI 1.0-13.7) were significant in the multivariate analysis. The relative increase in peripheral cord insertion and AV with abnormal growth was observed for both monochorionic and dichorionic placentas. Subgroups of discordant infants with and without SGA were both associated with peripheral cord insertion while only those with SGA had an increase in AV. Both peripheral cord insertion and AV were increased in the subgroup with SGA but no discordancy. In summary, two placental lesions, peripheral cord insertion indicating a spatially limited intrauterine compartment and AV indicating occlusion of fetal vessels in the placenta, were associated with abnormal growth in twins.

Imaging evaluation of suspected appendicitis in a pediatric population: effectiveness of sonography versus CT.

OBJECTIVE: The purpose of this study was to compare the diagnostic accuracy of graded compression sonography with that of helical CT for the diagnosis of appendicitis in a pediatric and young adult population. SUBJECTS AND METHODS: Between June 1996 and April 1999, 386 pediatric and young adult patients with suspected appendicitis were examined using sonography, CT, or both: 233 underwent sonography only, 71 underwent CT only, and 82 underwent sonography and CT. All sonograms and CT scans were prospectively interpreted as showing positive or negative findings for appendicitis by one of six pediatric radiologists. CT and sonographic findings were correlated with surgical and histopathologic findings or findings at clinical follow-up. RESULTS: Helical CT had a significantly higher sensitivity (95% versus 78%, p = 0.009) and accuracy (94% versus 89%, p = 0.05) than graded compression sonography for the diagnosis of appendicitis in children, adolescents, and young adults. The specificity of both techniques was 93%. Twenty of 82 patients who underwent both sonography and CT had discordance between the findings of the two examinations. The CT results were correct in a significantly greater number of patients with discordant examinations (17/20 patients [85%]). CONCLUSION: Helical CT has a significantly higher sensitivity and accuracy than graded compression sonography for the diagnosis of appendicitis in a pediatric and young adult population, particularly in children more than 10 years old.

Neurodevelopment and predictors of outcomes of children with birth weights of less than 1000 g: 1992-1995.

OBJECTIVE: To examine the neurosensory and cognitive status of extremely low-birth-weight (ELBW; < 1,000 g) children born from January 1, 1992, through December 31, 1995, and to identify the significant predictors of outcome. DESIGN: An inception cohort of ELBW infants admitted to the neonatal intensive care unit (NICU) and observed to 20 months' corrected age. SETTING: A tertiary level urban NICU and follow-up clinic at a university hospital. POPULATION: Of 333 ELBW infants without major congenital malformations admitted to the NICU, 241 (72%) survived to 20 months' corrected age. We studied 221 children (92%) at a mean of 20 months' corrected age. The mean birth weight was 813 g; mean gestational age, 26.4 weeks. MAIN OUTCOME MEASURES: Assessments of cognitive and neurosensory development. RESULTS: Major neurosensory abnormality was present in 54 children (24%), including 33 (15%) with cerebral palsy, 20 (9%) with deafness, and 2 (1%) with blindness. The mean (+/- SD) Bayley-Mental Developmental Index (MDI) score was 74.7 +/- 17. Ninety-two children (42%) had a subnormal MDI score (<70). Neurodevelopmental impairment (neurosensory abnormality and/or MDI score <70) was present in 105 children (48%). Multiple stepwise logistic regression analysis that considered sex, social risk, birth weight, and neonatal risk factors revealed significant predictors of a subnormal MDI score to be male sex (odds ratio [OR], 2.73; 95% confidence interval [CI], 1.52-4.92), social risk (OR, 1.48; 95% CI, 1.09-2.00), and chronic lung disease (OR, 2.18; 95% CI, 1.20-3.94). Predictors of neurologic abnormality were a severely abnormal finding on cerebral ultrasound (OR, 8.09; 95% CI, 3.69-17.71) and chronic lung disease (OR, 2.46; 95% CI, 1.12-5.40); predictors of deafness were male sex (OR, 2.79; 95% CI, 1.02-7.62), sepsis (OR, 3.15; 95% CI, 1.05-9.48), and jaundice (maximal bilirubin level, >171 micromol/L [>10 mg/dL]) (OR, 4.80; 95% CI, 1.46-15.73). CONCLUSION: There is an urgent need for research into the etiology and prevention of neonatal morbidity.

Thoracoabdominal compression and respiratory system compliance in HIV-infected infants.

The thoracoabdominal compression technique (TAC) is used to measure expiratory flow in infants. We investigated whether TAC caused a change in total thoracic compliance (Crs), resistance (Rrs), and respiratory system time constant (Trs). We studied 41 infants (mean age, 12.4 mo; SD, 7.5) from five centers studying longitudinal lung and cardiovascular function of infants from HIV-infected mothers. We measured Crs, Rrs, and Trs before and after TAC. Changes in Crs, Rrs, and Trs after TAC were not dependent on the length of time since TAC. Crs and Trs were reduced after TAC, p = 0.013 and p = 0.003, respectively, whereas Rrs did not change. When compared with uninfected infants, HIV-infected infants had a larger post-pre TAC percent decline in Crs (p = 0.003) and a post-pre TAC rise in mean Rrs (p = 0.03). These differences remained significant after adjusting for sex and age. When performing infant pulmonary function testing, TAC itself produces a temporary decrease in Crs and Trs that is more significant in infants at risk for abnormal lung volume or compliance. Therefore, the sequence of performing the infant lung function parameters should be the same each time the testing is repeated with TAC as the last parameter tested at each testing session.

A double-blind pilot study of risperidone in the treatment of conduct disorder.

OBJECTIVE: To examine whether risperidone is superior to placebo in the treatment of youths with conduct disorder. METHOD: This was a 10-week, randomized, double-blind, placebo-controlled study with 2 parallel arms. Ten youths were randomly assigned to receive placebo and 10 youths were randomly assigned to receive risperidone. Patients were seen weekly throughout the trial. Medications could be increased at weekly intervals during the first 6 weeks of the study from an initial dose of 0.25 mg or 0.50 mg each morning, depending on patient weight. Patients weighing less than 50 kg had a maximum total daily dose of risperidone of 1.5 mg. Patients weighing 50 kg or greater had a maximum total daily dose of risperidone of 3.0 mg. The primary outcome measure was the Rating of Aggression Against People and/or Property Scale. RESULTS: Risperidone was superior to placebo in ameliorating aggression on most measures. Risperidone was reasonably well tolerated, with none of the risperidone-treated patients developing extrapyramidal side effects. CONCLUSIONS: These data provide preliminary evidence that risperidone may have efficacy in the treatment of youths with conduct disorder. Because of the small sample size and the brief length of this study, further research is necessary to confirm these findings.

Feasibility of a clinical trial of augmentation therapy for alpha(1)-antitrypsin deficiency. The Alpha 1-Antitrypsin Deficiency Registry Study Group.

We examined the feasibility of a randomized clinical trial of intravenous augmentation therapy for individuals with alpha 1-antitrypsin (alpha1AT) deficiency, basing calculations on newly available data obtained from the NHLBI Registry of Patients with Severe Deficiency of Alpha 1-Antitrypsin. Using rate of FEV(1) decline as the primary outcome and adjusting for noncompliance, a study of subjects with Stage II chronic obstructive pulmonary disease (COPD) (initial FEV(1) 35 to 49% predicted) with biannual spirometry measures obtained over 4 yr of follow-up would require 147 subjects per treatment arm to detect a difference in FEV(1) decline of 23 ml/yr (i.e., a 28% reduction), the difference observed in the NHLBI Registry (1-sided test, alpha = 0.05, 90% power). To detect a 40% reduction in mortality in a 5-year study of subjects with baseline FEV(1) 35 to 49% predicted, recruited over the first 2 yr and then followed an additional 3 yr, 342 subjects per treatment arm would be needed. Though significant impediments to carrying out a clinical trial exist, including the cost of such a trial and the potential difficulties in recruiting patients for a placebo-controlled trial, we recommend a randomized controlled trial as the best method to evaluate the efficacy of intravenous augmentation therapy and of possible future treatments.

The losartan renal protection study--rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan).

The RENAAL Study is a double-blind, placebo-controlled trial to evaluate the renal protective effects of losartan in Type 2 diabetic patients with nephropathy. The study has enrolled 1513 patients and is expected to continue for 3.5 years after the last patient has been entered. Eligible patients must have a urinary albumin:creatinine ratio of at least 300 mg/g and serum creatinine between 1.3 to 3.0 mg/dL. Eligible hypertensive or normotensive patients are randomised to receive either losartan or placebo, in addition to their existing antihypertensive therapy. Medications that block angiotensin production or action, are excluded. The primary endpoint is a composite of the time to first event of doubling of serum creatinine, end-stage renal disease, or death; secondary endpoints include cardiovascular events, progression of renal disease, and changes in proteinuria; tertiary endpoints include quality of life, healthcare resource utilisation, and amputations. Patients include Caucasians (48.6%), Blacks (15.2%), Asians (16.7%), and Hispanics (18.2%). Baseline urinary albumin:creatinine ratio and serum creatinine levels average 1867 mg/g and 1.9 mg/dL, respectively. Mean systolic and diastolic blood pressures are 153 and 82 mmHg, respectively. RENAAL will document whether blockade of the AII receptor with losartan produces clinical benefits in patients with Type 2 diabetes and nephropathy.

Cardiac complications in children with human immunodeficiency virus infection. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group, National Heart, Lung, and Blood Institute.

OBJECTIVE: Although numerous cardiac abnormalities have been reported in HIV-infected children, precise estimates of the incidence of cardiac disease in these children are not well-known. The objective of this report is to describe the 2-year cumulative incidence of cardiac abnormalities in HIV-infected children. DESIGN: Prospective cohort (Group I) and inception cohort (Group II) study design. SETTING: A volunteer sample from 10 university and public hospitals. PARTICIPANTS: Group I consisted of 205 HIV vertically infected children enrolled at a median age of 22 months. This group was comprised of infants and children already known to be HIV-infected at the time of enrollment in the study. Most of the children were African-American or Hispanic and 89% had symptomatic HIV infection at enrollment. The second group included 611 neonates born to HIV-infected mothers, enrolled during fetal life or before 28 days of age (Group II). In contrast to the older Group I children, all the Group II children were enrolled before their HIV status was ascertained. INTERVENTIONS: According to the study protocol, children underwent a series of cardiac evaluations including two-dimensional echocardiogram and Doppler studies of cardiac function every 4 to 6 months. They also had a 12- or 15-lead surface electrocardiogram (ECG), 24-hour ambulatory ECG monitoring, and a chest radiograph every 12 months. OUTCOME MEASURES: Main outcome measures were the cumulative incidence of an initial episode of left ventricular (LV) dysfunction, cardiac enlargement, and congestive heart failure (CHF). Because cardiac abnormalities tended to cluster in the same patients, we also determined the number of children who had cardiac impairment which we defined as having either left ventricular fractional shortening (LV FS) 2) at the time of the first echocardiogram was 8. 3%. The cumulative incidence of LV end-diastolic enlargement was 11. 7% after 2 years. The cumulative incidence of CHF and/or the use of cardiac medications was 10.0% in Group I children. There were 14 prevalent cases of cardiac impairment (LV FS

Unexpected non-HIV causes of death in children born to HIV-infected mothers. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group.

INTRODUCTION: A high incidence of sudden, unexplained deaths in infants born to HIV-infected mothers has been noted in several epidemiologic studies. During the course of a prospective study of heart and lung disease in children born to HIV-infected mothers, we noted that of 5 unexpected non-HIV-related deaths, 4 were attributed to traumatic events. METHODS: The Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2) study is a multicenter, prospective investigation of the incidence of heart and lung disease in HIV-infected children. A total of 805 children were enrolled and followed for 5 to 7 years with serial immunologic, pulmonary and cardiac function studies. During the study, a multidisciplinary committee was formed to review the cause of death for those patients who died. The committee used results of pulmonary, cardiac, and laboratory tests, hospital summaries, as well as autopsy and coroners' reports. The committee formed a consensus about the underlying and contributing causes of death for each subject using the definitions from the 1989 US Standard Certificate of Death. RESULTS: A total of 121 deaths occurred during the course of the P2C2 study. Of the 121 deaths, 5 were traumatic or sudden and unexpected and judged by the Mortality Review Committee to be unrelated to HIV infection. The median age at the time of death was 1.3 months and ranged from 1.2 to 37.8 months. Two infants died of trauma: a skull fracture and subdural hematoma in 1 infant and multiple skeletal fractures consistent with battered child syndrome in the other infant. The third infant died of accidental suffocation at home at 1.2 months of age. The fourth infant died suddenly and unexpectedly at home at 1.3 months of age. The autopsy showed no sign of HIV or other infection and was consistent with sudden unexpected death or SIDS. One non-HIV-related death occurred when a 38-month-old child died together with the mother in an unwitnessed drowning. The cumulative mortality rate attributable to trauma and sudden death at 4 months of age was 0.95% (95% CI: 0.02-1. 87%) and the infant mortality rate was 9.5/1000 live births. Three children were born prematurely at 30, 33, and 36 weeks' gestational age, respectively, and 3 mothers admitted using recreational drugs before or during pregnancy. DISCUSSION: These traumatic and sudden non-HIV-related deaths accounted for 4.1% (5/121) of the deaths during the entire P2C2 study period and for 20% (4/20) of the deaths in the first year of life. Four deaths were attributable to accidental and nonaccidental trauma rather than to other common causes of infant death. One death was a sudden unexpected death, similar to SIDS, a leading cause of infant death in the United States. The majority of previously reported non-HIV-related deaths in infants born to HIV-infected mothers have been attributed to SIDS or to unexplained sudden death. In contrast with other reports, 4 of the 5 children in our series died of accidental or nonaccidental trauma and only 1 was a sudden unexplained death. It is unlikely that HIV exposure is related directly to the deaths described in this report; however, maternal HIV infection may be a marker for factors that place the child at risk for sudden or traumatic death. SUMMARY: This report suggests that children born to HIV-infected mothers may be at increased risk for traumatic or sudden, unexplained, non-HIV-related death. These children seem to be at risk regardless of their own HIV infection status. Furthermore, 4 of the deaths in our study occurred within the first few months of life, suggesting that this is a period of increased vulnerability. Studies to identify associated risk factors for non-HIV-related deaths are needed to identify these high-risk infants. Children born to HIV-infected mothers may be more vulnerable than was recognized previously and may be in need of increased social services, especially in early infancy.

Cytomegalovirus infection and HIV-1 disease progression in infants born to HIV-1-infected women. Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection Study Group.

BACKGROUND AND METHODS: Cytomegalovirus (CMV) has been implicated as a cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We assessed 440 infants (75 of whom were HIV-1-infected and 365 of whom were not) who had known CMV status and were born to HIV-1-infected women and who were followed prospectively. HIV-1 disease progression was defined as the presence of class C symptoms (according to the criteria of the Centers for Disease Control and Prevention [CDC]) or CD4 counts of less than 750 cells per cubic millimeter by 1 year of age and less than 500 cells per cubic millimeter by 18 months of age. RESULTS: At birth the frequency of CMV infection was similar in the HIV-1-infected and HIV-1-uninfected infants (4.3 percent and 4.5 percent, respectively), but the HIV-1-infected infants had a higher rate of CMV infection at six months of age (39.9 percent vs. 15.3 percent, P=0.001) and continued to have a higher rate of CMV infection through four years of age (P=0.04). By 18 months of age, the infants with both infections had higher rates of HIV-1 disease progression (70.0 percent vs. 30.4 percent, P=0.001), CDC class C symptoms or death (52.5 percent vs. 21.7 percent, P=0.008), and impaired brain growth or progressive motor deficits (35.6 percent vs. 8.7 percent, P=0.005) than infants infected only with HIV-1. In a Cox regression analysis, CMV infection was associated with an increased risk of HIV-1 disease progression (relative risk, 2.59; 95 percent confidence interval, 1.13 to 5.95). Among children infected with HIV-1 alone, but not among those infected with both viruses, children with rapid progression of HIV-1 disease had higher mean levels of HIV-1 RNA than those with slower or no progression of disease. CONCLUSIONS: HIV-1-infected infants who acquire CMV infection in the first 18 months of life have a significantly higher rate of disease progression and central nervous system disease than those infected with HIV-1 alone.

Risk factors for sleep-disordered breathing in children. Associations with obesity, race, and respiratory problems.

This study examined risk factors for sleep-disordered breathing (SDB) in children and adolescents; specifically, quantifying risk associated with obesity, race, and upper and lower respiratory problems. Subjects were participants in a genetic-epidemiologic study of SDB and included 399 children and adolescents 2 to 18 yr of age, recruited as members of families with a member (a proband) with known sleep apnea (31 index families) or as members of neighborhood control families (30 families). SDB was assessed with home overnight multichannel monitoring and SDB was defined based on an apneahypopnea index >/= 10 (moderately affected) or < 5 (unaffected). SDB of moderate level was significantly associated with obesity (odds ratio, 4.59; 95% confidence interval [CI], 1.58 to 13.33) and African-American race (odds ratio, 3.49; 95% CI, 1.56 to 8.32) but not with sex or age. After adjusting for obesity, proband sampling, race and familial clustering, sinus problems and persistent wheeze each independently (of the other) predicted SDB. These data suggest the importance of upper and lower respiratory problems and obesity as risk factors for SDB in children and adolescents. Increased risk in African Americans appears to be independent of the effects of obesity or respiratory problems.