Importance Cycled (intermittent) phototherapy (PT) might adequately control peak total serum bilirubin (TSB) level and avoid mortality associated with usual care (continuous PT) among extremely low-birth-weight (ELBW) infants (401-1000 g). Objective To identify a cycled PT regimen that substantially reduces PT exposure, with an increase in mean peak TSB level lower than 1.5 mg/dL in ELBW infants. Design, Setting, and Participants This dose-finding randomized clinical trial of cycled PT vs continuous PT among 305 ELBW infants in 6 US newborn intensive care units was conducted from March 12, 2014, to November 14, 2018. Interventions Two cycled PT regimens (≥15 min/h and ≥30 min/h) were provided using a simple, commercially available timer to titrate PT minutes per hour against TSB level. The comparator arm was usual care (continuous PT). Main Outcomes and Measures Mean peak TSB level and total PT hours through day 14 in all 6 centers and predischarge brainstem auditory-evoked response wave V latency in 1 center. Mortality and major morbidities were secondary outcomes despite limited power. Results Consent was requested for 452 eligible infants and obtained for 305 (all enrolled) (mean [SD] birth weight, 749 [152] g; gestational age, 25.7 [1.9] weeks; 81 infants [27%] were multiple births; 137 infants [45%] were male; 112 [37%] were black infants; and 107 [35%] were Hispanic infants). Clinical and demographic characteristics of the groups were similar at baseline. After a preplanned interim analysis of 100 infants, the regimen of 30 min/h or more was discontinued, and the study proceeded with 2 arms. Comparing 128 infants receiving PT of 15 min/h or more with 128 infants receiving continuous PT among those surviving to 14 days, mean peak TSB levels were 7.1 vs 6.4 mg/dL (adjusted difference, 0.7; 95% CI, 0.4-1.1 mg/dL) and mean total PT hours were 34 vs 72 (adjusted difference, -39; 95% CI, -45 to -32). Wave V latency adjusted for postmenstrual age was similar in 37 infants receiving 15 min/h or more of PT and 33 infants receiving continuous PT: 7.42 vs 7.32 milliseconds (difference, 0.10; 95% CI, -0.11 to 0.30 millisecond). The relative risk for death was 0.79 (95% CI, 0.40-1.54), with a risk difference of -4.5% (95% CI, -10.9 to 2.0). Morbidities did not differ between groups. Conclusions and Relevance Cycled PT can substantially reduce total PT with little increase in peak TSB level. A large, randomized trial is needed to assess whether cycled PT would increase survival and survival without impairment in small, preterm infants. Trial Registration ClinicalTrials.gov Identifier: NCT01944696.

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.

BACKGROUND:Concern for serious infection due to β-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 β-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 β-lactam agents was determined for 2011-2013 VGS bloodstream isolates.RESULTS:In vitro resistance to β-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 β-lactam as antimicrobial prophylaxis, receipt of a β-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 β-lactam-resistant VGS infection.

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.

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.

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 pre-specified 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. (J Pediatr 2013;162:685-90).

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.

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.

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.

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.

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. (C) 2011 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 69: 2014-2024, 2011

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 (Delta) between the 2 measurements is not statistically significantly different from 0 degrees. In addition, in the first pair, the Bland-Altman lower and upper limits of the Delta between the 2 measurements are within 1.5 degrees in pitch and within a subdegree in roll and yaw. In the second pair, the limits of the Delta in all 3 dimensions are within 0.5 degrees.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. (C) 2011 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 69:584-591, 2011

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). 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. The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management. 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 The Lancet today, Rebeccah Slater and colleagues1Slater R Cornelissen L Fabrizi L et al.Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial.Lancet. 2010; (published online Sept 1.)https://doi.org/10.1016/S0140-6736(10)61303-7Summary Full Text Full Text PDF Scopus (253) Google Scholar present a randomised trial in which they evaluated sucrose as an analgesic in newborn babies. The cortical evoked responses that they recorded from newborn babies treated with sucrose or sterile water were similar. They concluded that sucrose “might not be an effective analgesic drug”, but we think their conclusion is premature. Slater and colleagues' research is a laudatory mix of innovative research on cortical evoked responses to noxious stimulation and a rigorous randomised trial. However, evolving measurement methodologies and small sample sizes are not the basis for definitive evaluations of treatments. The results of initial small randomised trials are often not replicated by larger definitive randomised trials.2Chalmers I Sinclair JC Promoting perinatal health: is it time for a change of emphasis in research?.Early Hum Dev. 1985; 10: 171-191Crossref PubMed Scopus (14) Google Scholar, 3Bassler D Briel M Montori VM et al.the STOPIT-2 Study GroupStopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis.JAMA. 2010; 303: 1180-1187Crossref PubMed Scopus (476) Google Scholar TableSupport for Slater and colleagues' conclusion that sucrose “might not be an effective analgesic drug”Criteria for interpretable study resultsExtent that criteria were met by Slater and colleagues' studyStudy designed, executed, and presented according to Consort Statement7Schulz KF Altman DG Moher D for the CONSORT GroupCONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials.BMJ. 2010; 340: c332Crossref PubMed Scopus (5311) Google ScholarYes, with noted modification of primary outcomeClinically relevant interventionSucrose dosing was not evaluated but is in accord with current clinical practiceSignal acquisition and processingLimited in spatial (Cz) and temporal domains (1 s window of EEG, bandwidth 0·5–70 Hz); dimensionality was reduced by principal component analysisValidity of outcomeAuthors have not demonstrated that primary outcome is the necessary and sufficient measure of pain as assumed by their conclusionAdequacy of outcomeOutcome is component of cortical evoked response to heel lance; short-term and long-term clinical consequences were not evaluatedAdequate sample sizeStudy was powered to detect only large effects of sucrose (0·9 standard deviations)Adequate sample characteristicsSample was convenience sample; generalising results to all newborn babies and especially those at high risk for painful procedures is importantExchangeability of cases in the two treatment conditionsConcerns about imbalances between treatment conditions increase in small samples despite random allocation, and demonstrated comparability on measured variables (table 1 in the paper); additionally, we do not know whether adjusting response to noxious stimulus by differences in response to non-noxious stimulus as measure of cortical evoked responsiveness would alter resultsReplicated resultsNo Open table in a new tab Although the investigators recorded cortical evoked responses to a heel lance, those responses probably do not reflect activation of the neural pain pathway in its entirety. Slater and colleagues sampled a limited set of brain activity, both spatially and temporally; the spatial component was restricted to a single electrode location, and temporally they restricted their sampling to 1 s after stimulus onset within the electroencephalogram (EEG) frequency band. The EEG traces were further processed with a Woody filter, signal averaging, and principal component analysis. In previous work, Slater and colleagues applied the same technique to a set of 12 electrodes and showed that the weight of the first principal component for temporal electrode T3 and the weights of the second principal component for central locations Cz and CPz related to the presence of noxious stimuli.4Slater R Worley A Fabrizi L et al.Evoked potentials generated by noxious stimulation in the human infant brain.Eur J Pain. 2010; 14: 321-326Crossref PubMed Scopus (123) Google Scholar They subsequently focused on both central electrodes, and in today's study they limited this procedure further to activity at Cz and the second principal component. Multichannel EEG recordings associated with signal decomposition and source localisation procedures might provide an improved basis for the localisation of relevant circuitry, and consequently for the selection of signals and metrics that represent nociception.5Michel CM Murray MM Lantz G Gonzalez S Spinelli L Grave de Peralta R EEG source imaging.Clin Neurophysiol. 2004; 115: 2195-2222Crossref PubMed Scopus (1361) Google Scholar In today's approach, sucrose might modulate the activity of components of the pain pathway that Slater and colleagues did not measure. Slater and colleagues' study was powered to detect only a very large sucrose-induced reduction in cortical evoked responses. Standardised effect sizes (in this study, the difference in mean weights of the second principal component in the two treatment conditions divided by the pooled standard deviation [SD]) are used in sample size calculations when the primary outcomes are not intrinsically meaningful, such as in this study. This study was powered to detect a standardised effect size of 0·9 SDs, a very large effect size by any standard, including Cohen's classification.6Cohen J A power primer.Psychol Bull. 1992; 112: 155-159Crossref PubMed Scopus (30702) Google Scholar There was only a one in three chance of detecting a medium effect size (0·5 SDs) and a discouraging one in ten chance of detecting a small effect size (0·2 SDs). Therefore we should not be surprised that the study failed to detect an effect of sucrose on cortical evoked responses. Small sample sizes also increase concerns that treatment–condition imbalances, despite random allocation, could account for the study's results. A more definitive evaluation of sucrose as an analgesic requires a larger study that follows guidelines for interpretable randomised trials, as articulated in the CONSORT Statement.7Schulz KF Altman DG Moher D for the CONSORT GroupCONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials.BMJ. 2010; 340: c332Crossref PubMed Scopus (5311) Google Scholar The results of a definitive study also need to be generalised to sick and preterm newborn babies at risk for multiple painful procedures over extended stays in the hospital. Slater and colleagues characterise the cortical evoked responses that they recorded as a more direct measure than other responses used to measure pain in newborn babies. But it is the wellbeing of the infant that is the definitive outcome in determining the efficacy of medical interventions and not surrogate outcomes, regardless of how central they are hypothesised to be to the pain response in the newborn baby. There are noteworthy examples of interventions that affect compelling surrogate outcomes but fail to improve and might even adversely affect the health status of patients.8Rosen CJ The rosiglitazone story—lessons from an FDA Advisory Committee meeting.N Engl J Med. 2007; 357: 844-846Crossref PubMed Scopus (194) Google Scholar, 9Rosen CJ Revisiting the rosiglitazone story—lessons learned.N Engl J Med. 2010; 363: 803-806Crossref PubMed Scopus (118) Google Scholar The opposite result is possible as well. Despite the limitations outlined above, Slater and colleagues' study adds an important and innovative measurement to evaluating pain management in newborn babies. Such research has just begun but promises better understanding of pain and more effective pain management. However, until we better understand pain pathways and the short-term and long-term sequelae of painful procedures, it seems premature to conclude that sucrose might not be an effective analgesic for newborn babies. We declare that we have no conflicts of interest. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trialOur data suggest that oral sucrose does not significantly affect activity in neonatal brain or spinal cord nociceptive circuits, and therefore might not be an effective analgesic drug. The ability of sucrose to reduce clinical observational scores after noxious events in newborn infants should not be interpreted as pain relief. Full-Text PDF Open Access

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.

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.

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 (≥T3) 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. Clin Cancer Res; 16(17); 4461–7. ©2010 AACR.

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.