Neurodevelopmental Outcomes of Extremely Preterm Infants Randomized to Stress Dose Hydrocortisone.

OBJECTIVE: To compare the effects of stress dose hydrocortisone therapy with placebo on survival without neurodevelopmental impairments in high-risk preterm infants. STUDY DESIGN: We recruited 64 extremely low birth weight (birth weight ≤1000 g) infants between the ages of 10 and 21 postnatal days who were ventilator-dependent and at high-risk for bronchopulmonary dysplasia. Infants were randomized to a tapering 7-day course of stress dose hydrocortisone or saline placebo. The primary outcome at follow-up was a composite of death, cognitive or language delay, cerebral palsy, severe hearing loss, or bilateral blindness at a corrected age of 18-22 months. Secondary outcomes included continued use of respiratory therapies and somatic growth. RESULTS: Fifty-seven infants had adequate data for the primary outcome. Of the 28 infants randomized to hydrocortisone, 19 (68%) died or survived with impairment compared with 22 of the 29 infants (76%) assigned to placebo (relative risk: 0.83; 95% CI, 0.61 to 1.14). The rates of death for those in the hydrocortisone and placebo groups were 31% and 41%, respectively (P = 0.42). Randomization to hydrocortisone also did not significantly affect the frequency of supplemental oxygen use, positive airway pressure support, or need for respiratory medications. CONCLUSIONS: In high-risk extremely low birth weight infants, stress dose hydrocortisone therapy after 10 days of age had no statistically significant effect on the incidence of death or neurodevelopmental impairment at 18-22 months. These results may inform the design and conduct of future clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00167544.

Development and validation of a clinical model to predict the presence of ß-lactam resistance in viridans group streptococci causing bacteremia in neutropenic cancer patients.

BACKGROUND: Concern for serious infection due to ß-lactam-resistant viridans group streptococci (VGS) is a major factor driving empiric use of an anti-gram-positive antimicrobial in patients with febrile neutropenia. We sought to develop and validate a prediction model for the presence of ß-lactam resistance in VGS causing bloodstream infection (BSI) in neutropenic patients. METHODS: Data from 569 unique cases of VGS BSI in neutropenic patients from 2000 to 2010 at the MD Anderson Cancer Center were used to develop the clinical prediction model. Validation was done using 163 cases from 2011 to 2013. In vitro activity of ß-lactam agents was determined for 2011-2013 VGS bloodstream isolates. RESULTS: In vitro resistance to ß-lactam agents commonly used in the empiric treatment of febrile neutropenia was observed only for VGS isolates with a penicillin minimum inhibitory concentration (MIC) of ≥ 2 µg/mL. One hundred twenty-nine of 732 patients (17%) were infected with VGS strains with a penicillin MIC ≥ 2 µg/mL. For the derivation and validation cohorts, 98% of patients infected by VGS with a penicillin MIC of ≥ 2 µg/mL had at least 1 of the following risk factors: current use of a ß-lactam as antimicrobial prophylaxis, receipt of a ß-lactam antimicrobial in the previous 30 days, or nosocomial VGS BSI onset. Limiting empiric anti-gram-positive therapy to neutropenic patients having at least 1 of these 3 risk factors would have reduced such use by 42%. CONCLUSIONS: Simple clinical criteria can assist with targeting of anti-gram-positive therapy to febrile neutropenic patients at risk of serious ß-lactam-resistant VGS infection.

Outcome predictors of limb salvage in traumatic popliteal artery injury.

BACKGROUND: Significantly reduced amputation rates for traumatic popliteal artery injuries have been achieved with improved revascularization and resuscitative techniques. Predictive scores have failed to accurately predict outcomes in patients who sustain popliteal artery damage. This study aimed to identify predictors of limb salvage in a civilian cohort after popliteal artery trauma. METHODS: A single-institution, retrospective review was performed of all patients with popliteal artery trauma presenting between January 2002 and June 2009. Data were compiled using the institutional trauma registry, with demographics, mechanism of injury, associated injury, fasciotomy, Mangled Extremity Severity Score (MESS), and Injury Severity Score (ISS) all documented. Statistical analysis included descriptive statistics, univariate analysis, and multiple exact logistic regression. RESULTS: Seventy traumatic popliteal artery injuries were identified in 68 patients with a mean age of 33 years (range: 5-88 years). The majority of patients were male (n = 57; 81%), and 73% sustained blunt injury. Associated venous injury was present in 16 (23%) cases. Associated orthopedic injuries included 19 (27%) dislocations and 49 (70%) fractures. The median MESS was 5 (range: 2-9) and the median ISS was 9 (range: 4-41). Revascularization was performed in 62 cases (89%). Twenty-three percent of patients had compartment syndrome and 56% underwent fasciotomy. Fifteen (21%) patients required amputation, 11% of which were primary and 10% secondary. Variables associated with amputation included ISS >10 compared to ISS <9 (odds ratio [OR]: 7.4; P < 0.045), blunt injury (OR: 10.7; P = 0.009), MESS >7 (OR: 2.4; P < 0.0001), and fractures (OR: 0.13; P < 0.045). In a multiple exact logistic regression analysis, a MESS >7 (P < 0.05) was the only significant predictor of amputation. CONCLUSION: Patients with traumatic popliteal artery injury are at high risk for amputation. Blunt injury, fractures, ISS >9, and MESS >7 were associated with an increased odds of amputation. Although in our data, MESS was the strongest predictor of amputation, we recognize that MESS was previously invalidated as a scoring system. New methods to determine limb viability in the mangled extremity are needed.

Standardized reporting for congenital diaphragmatic hernia--an international consensus.

BACKGROUND/PURPOSE: Congenital diaphragmatic hernia (CDH) remains a significant cause of neonatal death. A wide spectrum of disease severity and treatment strategies makes comparisons challenging. The objective of this study was to create a standardized reporting system for CDH. METHODS: Data were prospectively collected on all live born infants with CDH from 51 centers in 9 countries. Patients who underwent surgical correction had the diaphragmatic defect size graded (A-D) using a standardized system. Other data known to affect outcome were combined to create a usable staging system. The primary outcome was death or hospital discharge. RESULTS: A total of 1,975 infants were evaluated. A total of 326 infants were not repaired, and all died. Of the remaining 1,649, the defect was scored in 1,638 patients. A small defect (A) had a high survival, while a large defect was much worse. Cardiac defects significantly worsened outcome. We grouped patients into 6 categories based on defect size with an isolated A defect as stage I. A major cardiac anomaly (+) placed the patient in the next higher stage. Applying this, patient survival is 99% for stage I, 96% stage II, 78% stage III, 58% stage IV, 39% stage V, and 0% for non-repair. CONCLUSIONS: The size of the diaphragmatic defect and a severe cardiac anomaly are strongly associated with outcome. Standardizing reporting is imperative in determining optimal outcomes and effective therapies for CDH and could serve as a benchmark for prospective trials.

Perinatal clinical antecedents of white matter microstructural abnormalities on diffusion tensor imaging in extremely preterm infants.

OBJECTIVE: To identify perinatal clinical antecedents of white matter microstructural abnormalities in extremely preterm infants. METHODS: A prospective cohort of extremely preterm infants (N = 86) and healthy term controls (N = 16) underwent diffusion tensor imaging (DTI) at term equivalent age. Region of interest-based measures of white matter microstructure - fractional anisotropy and mean diffusivity - were quantified in seven vulnerable cerebral regions and group differences assessed. In the preterm cohort, multivariable linear regression analyses were conducted to identify independent clinical factors associated with microstructural abnormalities. RESULTS: Preterm infants had a mean (standard deviation) gestational age of 26.1 (1.7) weeks and birth weight of 824 (182) grams. Compared to term controls, the preterm cohort exhibited widespread microstructural abnormalities in 9 of 14 regional measures. Chorioamnionitis, necrotizing enterocolitis, white matter injury on cranial ultrasound, and increasing duration of mechanical ventilation were adversely correlated with regional microstructure. Conversely, antenatal steroids, female sex, longer duration of caffeine therapy, and greater duration of human milk use were independent favorable factors. White matter injury on cranial ultrasound was associated with a five weeks or greater delayed maturation of the corpus callosum; every additional 10 days of human milk use were associated with a three weeks or greater advanced maturation of the corpus callosum. CONCLUSIONS: Diffusion tensor imaging is sensitive in detecting the widespread cerebral delayed maturation and/or damage increasingly observed in extremely preterm infants. In our cohort, it also aided identification of several previously known or suspected perinatal clinical antecedents of brain injury, aberrant development, and neurodevelopmental impairments.

Perinatal factors and regional brain volume abnormalities at term in a cohort of extremely low birth weight infants.

Our objective was to investigate diverse clinical antecedents of total and regional brain volume abnormalities and white matter hyperintensity volume on term MRI in extremely low birth weight (birth weight ≤1000 g) survivors. A consecutive cohort of extremely low birth weight infants who survived to 38 weeks postmenstrual age (n = 122) and a control group of 16 healthy term newborns underwent brain MRI at term-equivalent age. Brain volumes were measured using semi-automated and manual segmentation methods. Using multivariable linear regression, clinical antecedents were correlated with volumes of total brain tissue, white matter hyperintensities, and regional tissues/structures, adjusted for age at MRI, total cranial volume, and total tissue volume. Regional brain volumes were markedly reduced in extremely low birth weight infants as compared to term newborns (relative difference range: -11.0%, -35.9%). Significant adverse clinical associations for total brain tissue volume included: small for gestational age, seizures, caffeine therapy/apnea of prematurity, duration of parenteral nutrition, pulmonary hemorrhage, and white matter injury (p<0.01 for each; relative difference range: -1.4% to -15.0%). Surgery for retinopathy of prematurity and surgery for necrotizing enterocolitis or spontaneous intestinal perforation were significantly associated with increasing volume of white matter hyperintensities. Regional brain volumes are sensitive to multiple perinatal factors and neonatal morbidities or interventions. Brain growth measurements in extremely low birth weight infants can advance our understanding of perinatal brain injury and development.

Pilot randomized trial of hydrocortisone in ventilator-dependent extremely preterm infants: effects on regional brain volumes.

OBJECTIVE: To test the hypothesis that high-risk ventilator-dependent extremely low birth weight (birth weight ≤1000 g) infants treated with 7 days of hydrocortisone will have larger total brain tissue volumes than placebo treated infants. STUDY DESIGN: A predetermined sample size of 64 extremely low birth weight infants, between 10-21 days old and ventilator-dependent with a respiratory index score ≥2, were randomized to systemic hydrocortisone (17 mg/kg cumulative dose) or saline placebo. Primary outcome was total brain tissue volume. Volumetric magnetic resonance imaging was performed at 38 weeks postmenstrual age; brain tissue regions were segmented and quantified automatically with a high degree of accuracy and 9 structures were segmented manually. All analyses of regional brain volumes were adjusted by postmenstrual age at magnetic resonance imaging scan. RESULTS: The study groups were similar at baseline and 8 infants died in each arm. Unadjusted total brain tissue volume (mean ± SD) in the hydrocortisone (N = 23) and placebo treated infants (N = 21) was 272 ± 40.3 cm(3) and 277.8 ± 59.1 cm(3), respectively (adjusted mean difference: 6.35 cm(3) (95% CI: (-20.8, 32.5); P = .64). Three of the 31 hydrocortisone treated infants and 5 of the 33 placebo treated infants survived without severe bronchopulmonary dysplasia (relative risk 0.62, 95% CI: 0.13, 2.66; P = .49). No significant differences were noted in prespecified secondary outcomes of regional structural volumes or days on respiratory support. No adverse effects of hydrocortisone were observed. CONCLUSIONS: Low dose hydrocortisone in high-risk ventilator-dependent infants after a week of age had no discernible effect on regional brain volumes or pulmonary outcomes prior to neonatal intensive care unit discharge.

Sound levels, staff perceptions, and patient outcomes during renovation near the neonatal intensive care unit.

OBJECTIVE: Sound levels, staff perceptions, and patient outcomes were evaluated during a year-long hospital renovation project on the floor above a neonatal intensive care unit (NICU). BACKGROUND: Construction noise may be detrimental to NICU patients and healthcare professionals. There are no comprehensive studies evaluating the impact of hospital construction on sound levels, staff, and patients. METHODS: Prospective observational study comparing sound measures and patient outcomes before, during, and after construction. Staff were surveyed about the construction noise, and hospital employee satisfaction scores are reported. RESULTS: Equivalent sound levels were not significantly higher during construction. Most staff members (89%) perceived the renovation period as louder, and 83% reported interruptions of their work. Patient outcomes were the same or more positive during construction. Very low birth weight (VLBW) infants were less likely to require 24+ hours' mechanical ventilation during construction: 54% vs. 59% before (OR = 1.6, p = 0.018) and 62% after (OR = 1.48, p = 0.065); and they required a shorter total period of mechanical ventilation: 3.6 days vs. 8.0 before (p = 0.011) and 9.5 after (p = 0.001). VLBW newborns' differences in ventilation days were mostly in the upper extremes; medians were similar in all periods: 0.6 days vs. 1 day preconstruction and 2 days postconstruction. CONCLUSIONS: Construction above the NICU did not cause substantially louder sound levels, but staff perceived important changes in noise and work routines. No evidence suggested that patients were negatively affected by the renovation period. Meticulous construction planning remains necessary to avoid interference with patient care and caregiver work environments.

The role of voltage dependence of the NMDA receptor in cellular and network oscillation.

Unraveling the mechanisms underlying oscillatory behavior is critical for understanding normal and pathological brain processes. Here we used electrophysiology in mouse neocortical slices and principles of nonlinear dynamics to demonstrate how an increase in the N-methyl-d-aspartic acid receptor (NMDAR) conductance can create a nonlinear whole-cell current-voltage (I-V) relationship which leads to changes in cellular stability. We discovered two behaviorally and morphologically distinct pyramidal cell populations. Under control conditions, both cell types responded to depolarizing current injection with regular spiking patterns. However, upon NMDAR activation, an intrinsic oscillatory (IO) cell type (n = 44) showed a nonlinear whole-cell I-V relationship, intrinsic voltage-dependent oscillations plus amplification of alternating input current, and these properties persisted after disabling action potential generation with tetrodotoxin (TTX). The other non-oscillatory (NO) neuronal population (n = 24) demonstrated none of these behaviors. Simultaneous intra- and extracellular recordings demonstrated the NMDAR's capacity to promote low-frequency seizure-like network oscillations via its effects on intrinsic neuronal properties. The two pyramidal cell types demonstrated different relationships with network oscillation--the IO cells were leaders that were activated early in the population activity cycle while the activation of the NO cell type was distributed across network bursts. The properties of IO neurons disappeared in a low-magnesium environment where the voltage dependence of the receptor is abolished; concurrently, the cellular contribution to network oscillation switched to synchronous firing. Thus, depending upon the efficacy of NMDAR in altering the linearity of the whole-cell I-V relationship, the two cell populations played different roles in sustaining network oscillation.

The effects of aggressive vs. conservative phototherapy on the brainstem auditory evoked responses of extremely-low-birth-weight infants.

INTRODUCTION: This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g). RESULTS: BAER latencies of 751-1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501-750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results. DISCUSSION: The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management. METHODS: Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.

In vitro evaluation of new approach to digital dental model articulation.

PURPOSE: The purpose of the present study was to evaluate the accuracy of our newly developed approach to digital dental model articulation. MATERIALS AND METHODS: Twelve sets of stone dental models from patients with craniomaxillofacial deformities were used for validation. All the models had stable occlusion and no evidence of early contact. The stone models were hand articulated to the maximal intercuspation (MI) position and scanned using a 3-dimensional surface laser scanner. These digital dental models at the MI position served as the control group. To establish an experimental group, each mandibular dental model was disarticulated from its original MI position to 80 initial positions. Using a regular office personal computer, they were digitally articulated to the MI position using our newly developed approach. These rearticulated mandibular models served as the experimental group. Finally, the translational, rotational, and surface deviations in the mandibular position were calculated between the experimental and control groups, and statistical analyses were performed. RESULTS: All the digital dental models were successfully articulated. Between the control and experimental groups, the largest translational difference in mandibular position was within 0.2 mm ± 0.6 mm. The largest rotational difference was within 0.1° ± 1.1°. The averaged surface deviation was 0.08 ± 0.07. The results of the Bland and Altman method of assessing measurement agreement showed tight limits for the translational, rotational, and surface deviations. In addition, the final positions of the mandibular articulated from the 80 initial positions were absolutely agreed on. CONCLUSION: The results of our study have demonstrated that using our approach, the digital dental models can be accurately and effectively articulated to the MI position. In addition, the 3-dimensional surface geometry of the mandibular teeth played a more important role in digital dental articulation than the initial position of the mandibular teeth.

Outcome study of computer-aided surgical simulation in the treatment of patients with craniomaxillofacial deformities.

PURPOSE: The purpose of this study was to determine whether the surgical outcomes achieved with computer-aided surgical simulation (CASS) are better than those achieved with traditional methods. MATERIALS AND METHODS: Twelve consecutive patients with craniomaxillofacial (CMF) deformities were enrolled. According to the CASS clinical protocol, a 3-dimensional computer composite skull model for each patient was generated and reoriented to the neutral head posture. These models underwent 2 virtual surgeries: 1 was based on CASS (experimental group) and the other was based on traditional methods 1 year later (control group). Once the 2 virtual surgeries were completed, 2 experienced oral and maxillofacial surgeons at 2 different settings evaluated the 2 surgical outcomes. They were blinded to the planning method used on the virtual models and each other's evaluation results. The primary outcome was overall CMF skeletal harmony. The secondary outcomes were individual maxillary, mandibular, and chin harmonies. Statistical analyses were performed. RESULTS: Overall CMF skeletal harmony achieved with CASS was statistically significantly better than that achieved with traditional methods. In addition, the maxillary and mandibular surgical outcomes achieved with CASS were significantly better. Furthermore, although not included in the statistical model, the chin symmetry achieved by CASS tended to be better. A regression model was established between mandibular symmetry and overall CMF skeletal harmony. CONCLUSION: The surgical outcomes achieved with CASS are significantly better than those achieved with traditional planning methods. In addition, CASS enables the surgeon to better correct maxillary yaw deformity, better place proximal/distal segments, and better restore mandibular symmetry. The critical step in achieving better overall CMF skeletal harmony is to restore mandibular symmetry.

A new method to orient 3-dimensional computed tomography models to the natural head position: a clinical feasibility study.

PURPOSE: The purpose of this study was to evaluate the clinical feasibility of a new method to orient 3-dimensional (3D) computed tomography models to the natural head position (NHP). This method uses a small and inexpensive digital orientation device to record NHP in 3 dimensions. This device consists of a digital orientation sensor attached to the patient via a facebow and an individualized bite jig. The study was designed to answer 2 questions: 1) whether the weight of the new device can negatively influence the NHP and 2) whether the new method is as accurate as the gold standard. PATIENTS AND METHODS: Fifteen patients with craniomaxillofacial deformities were included in the study. Each patient's NHP is recorded 3 times. The first NHP was recorded with a laser scanning method without the presence of the digital orientation device. The second NHP was recorded with the digital orientation device. Simultaneously, the third NHP was also recorded with the laser scanning method. Each recorded NHP measurement was then transferred to the patient's 3D computed tomography facial model, resulting in 3 different orientations for each patient: the orientation generated via the laser scanning method without the presence of the digital orientation sensor and facebow (orientation 1), the orientation generated by use of the laser scanning method with the presence of the digital orientation sensor and facebow (orientation 2), and the orientation generated with the digital orientation device (orientation 3). Comparisons are then made between orientations 1 and 2 and between orientations 2 and 3, respectively. Statistical analyses are performed. RESULTS: The results show that in each pair, the difference (Δ) between the 2 measurements is not statistically significantly different from 0°. In addition, in the first pair, the Bland-Altman lower and upper limits of the Δ between the 2 measurements are within 1.5° in pitch and within a subdegree in roll and yaw. In the second pair, the limits of the Δ in all 3 dimensions are within 0.5°. CONCLUSION: Our technique can accurately record NHP in 3 dimensions and precisely transfer it to a 3D model. In addition, the extra weight of the digital orientation sensor and facebow has minimal influence on the self-balanced NHP establishment.

Comprehensive brain MRI segmentation in high risk preterm newborns.

Most extremely preterm newborns exhibit cerebral atrophy/growth disturbances and white matter signal abnormalities on MRI at term-equivalent age. MRI brain volumes could serve as biomarkers for evaluating the effects of neonatal intensive care and predicting neurodevelopmental outcomes. This requires detailed, accurate, and reliable brain MRI segmentation methods. We describe our efforts to develop such methods in high risk newborns using a combination of manual and automated segmentation tools. After intensive efforts to accurately define structural boundaries, two trained raters independently performed manual segmentation of nine subcortical structures using axial T2-weighted MRI scans from 20 randomly selected extremely preterm infants. All scans were re-segmented by both raters to assess reliability. High intra-rater reliability was achieved, as assessed by repeatability and intra-class correlation coefficients (ICC range: 0.97 to 0.99) for all manually segmented regions. Inter-rater reliability was slightly lower (ICC range: 0.93 to 0.99). A semi-automated segmentation approach was developed that combined the parametric strengths of the Hidden Markov Random Field Expectation Maximization algorithm with non-parametric Parzen window classifier resulting in accurate white matter, gray matter, and CSF segmentation. Final manual correction of misclassification errors improved accuracy (similarity index range: 0.87 to 0.89) and facilitated objective quantification of white matter signal abnormalities. The semi-automated and manual methods were seamlessly integrated to generate full brain segmentation within two hours. This comprehensive approach can facilitate the evaluation of large cohorts to rigorously evaluate the utility of regional brain volumes as biomarkers of neonatal care and surrogate endpoints for neurodevelopmental outcomes.

Neuronal bursting properties in focal and parafocal regions in pediatric neocortical epilepsy stratified by histology.

To test the hypothesis that focal and parafocal neocortical tissue from pediatric patients with intractable epilepsy exhibits cellular and synaptic differences, the authors characterized the propensity of these neurons to generate (a) voltage-dependent bursting and (b) synaptically driven paroxysmal depolarization shifts. Neocortical slices were prepared from tissue resected from patients with intractable epilepsy. Multiunit network activity and simultaneous whole-cell patch recordings were made from neurons from three patient groups: (1) those with normal histology; (2) those with mild and severe cortical dysplasia; and (3) those with abnormal pathology but without cortical dysplasia. Seizure-like activity was characterized by population bursting with concomitant bursting in intracellularly recorded cortical neurons (n = 59). The authors found significantly more N-methyl-D-aspartic acid-driven voltage-dependent bursting neurons in focal versus parafocal tissue in patients with severe cortical dysplasia (P < 0.01). Occurrence of paroxysmal depolarization shifts and burst amplitude and burst duration were significantly related to tissue type: focal or parafocal (P < 0.05). The authors show that functional differences between focal and parafocal tissue in patients with severe cortical dysplasia exist. There are functional differences between patient groups with different histology, and bursting properties can be significantly associated with the distinction between focal and parafocal tissue.

Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort.

INTRODUCTION: The objective of the present study was to examine the association of baseline demographic and clinical characteristics with sequentially obtained measurements of forced vital capacity (FVC), expressed as a percentage of the predicted value, and to identify predictors of the decline rate in FVC over time in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS). METHODS: To date, 266 patients have been enrolled in GENISOS, a prospective, observational cohort of patients with early systemic sclerosis. In addition to pulmonary function tests (PFTs), clinical and laboratory data were obtained from each patient. We analyzed 926 FVC measurements utilizing generalized linear mixed models. The predictive significance of baseline variables for the decline rate in FVC was investigated by the interaction term between the variable and the follow-up time within the first 3 years after enrollment as well as throughout the entire follow-up time. RESULTS: The cohort consisted of 125 white, 54 African American, and 77 Hispanic patients with average disease duration of 2.5 years at enrollment. The mean follow-up time was 3.8 years, ranging up to 11.4 years. A number of baseline variables, including antibody status, African American ethnicity, disease type, baseline PFT values, modified Rodnan Skin Score, fibrosis on chest radiograph, and lung and skin subscores of the Severity Index, were associated with serially measured FVC levels. However, only the presence of anti-topoisomerase I antibodies (ATA) was associated with lower FVC levels (P < 0.001) as well as accelerated decline rate in FVC within the first 3 years of follow-up (P = 0.02). None of the baseline variables predicted the rate of decline in FVC on long-term follow-up. Patients with rapidly progressive ILD, however, were under-represented in the long-term follow-up group because the accelerated rate of decline in FVC was associated with poor survival (P = 0.001). CONCLUSIONS: Presence of ATA was the only baseline variable associated with differential FVC levels, predicting the rate of decline in FVC within the first 3 years of follow-up. The association of faster decline in FVC with poor survival further emphasizes the need for identification of predictive biomarkers by collection of genetic information and serial blood samples in cohort studies.

The effectiveness of off-protocol adjuvant chemotherapy for patients with urothelial carcinoma of the urinary bladder.

PURPOSE: The role of adjuvant chemotherapy for patients with high-risk urothelial carcinoma of the bladder (UCB) is not well defined. Here we address the value of adjuvant chemotherapy in patients undergoing radical cystectomy for UCB in an off-protocol routine clinical setting. EXPERIMENTAL DESIGN: We collected and analyzed data from 11 centers contributing retrospective cohorts of patients with UCB treated with radical cystectomy without neoadjuvant chemotherapy. Patients were grouped into quintiles based on their risk of disease progression using estimates from a fitted multivariable Cox proportional hazards model. The association of adjuvant chemotherapy with survival was explored across separate quintiles. RESULTS: The cohort consisted of 3,947 patients, 932 (23.6%) of whom received adjuvant chemotherapy. Adjuvant chemotherapy was independently associated with improved survival (hazard ratio, 0.83; 95% confidence interval, 0.72-0.97%, P = 0.017). However, the effect of adjuvant chemotherapy was significantly modified by the individual's risk of disease progression such that an increasing benefit from adjuvant chemotherapy was seen across higher-risk subgroups (P < 0.001). There was a significant improvement in survival between the treated and nontreated patients in the highest-risk quintile (hazard ratio, 0.75; 95% confidence interval, 0.62-0.90; P = 0.002). This group was characterized by an estimated 32.8% 5-year probability of cancer-specific survival, with 86.6% of patients having both advanced pathologic stage (> or =T(3)) and nodal involvement. CONCLUSION: Adjuvant chemotherapy is associated with a significant improvement in survival for patients treated in an off-protocol clinical setting. Selective administration in patients at the highest risk for disease progression, such as those with advanced pathologic stage and nodal involvement, may optimize the therapeutic benefit of adjuvant chemotherapy.

Team training in the neonatal resuscitation program for interns: teamwork and quality of resuscitations.

OBJECTIVE: Poor communication and teamwork may contribute to errors during neonatal resuscitation. Our objective was to evaluate whether interns who received a 2-hour teamwork training intervention with the Neonatal Resuscitation Program (NRP) demonstrated more teamwork and higher quality resuscitations than control subjects. METHODS: Participants were noncertified 2007 and 2008 incoming interns for pediatrics, combined pediatrics and internal medicine, family medicine, emergency medicine, and obstetrics and gynecology (n = 98). Pediatrics and combined pediatrics/internal medicine interns were eligible for 6-month follow-up (n = 34). A randomized trial was conducted in which half of the participants in the team training arm practiced NRP skills by using high-fidelity simulators; the remaining practiced with low-fidelity simulators, as did control subjects. Blinded, trained observers viewed video recordings of high-fidelity-simulated resuscitations for teamwork and resuscitation quality. RESULTS: High-fidelity training (HFT) group had higher teamwork frequency than did control subjects (12.8 vs 9.0 behaviors per minute; P < .001). Intervention groups maintained more workload management (control subjects: 89.3%; low-fidelity training [LFT] group: 98.0% [P < .001]; HFT group: 98.8%; HFT group versus control subjects [P < .001]) and completed resuscitations faster (control subjects: 10.6 minutes; LFT group: 8.6 minutes [P = .040]; HFT group: 7.4 minutes; HFT group versus control subjects [P < .001]). Overall, intervention teams completed the resuscitation an average of 2.6 minutes faster than did control subjects, a time reduction of 24% (95% confidence interval: 12%-37%). Intervention groups demonstrated more frequent teamwork during 6-month follow-up resuscitations (11.8 vs 10.0 behaviors per minute; P = .030). CONCLUSIONS: Trained participants exhibited more frequent teamwork behaviors (especially the HFT group) and better workload management and completed the resuscitation more quickly than did control subjects. The impact on team behaviors persisted for at least 6 months. Incorporating team training into the NRP curriculum is a feasible and effective way to teach interns teamwork skills. It also improves simulated resuscitation quality by shortening the duration.

Heart rate variability in response to pain stimulus in VLBW infants followed longitudinally during NICU stay.

The objective of this longitudinal study, conducted in a neonatal intensive care unit, was to characterize the response to pain of high-risk very low birth weight infants (<1,500 g) from 23 to 38 weeks post-menstrual age (PMA) by measuring heart rate variability (HRV). Heart period data were recorded before, during, and after a heel lanced or wrist venipunctured blood draw for routine clinical evaluation. Pain response to the blood draw procedure and age-related changes of HRV in low-frequency and high-frequency bands were modeled with linear mixed-effects models. HRV in both bands decreased during pain, followed by a recovery to near-baseline levels. Venipuncture and mechanical ventilation were factors that attenuated the HRV response to pain. HRV at the baseline increased with post-menstrual age but the growth rate of high-frequency power was reduced in mechanically ventilated infants. There was some evidence that low-frequency HRV response to pain improved with advancing PMA.