Objective Although many perinatal factors have been linked to adverse neurodevelopmental outcomes in very premature infants, much of the variation in outcome remains unexplained. The impact on brain development of one potential factor, exposure to stressors in the Neonatal Intensive Care Unit, has not yet been studied in a systematic, prospective manner. Methods In this prospective cohort study of infants born at <30 weeks gestation, nurses were trained in recording procedures and cares. These recordings were used to derive Neonatal Infant Stressor Scale scores, which were employed to measure exposure to stressors. Magnetic resonance imaging (brain metrics, diffusion, and functional magnetic resonance imaging) and neurobehavioral examinations at term equivalent postmenstrual age were used to assess cerebral structure and function. Simple and partial correlations corrected for confounders including immaturity and severity of illness were used to explore these relationships. Results Exposure to stressors was highly variable, both between infants and throughout a single infant’s hospital course. Exposure to a greater number of stressors was associated with decreased frontal and parietal brain width, altered diffusion measures and functional connectivity in the temporal lobes, and abnormalities in motor behavior on neurobehavioral examination. Interpretation Exposure to stressors in the Neonatal Intensive Care Unit is associated with regional alterations in brain structure and function. Further research into interventions that may decrease or mitigate exposure to stressors in the Neonatal Intensive Care Unit is warranted.

Objective To evaluate associations between neonatal intensive care unit (NICU) room type (open ward and private room) and medical outcomes; neurobehavior, electrophysiology and brain structure at hospital discharge; and developmental outcomes at two years of age. Study design In this prospective longitudinal cohort study, we enrolled 136 preterm infants born <30 weeks gestation from an urban, 75-bed level III NICU from 2007-2010. Upon admission, each participant was assigned to a bedspace in an open ward or private room within the same hospital, based on space and staffing availability, where they remained for the duration of hospitalization. The primary outcome was developmental performance at two years of age (n=86 infants returned for testing, which was 83% of survivors) measured using the Bayley Scales of Infant and Toddler Development, 3rd Edition. Secondary outcomes were 1) medical factors throughout the hospitalization, 2) neurobehavior, and 3) cerebral injury and maturation (determined by magnetic resonance imaging and electroencephalography). Results At term equivalent age, infants in private rooms were characterized by a diminution of normal hemispheric asymmetry and a trend toward having lower amplitude integrated electroencephalography cerebral maturation scores [p= 0.02; β=−0.52 (CI −0.95, −0.10)]. At age two years, infants from private rooms had lower language scores [p= 0.006; β=−8.3 (CI −14.2, −2.4)] and a trend toward lower motor scores [p= 0.02; β=−6.3 (CI −11.7, −0.99)], which persisted after adjustment for potential confounders. Conclusion These findings raise concerns that highlight the need for further research into the potential adverse effects of different amounts of sensory exposure in the NICU environment.

BACKGROUND: The impact of treating electrographic seizures in hypoxic ischemic encephalopathy (HIE) is unknown. METHODS:Neonates $36 weeks with moderate or severe HIE were randomly assigned to either treatment of electrographic seizures alone (ESG) or treatment of clinical seizures (CSG). Conventional EEG video was monitored in both groups for up to 96 hours. Cumulative electrographic seizure burden (SB) was calculated in seconds and converted to log units for analysis. MRI scans were scored for severity of brain injury. Infants underwent neurodevelopmental evaluation at 18 to 24 months. Statistical analyses were performed by using SAS 9.3 version (SAS Institute, Inc, Cary, NC).RESULTS: Thirty-five of 69 neonates (51%) who were randomly assigned and included in the study developed seizures (15 in ESG and 20 in CSG). Excluding infants with status epilepticus, median SB (interquartile range) in seconds in ESG (n = 10) was lower than in CSG (n = 16) (449 [113-2070] vs 2226 [760-7654]; P = .02). ESG had fewer seizures with shorter time to treatment (P = .04). Twenty-four of 30 (80%) surviving infants with seizures underwent neurodevelopmental evaluation at 18 to 24 months. Increasing SB in the combined cohort was significantly associated with higher brain injury scores (P , .03) and lower performance scores across all 3 domains on BSID III (P = .03). CONCLUSIONS:In neonates with HIE, EEG monitoring and treatment of electrographic seizures results in significant reduction in SB. SB is associated with more severe brain injury and significantly lower performance scores across all domains on BSID III. WHAT'S KNOWN ON THIS SUBJECT:Continuous conventional EEG video is currently gold standard for identifying neonatal seizures and a substantial proportion of neonatal seizures are electrographic. Currently there is no direct evidence that EEG monitoring, seizure identification, or treatment impacts long-term outcomes. WHAT THIS STUDY ADDS:In neonates with hypoxic ischemic encephalopathy, EEG monitoring and treatment of electrographic seizures results in significant reduction in seizure burden. Increasing seizure burden is associated with more severe brain injury and significantly lower performance scores on Bayley Scales of Infant Development III.

ObjectiveWe investigated whether particular demographic, maternal psychosocial, and infant factors identified mothers of very preterm infants at risk for postpartum depression or anxiety at the time of discharge from a level III urban Neonatal Intensive Care Unit (NICU).Study DesignA racially diverse cohort of mothers (N=73) of preterm infants (gestational age <30 weeks) completed a comprehensive questionnaire at discharge from the NICU assessing postpartum depression, anxiety, and psychosocial and demographic factors. Additionally, infants underwent brain magnetic resonance imaging prior to discharge.ResultTwenty percent of mothers had clinically significant levels of depression while 43% had moderate-severe anxiety. Being married (p<.01), parental role alteration (p<.01) and prolonged ventilation (p<.05) were associated with increased depressive symptoms. No psychosocial, demographic, or infant factors, including severity of brain injury, were associated with state anxiety levels.ConclusionMaternal factors, such as marital status, stress from parental role alteration, and infant factors, such as prolonged ventilation, are associated with increased depression. However, clinically significant levels of anxiety are common in mothers of very preterm infants with few identifiable risk factors. These findings support the need for universal screening within the NICU.

Premalignant lesions of cutaneous squamous cell carcinoma (SCC) are identified clinically as actinic keratoses (12,13). Several field-directed treatments including 5-fluorouracil (5-FU), diclofenac, ingenol, and imiquimod have been approved for the treatment of sun-damaged skin with multiple actinic keratoses (13-15). However, the long treatment duration and the severity BACKGROUND. Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis. METHODS.The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed. RESULTS.Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4 + T cell infiltration, which peaked on days 10-11 after treatment, without pain, crusting, or ulceration.CONCLUSION. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4 + T cell-mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs.TRIAL REGISTRATION. ClinicalTrials.gov NCT02019355. FUNDING. Not applicable (investigator-initiated clinical trial).

Objectives To develop a cognitive and functional screening battery for the on-road performance of older drivers with dementia. Design A prospective observational study. Setting On-road driving evaluation clinic at an academic rehabilitation center Participants Ninety-nine older people with dementia (63% male, mean age = 74.2 years, SD= 9), referred by community physicians to an Occupational Therapy driving clinic. Measurements The outcome variable was pass/fail on the modified Washington University Road Test. Predictor measures were tests of visual, motor and cognitive functioning, selected for their empirical or conceptual relationship to the complex task of driving safely. Results Sixty-five (65%) of participants failed the on-road driving test. The best predictive model, with an overall accuracy of up to 85% when participants were blinded, included AD-8 score, the Clock Drawing Test score, and the time to complete either the Snellgrove Maze Test (SMT) or Trail Making Test A. Visual and motor functioning were not associated with road driving test failure. Conclusion A screening battery that could be performed in less than 10 minutes predicted with good accuracy a failure rating on the on-road driving test in this sample of older drivers with dementia. A “probability of failure” calculator is provided from a logistic regression model that may be useful for clinicians in their decision to refer impaired older adults for further testing. More studies are needed in larger community based samples, along with discussions with patients, families and clinicians, in regards to acceptable levels of test uncertainty.

Objective Preterm children are at risk for social-emotional difficulties, including autism and attention deficit hyperactivity disorder. We assessed the relationship of regional brain development in preterm children, evaluated via MRI at term-equivalent postmenstrual age (TEA), to later social-emotional difficulties. Method MR images obtained at TEA from 184 very preterm infants (gestation <30 weeks or birthweight <1250 g) were analyzed for white matter abnormalities, hippocampal volume, and brain metrics. 111 infants underwent diffusion tensor imaging, which provided values for fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Social-emotional development was assessed with the Infant Toddler Social and Emotional Assessment (ITSEA) at age 2 and the Strengths and Difficulties Questionnaire (SDQ) at age 5. Results Higher ADC in the right orbitofrontal cortex was associated with social-emotional problems at age 5 (peer problems, p<0.01). In females, smaller hippocampal volume was associated with increased hyperactivity (p<0.01), peer problems (p<0.05) and SDQ total score (p<0.01). In males, a smaller frontal region was associated with poorer prosocial (p<0.05) scores. Many of the hippocampal findings remained significant after adjusting for birthweight z score, intelligence, social risk, immaturity at birth, and parental mental health. These associations were present in children who had social-emotional problems in similar domains at age 2 and those who did not. Conclusions Early alterations in regional cerebral development in very preterm infants relate to specific deficits in social-emotional performance by school-age. These results vary by gender. Our results provide further evidence for a neuroanatomical basis for behavioral challenges found in very preterm children.

IMPORTANCE Elucidation of optimal dosing and treatment content is critical for health care providers, payers, and policy makers, as well as mechanisms of change to inform intervention delivery and training initiatives for childhood obesity.OBJECTIVES To evaluate effects, following a 4-month family-based behavioral weight loss treatment (FBT), of 2 doses (HIGH or LOW) of a weight-control intervention (enhanced social facilitation maintenance [SFM+]) vs a weight-control education condition (CONTROL; matched for dose with LOW), on child anthropometrics, and to explore putative mediators of weight loss outcomes. DESIGN, SETTING, AND PARTICIPANTS For this parallel-group randomized clinical trial conducted at 2 US academic medical centers from December 2009 to March 2013, 172 parent-child dyads completed FBT and were then randomized to 8 months of SFM+ (HIGH, n = 59; LOW, n = 56) or CONTROL (n = 57). Children (aged 7-11 years) with overweight and obesity (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared] Ն85th percentile) with at least 1 parent with overweight and obesity (BMI Ն25) were recruited. INTERVENTIONS HIGH SFM+ vs LOW SFM+ (CONTROL matched the dose of LOW).MAIN OUTCOMES AND MEASURES Intention-to-treat analysis using mixed-effects models estimated change in child percentage overweight (percentage above the median BMI for a child's age and sex) for the FBT period (0-4 months) and the SFM+ period (4-12 months), and proportion of children achieving a clinically significant change in percentage overweight (Ն9-unit decrease; months 0-12). Theory-based outcome mediators were also evaluated. RESULTSThis study recruited 172 parent-child dyads (mean [SD] age: parents 42.3 [6.4] years; children, 9.4 [1.3] years). The omnibus treatment × time interaction for child percentage overweight was significant (F 8, 618.9 = 2.89; P = .004). Planned pairwise comparisons revealed that from months 4 to 12, LOW had better outcomes than CONTROL (difference, −3.34; 95% CI, −6.21 to −0.47; d = −0.40; P = .02). HIGH had better outcomes than LOW (difference, −3.37; 95% CI, −6.15 to −0.59; d = −0.38; P = .02) and CONTROL (difference, −6.71; 95% CI, −9.57 to −3.84; d = −0.77; P < .001). A greater proportion of children in HIGH (45 [82%]) vs LOW (34 [64%]) (difference, 18.00; 95% CI, 1.00-34.00; P = .03; number needed to treat = 5.56) and CONTROL (25 [48%]) (difference, 34.00; 95% CI, 16.00-51.00; P < .001; number needed to treat = 2.94) had clinically significant percentage overweight reductions. Food and activity monitoring and goal setting mediated the effect of LOW vs CONTROL (50%). Monitoring and goal setting, family and home environment, and healthy behaviors with peers mediated the effect of HIGH vs CONTROL (25%-42%).CONCLUSIONS AND RELEVANCE Following FBT, specialized intervention content (SFM+) enhanced children's weight outcomes and outperformed a credible control condition, with high dose delivery yielding the best outcomes. Sustained monitoring and goal setting, support from the family a...