Predictors of neurodevelopmental outcomes in preterm infants with intraparenchymal hemorrhage.

OBJECTIVE: To determine which neuroimaging, clinical and sociodemographic factors predict neurodevelopment at 18-22 months age among extremely preterm infants with intraparenchymal hemorrhage (IPH). STUDY DESIGN: Cranial ultrasounds performed before 42 days of age and cranial ultrasounds/magnetic resonance images of the brain performed near discharge were reviewed for hemorrhage location and other abnormalities. Clinical and sociodemographic factors were extracted from existing databases. The primary outcome was presence of cerebral palsy (CP) and the secondary outcome was cognitive development (Bayley Scales of Infant Development). RESULT: Of 1168 infants (<1000 g or <27 weeks), 141 infants had an IPH and 48 infants were seen in follow-up. All infants with extensive hemorrhages (involving three or more lobes) developed CP. In early imaging (before 42 days of age), ventriculomegaly, intraventricular hemorrhage (IVH) and extensive hemorrhage were predictors of CP. In imaging performed near discharge, ventriculomegaly, intraventricular echodensity and having a ventricular shunt were predictors of CP. Clinical, imaging and sociodemographic factors were not associated with low cognitive score. CONCLUSION: In preterm infants surviving with IPH, extensive hemorrhage, ventriculomegaly, IVH and having a shunt increased the risk of developing CP.

Role of diffusion tensor imaging as an independent predictor of cognitive and language development in extremely low-birth-weight infants.

BACKGROUND AND PURPOSE: Diffusion tensor imaging at term can predict later development of cerebral palsy. Less is known about its ability to independently predict cognitive and language development in extremely preterm infants. The goals of the study were to investigate the following: 1) whether regional DTI measures at term-equivalent age in extremely low-birth-weight infants (birth weight, ≤1000 g) are predictive of Bayley III developmental scores at 18- to 22-months' corrected age, and 2) to compare white matter microstructural development at term and neurodevelopmental outcomes of extremely low-birth-weight infants with healthy term controls. MATERIALS AND METHODS: Fractional anisotropy and mean diffusivity in 7 vulnerable cerebral regions were measured in 42 extremely low-birth-weight and 16 term infants with high-quality DTI scans. The Bayley mental scale score (average of cognitive and language scale scores) was the primary outcome of interest with individual scores serving as secondary outcomes. Multiple linear regression modeling was used to identify the incremental ability of DTI measures to predict Bayley scores over known predictors. RESULTS: Compared with healthy term infants, extremely low-birth-weight infants exhibited significantly higher mean diffusivity and lower fractional anisotropy in 6 of 7 regions. At 18- to 22-months' corrected age, 39 extremely low-birth-weight infants (93%) and 14 term infants (88%) had undergone neurodevelopmental assessments. Although not statistically significant, extremely low-birth-weight infants averaged 7-9 points lower on Bayley subtests than term controls. In multivariable analyses, centrum semiovale mean diffusivity was a significant predictor of mental and language scale scores, and subventricular zone fractional anisotropy was a significant predictor of cognitive scale scores. A 10% increase in centrum semiovale mean diffusivity was associated with a 4.6 (95% CI, 1.6-7.6) point lower mental scale score (adjusted R(2) = 0.341, P = .001). CONCLUSIONS: In our extremely low-birth-weight cohort, DTI was an independent predictor of later cognitive and language development.

Teamwork behaviours and errors during neonatal resuscitation.

OBJECTIVE: To describe relationships between teamwork behaviours and errors during neonatal resuscitation. METHODS: Trained observers viewed video recordings of neonatal resuscitations (n = 12) for the occurrence of teamwork behaviours and errors. Teamwork state behaviours (such as vigilance and workload management, which extend for some duration) were assessed as the percentage of each resuscitation that the behaviour was observed and correlated with the percentage of observed errors. Teamwork event behaviours (such as information sharing, inquiry and assertion, which occur at specific times) were counted in 20-s intervals before and after resuscitation steps, and a generalised linear mixed model was calculated to evaluate relationships between these behaviours and errors. RESULTS: Resuscitation teams who were more vigilant committed fewer errors (Spearman's rho for vigilance and errors = -0.62, 95% CI -0.07 to -0.87, p = 0.031). Assertions were more likely to occur before errors than correct steps (OR = 1.44, 95% CI 1.10 to 1.89, p = 0.008) and teaching/advising occurred less frequently after errors (OR = 0.59, 95% CI 0.37 to 0.94, p = 0.028). Though not statistically significant, there was less information sharing before errors (OR = 0.90, 95% CI 0.77 to 1.05, p = 0.172). CONCLUSIONS: Vigilance is an important behaviour for error management. Assertion may have caused errors, or perhaps was an indicator for some other factor that caused errors. Teams may have preferred to resolve errors directly, rather than using errors as opportunities to teach their teammates. These observations raise important questions about the appropriate use of some teamwork behaviours and how to include them in team training programmes.

Evaluation of heterogeneity in pharmacotherapy trials for drug dependence: a Bayesian approach.

AIMS: Difficulty identifying effective pharmacotherapies for cocaine dependence has led to suggestions that subgroup differences may account for some of the heterogeneity in treatment response. Well-attested methodological difficulties associated with these analyses recommend the use of Bayesian statistical reasoning for evaluation of salient interaction effects. METHODS: A secondary data analysis of a previously published, double-blind, randomized controlled trial examines the interaction of decision-making, as measured by the Iowa Gambling Task, and citalopram in increasing longest sustained abstinence from cocaine use. RESULTS: Bayesian analysis indicated that there was a 99% chance that improved decision-making enhances response to citalopram. Given the strong positive nature of this finding, a formal, quantitative Bayesian approach to evaluate the result from the perspective of a skeptic was applied. CONCLUSIONS: Bayesian statistical reasoning provides a formal means of weighing evidence for the presence of an interaction in scenarios where conventional, Frequentist analyses may be less informative. [Supplementary materials are available for this article. Go to the publisher's online edition of The American Journal of Drug and Alcohol Abuse for the following free supplemental resource: Appendix 1].

A randomized clinical trial evaluating silicone earplugs for very low birth weight newborns in intensive care.

OBJECTIVE: To determine whether very low birth weight (VLBW) newborns (<1500 g) wearing silicone earplugs grow larger and perform better on developmental exams than controls. STUDY DESIGN: VLBW newborns (n=34) were randomized to wearing earplugs or not. Hospital outcomes were abstracted from medical charts by research staff masked to intervention status. Fourteen extremely low birth weight (ELBW) newborns (<1000 g) were also evaluated at 18 to 22 months. RESULT: After adjusting for birth weight, 11 surviving newborns in the earplug group were 225 g (95% CI: 45, 405) heavier at 34 weeks post menstrual age than the 13 controls. Six ELBW earplug infants scored 15.53 points (95% CI: 3.03, 28.02) higher than six controls on the Bayley Mental Development Index. Their head circumferences were 2.59 cm (95% CI: 0.97, 4.21) larger. CONCLUSION: Earplugs may facilitate weight gain in VLBW newborns. Better outcomes may persist at 18 to 22 months at least in ELBW infants.

Volumetric and anatomical MRI for hypoxic-ischemic encephalopathy: relationship to hypothermia therapy and neurosensory impairments.

OBJECTIVE: To relate volumetric magnetic resonance imaging (MRI) findings to hypothermia therapy and neurosensory impairments. STUDY DESIGN: Newborns > or =36 weeks' gestation with hypoxic-ischemic encephalopathy who participated in the National Institute of Child Health and Human Development hypothermia randomized trial at our center were eligible. We determined the relationship between hypothermia treatment and usual care (control) to absolute and relative cerebral tissue volumes. Furthermore, we correlated brain volumes with death or neurosensory impairments at 18 to 22 months. RESULT: Both treatment groups were comparable before randomization. Total brain tissue volumes did not differ in relation to treatment assignment. However, relative volumes of subcortical white matter were significantly larger in hypothermia-treated than control infants. Furthermore, relative total brain volumes correlated significantly with death or neurosensory impairments. Relative volumes of the cortical gray and subcortical white matter also correlated significantly with Bayley Scales psychomotor development index. CONCLUSION: Selected volumetric MRI findings correlated with hypothermia therapy and neurosensory impairments. Larger studies using MRI brain volumes as a secondary outcome measure are needed.

Statins benefit outcomes of renal transplant recipients on a sirolimus-cyclosporine regimen.

BACKGROUND: Statins offer a strategy to address dyslipidemia commonly experienced by immunosuppressed transplant recipients. METHODS: This single-center, retrospective study of 325 recipients (mean posttransplant follow-up of over 6 years; 75.0+/-26.0 months) correlated four adverse outcomes-biopsy-confirmed acute rejection episodes, biopsy-confirmed chronic rejection/allograft nephropathy, graft loss, or death-with demographic and posttreatment variables. Patients were treated with a combination of sirolimus (SRL), cyclosporine (CsA), and various durations of steroids. Statins were prescribed for 259/325 (79%) recipients whose serum cholesterol exceeded 240 mg/dL and discontinued when the creatine phosphokinase increased fivefold (3.4%) or the liver function, threefold (3.0%) above normal. RESULTS: Upon univariate (hazard ratio [HR] 0.16; P<.001) and multivariate analysis (HR 0.38; P=.02), statins were markedly protective against acute rejection episodes. They reduced occurrence of chronic nephropathy/chronic rejection (HR 0.60; P=.03 and HR 0.52; P=.01, respectively). Incidences of graft loss were diminished (HR 0.26; P<.001 and HR 0.49; P=.01, respectively). Finally, the mortality rate was decreased (HR 0.21, P=.001 and HR 0.26, P=.01, respectively). Upon multivariate analysis, a reduced incidence of acute rejection was correlated with greater exposure to SRL (HR 0.78, P=.016) and CsA (HR 0.39; P=.006). CONCLUSIONS: This study demonstrated compelling effects of statins against all adverse outcomes among patients treated with SRL-based, CsA-containing regimens. The profoundly dyslipidemic properties of SRL may explain these unique findings compared with previous studies on patients treated with CsA-based regimens.

Teaching teamwork during the Neonatal Resuscitation Program: a randomized trial.

OBJECTIVE: To add a team training and human error curriculum to the Neonatal Resuscitation Program (NRP) and measure its effect on teamwork. We hypothesized that teams that received the new course would exhibit more teamwork behaviors than those in the standard NRP course. STUDY DESIGN: Interns were randomized to receive NRP with team training or standard NRP, then video recorded when they performed simulated resuscitations at the end of the day-long course. Outcomes were assessed by observers blinded to study arm allocation and included the frequency or duration of six team behaviors: inquiry, information sharing, assertion, evaluation of plans, workload management and vigilance. RESULT: The interns in the NRP with team training group exhibited more frequent team behaviors (number of episodes per minute (95% CI)) than interns in the control group: information sharing 1.06 (0.24, 1.17) vs 0.13 (0.00, 0.43); inquiry 0.35 (0.11, 0.42) vs 0.09 (0.00, 0.10); assertion 1.80 (1.21, 2.25) vs 0.64 (0.26, 0.91); and any team behavior 3.34 (2.26, 4.11) vs 1.03 (0.48, 1.30) (P-values <0.008 for all comparisons). Vigilance and workload management were practiced throughout the entire simulated code by nearly all the teams in the NRP with team training group (100% for vigilance and 88% for workload management) vs only 53 and 20% of the teams in the standard NRP. No difference was detected in the frequency of evaluation of plans. CONCLUSION: Compared with the standard NRP, NRP with a teamwork and human error curriculum led interns to exhibit more team behaviors during simulated resuscitations.

Teamwork and quality during neonatal care in the delivery room.

OBJECTIVE: Experts believe good teamwork among health care providers may improve quality. We sought to measure the frequency of team behaviors during delivery room care and to explore how these behaviors relate to the quality of care. STUDY DESIGN: We video recorded neonatal resuscitation teams then used independent observers to measure teamwork behaviors and compliance with Neonatal Resuscitation Program (NRP) guidelines (a measure of quality of care). RESULTS: Observer agreement was either fair or good for all teamwork behaviors except workload management, vigilance, and leadership, for which agreement was slight. All teams (n=132) exhibited the behaviors information sharing and inquiry, and all but one team exhibited vigilance and workload management. Other behaviors were present less often: assertion in 19.9% of teams, teaching 16.7%, leadership 19.7%, evaluation of plans 12.9%, and intentions stated 9.1%. Factor analysis identified three fundamental components of teamwork: communication (comprised of information sharing and inquiry); management (workload management and vigilance); and leadership (assertion, intentions shared, evaluation of plans, and leadership). All three components were weakly but significantly correlated with independent assessments of NRP compliance and an overall rating of the quality of care. CONCLUSION: Most team behaviors can be reliably observed during delivery room care by neonatal resuscitation teams, and some are infrequently used. We found weak but significant and consistent correlations among these behaviors with independent assessments of NRP compliance and an overall rating of the quality of care. These findings support additional efforts to study team training for delivery room care and other areas of healthcare.

The effects of elevated blood lead levels and succimer chelation therapy on physical growth in developing rhesus monkeys.

Seventy-two female rhesus monkeys were randomly assigned to three lead exposure conditions (none, birth to 1 year, birth to 2 years). In a completely crossed design, the lead-exposed and control monkeys were randomized to placebo or chelation therapy which began at 1 year of age. Dosing was conducted daily beginning on day 8 postpartum. The lead dose levels were adjusted biweekly to gradually elevate the blood lead level of each monkey to a target of 1.69-1.93 micromol/L (35-40 microg/dL). Succimer (or placebo) was administered orally (30 mg/kg/day for 5 days and 20 mg/kg/day for 14 additional days) for a total 19-day treatment regimen. There were two separate chelation regimes at 53 and 65 weeks of age. Succimer therapy in combination with lead abatement reduced blood lead levels significantly faster than lead abatement alone; however, that advantage disappeared once succimer therapy was discontinued. Weight, crown-rump length, and head circumference were measured regularly. Growth in weight, length, and head circumference did not vary significantly as a function of blood lead levels. Succimer chelation therapy did not significantly affect weight, length, or head circumference through 2 years of age.

Exploring a partially enclosed space by lead-exposed female rhesus monkeys.

Beginning on Day 8 postpartum, lead acetate was administered to female rhesus monkeys (n=48). Their blood lead levels rose to 35-40 microg/dl (the level maintained for the duration of the study period) by 12 weeks of age. Weekly, these lead-exposed monkeys and their controls (n=23) were placed in a partially enclosed space from the second postnatal week until they escaped three times or were 26 weeks old. The lead-exposed monkeys exhibited more fear, were more likely to be agitated, and climbed more frequently during the first testing session. In subsequent sessions, they more frequently explored the periphery of the test area than the controls. The lead-exposed monkeys also tended to escape sooner although that trend did not consistently reach the.05 level of significance. The increased activity and agitation of the lead-exposed monkeys is suggestive of deficits reported in human children with high blood lead levels.

The effects of succimer chelation therapy on auditory function in rhesus monkeys.

Sixty-six female rhesus monkeys were randomly assigned to three lead exposure conditions (none, from birth to 1 year, and from birth to 2 years) by two chelation treatment (succimer and no succimer) conditions. Blood lead levels were maintained at 35-40 microg/dl beginning shortly after birth and continuing for 1 or 2 years postnatally. There were two separate chelation regimes: 53 and 65 weeks of age. Lead and lead-vehicle dosing were discontinued while succimer was administered. Succimer (or placebo) was administered orally at a dose of 30 mg/kg/day (divided into three doses per day) for 5 days and for 14 additional days at 20 mg/kg/day (divided into two doses per day) for a total 19-day treatment regimen. Auditory function was assessed in these monkeys at least 1 year after lead intake had been discontinued. The outcome measures included tympanometry to assess middle ear function, OAEs to assess cochlear function, and ABRs to assess the auditory nerve and brainstem pathways. There were no significant differences as a function of succimer treatment for any of the tympanometric variables measured. Suprathreshold and threshold distortion product otoacoustic emissions were comparable among the succimer and vehicle groups. However, there was a nonsignificant trend to smaller amplitude distortion products at the highest frequencies assessed (6.4-10.0 kHz). Finally, the auditory evoked response at levels from the auditory nerve to the cerebral cortex did not significantly differ as a function of succimer treatment.

The effects of early lead exposure on auditory function in rhesus monkeys.

Thirty-one female rhesus monkeys were randomly assigned to three lead exposure conditions (none, birth to 1 year, and birth to 2 years). Blood lead levels were maintained at 35-40 microg/dl beginning shortly after birth and continuing for 1 or 2 years postnatally. Auditory function was assessed in these monkeys at least 1 year after exposure to lead. The outcome measures included tympanometry to assess middle ear function, otoacoustic emissions (OAEs) to assess cochlear function, and auditory brainstem-evoked responses (ABRs) to assess the auditory nerve and brainstem pathways. There were no significant differences among the three experimental groups for any of the tympanometric variables measured suggesting no effect of lead exposure on middle ear function. Suprathreshold and threshold distortion product OAEs (DPOAEs) were comparable among the three groups. Finally, the auditory-evoked response at levels from the auditory nerve to the cerebral cortex did not significantly differ as a function of lead exposure. The lead exposure in this study had little effect on auditory function.

Immittance and otoacoustic emissions in rhesus monkeys and humans.

The purpose of this study was to compare multifrequency tympanometry and otoacoustic emissions (OAEs) in rhesus monkeys (Macaca mulatta) and humans. Tympanometry and OAEs can be recorded efficiently in Macaca mulatta to assess peripheral auditory function with results comparable to those in humans. Differences include (1) greater admittances and conductances in humans from 226 to 630 Hz, the frequency range validly assessed; (2) larger amplitude transient evoked OAEs (TEOAEs) and noise levels in humans; (3) larger amplitude monkey 2f(1)-f(2) distortion product OAEs (DPOAES) (f(2)s>2 kHz); (4) more prominent DPOAEs other than 2f(1)-f(2) in monkeys; (5) more narrowly tuned human f(2)/f(1) X 2f(1)-f(2) amplitude functions at the lower frequencies tested; and (6) lower 2f(1)-f(2) DPOAE thresholds at f(2)=0.5 kHz and > or = 8 kHz in monkeys.

Aging and middle ear function in rhesus monkeys (Macaca mulatta).

This study provided tympanometric data on rhesus monkeys (Macaca mulatta) and more support for this monkey as a good model for human peripheral auditory function. There have been few published reports concerning middle ear function in rhesus monkeys, and these experiments addressed that need. In the first experiment, peak acoustic admittance (Ytm) and ear-canal volume (Vea) were measured in 17 older adult monkeys and 16 younger adult monkeys. In the second experiment, middle ear resonance frequency was measured in eight younger adult monkeys and four older adult monkeys. Overall, peak Ytm, Vea, and resonance frequency were similar for monkeys and humans. Specifically, peak mean Ytm and mean Vea in monkeys were comparable to those values in human children. There was a trend for older monkeys to have decreased peak Ytm and Vea, but these trends did not reach statistical significance. There was a significant sex effect similar to what has been reported in humans. Male monkeys had larger peak Ytm values and larger Vea values compared with female monkeys regardless of age. Finally, there were no significant age or sex effects on resonance frequency.

Lead effects on neurobehavioral development in the neonatal rhesus monkey (Macaca mulatta).

Effects of lead exposure on behavioral development during the first month of postnatal life were examined in rhesus monkeys using a multi-item assessment scale developed for the evaluation of neonatal rhesus monkeys. Lead was administered daily beginning at day 8 postpartum at levels that produced blood lead levels of about 20 microg/dl by week 4 (n = 48); controls were treated identically but given vehicle only (n = 24). All monkeys were tested once a week for the first 4 weeks postpartum. The first principal component explained a substantial portion of the variance and was relatively consistent across ages for both groups. Analyses of the individual items and of both conceptually derived and empirically defined summary scores yielded no significant effects of lead. Furthermore, there were no systematic relationships between blood lead level and performance on the test. Correlation coefficients indicated more similarity across age for control monkeys than for lead-exposed monkeys suggesting that continuity of development, as measured by this test, was disrupted by lead. The relationship between outcome on these early assessments and later behavior will be explored in subsequent studies of these monkeys.

Otoacoustic emission, evoked potential, and behavioral auditory thresholds in the rhesus monkey (Macaca mulatta).

Distortion product otoacoustic emission (DPOAE), auditory brainstem evoked response (ABR), and behavioral thresholds were recorded in a group of 15 adult rhesus monkeys with normal auditory function. DPOAE thresholds were recorded with stimulus parameters selected to maximize signal-to-noise ratio. Additional averaging at the lowest frequencies ensured comparable noise levels across frequencies. DPOAE thresholds decreased with increasing frequency (f(2)=0.5-16 kHz) and at 16 kHz were close to 0 dB SPL. ABR thresholds were best from 1 through 16 kHz (32-38 dB peSPL); higher at 0.5 (45 dB peSPL), 24 (39 dB peSPL), and 30 kHz (49 dB peSPL). At all levels including threshold, the early ABR waves (II and I) were more prominent at the high frequencies while the later waves (IV and V) were more prominent at the low frequencies. The behavioral thresholds recorded were similar to those reported by other researchers although elevated by about 10 dB presumably because of the complexity of the threshold task. DPOAE and ABR thresholds can be reliably and efficiently recorded in the rhesus monkey and provide information concerning site of processing in the auditory pathway not directly available from behavioral data.

Neural networks applied to retrocochlear diagnosis.

Methodologies have been developed, based on insights from signal detection theory, to evaluate quantitatively the diagnostic performance of tests. Several studies have demonstrated that, in fact, performance of a test battery can be inferior to the best of the tests it includes. These studies have been quite persuasive in damping enthusiasm for the test battery approach. Because the results of all tests in a battery were weighted equally in these studies, it is not surprising that an individual test with good sensitivity and specificity is more effective diagnostically than a combination of tests with poorer sensitivity and specificity. The authors of many of these studies were well aware of the limitations of this approach. In the present study, neural networks were applied to evaluate audiological tests used to predict retrocochlear pathology by differentially weighting the results of the tests in the battery. This technique avoids some of the limitations of previous approaches. Of the audiological tests evaluated in the present analysis, the superiority of the auditory brainstem evoked response (ABR) in predicting retrocochlear disease was again demonstrated. However, the results also demonstrated that identification accuracy could be improved by combining the ABR with other tests (in this case contralateral acoustic reflex at 2000 Hz, ipsilateral acoustic reflex at 2000 Hz, tone decay, and word recognition score). Further, it was demonstrated that performance could be improved over that obtained using dichotomous test measures (i.e., positive or negative presence of pathology) by using raw test measures in conjunction with ABR.

The development of auditory event related potentials in the rhesus monkey (Macaca mulatta).

Auditory event related potentials were recorded from neonatal, 3-month, and 3-year old rhesus monkeys. Auditory brainstem evoked responses (ABRs) were reliably recorded at all ages. ABR latencies decreased with age. Age effects were greater the more centrally generated the wave. Wave I amplitude decreased with age, Wave II increased, and Wave IV remained about the same. Stimulus rate effects were greater in neonates than older monkeys. Stimulus frequency also affected the ABR, but not differentially as a function of age. Recording montage had a significant effect on the recorded waveform. Wave I tended to be larger in amplitude in horizontal recordings and front-back recordings, while the later waves were relatively more prominent in more vertical montages. Middle latency evoked responses and late potentials were less reliably recorded than the ABR. Their reproducibility improved with age. Auditory event related potentials are promising measures of auditory function for research requiring nonhuman primate models of the developing human.

Nonlinear functional modeling of scalp recorded auditory evoked responses to maximum length sequences.

The purpose of this study was to model the adult human's scalp recorded evoked response to auditory pulses separated by varying inter pulse intervals (IPIs). The responses modeled probably reflect auditory nerve and brainstem generators. The subjects were 10 young adult humans with normal hearing. They were presented pseudo random sequences of pulses (maximum length sequences, MLSs) in order to characterize their system response. For the stimuli and the responses modeled accounting for temporal nonlinearities (interactions among the pulses) improved model performance only marginally. Nonlinear contributions to the models decreased with increasing interval between the input pulses. Increasing the memory of the model beyond 20 ms did not increase modeled performance dramatically. Model performance varied as a function of minimum IPI (MIPI) of the MLSs. At the shortest MIPI overall model performance deteriorated (due, in part, to a decrease in SNR), but nonlinear effects became relatively more important. At the longest MIPI performance also deteriorated, possibly due to the increasing influence of longer latency, more variable evoked potential components. Modeled performance generalized to responses recorded in the same recording session to the same and different MLSs. This study confirms the similarity between MLS linear kernels and conventionally averaged evoked responses--both are adapted responses reflecting the IPIs of the evoking stimuli.