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Rationale: Racial disparities in pain management have been previously reported for children receiving emergency care. Objectives: To determine whether patient race or ethnicity is associated with the broader goal of pain management and sedation among pediatric patients mechanically ventilated for acute respiratory failure. Methods: Planned secondary analysis of RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure). RESTORE, a cluster-randomized clinical trial conducted in 31 U.S. pediatric intensive care units, compared protocolized sedation management (intervention arm) with usual care (control arm). Participants included 2,271 children identified as non-Hispanic white (white, n = 1,233), non-Hispanic Black (Black, n = 502), or Hispanic of any race (Hispanic, n = 536). Results: Within each treatment arm, neither opioid nor benzodiazepine selection, nor cumulative dosing, differed significantly among race and ethnicity groups. Black patients experienced fewer days with an episode of pain (compared with white patients in the control arm and with Hispanic patients in the intervention arm) and experienced less iatrogenic withdrawal syndrome (compared with white patients in either arm or with Hispanic patients in the intervention arm). The percentage of days awake and calm while intubated was not significantly different in pairwise comparisons by race and ethnicity groups in either the control arm (median: white, 75%; Black, 71%; Hispanic, 75%) or the intervention arm (white, 86%; Black, 88%; Hispanic, 85%). Conclusions: Across multiple measures, our study found scattered differences in sedation management among critically ill Black, Hispanic, and white children that did not consistently favor any group. However, racial disparities related to implicit bias cannot be completely ruled out. Clinical trial registered with clinicaltrials.gov (NCT 00814099).

Objectives Adverse events that affect patient safety are a significant concern in pediatrics. Increasing situational awareness, identifying errors and near misses, and reporting them using organizational incident reporting systems enables mitigation of harm. Methods We designed and tested a brief, interactive, and easily replicable simulation activity for medical students, and emergency medicine interns and pediatric interns to strengthen their skills and enhance their self-efficacy in identifying and reporting patient safety hazards. Hazards fell into the categories of situational safety, patient identification and privacy, infection prevention, treatment errors, and issues with electronic health records (EHRs). Results The simulation training significantly increased the self-efficacy of medical students and interns in identifying and reporting patient safety hazards. Learners were very satisfied with the simulation training, successfully recognized key patient safety hazards, provided feedback to improve the training, and improved their ability to report hazards through organizational incident reporting systems. Patient safety hazards associated with patient misidentification were recognized most frequently, whereas safety hazards associated with EHRs were missed with the greatest frequency. Conclusions The simulation training enabled learners to identify hazards and near misses and enhanced their ability to report hazards through organizational incident reporting systems. Learners at all levels of training identified safety hazards at comparable rates, which demonstrates the role that trainees play in critically observing clinical settings with fresh eyes and identifying and reporting patient safety hazards. Interventions to promote patient safety need to prioritize building situational awareness of potential hazards associated with EHR use.

The COVID-19 pandemic has created multiple, complex and intense demands on hospitals, including the need for surge planning in the many locations outside epicenters such as northern Italy or New York City. We here describe such surge planning in an Academic Health Center that encompasses a children's hospital. Interprofessional teams from every aspect of inpatient care and hospital operations worked to prepare for a COVID-19 surge. In so doing, they successfully innovated ways to integrate pediatric and adult care and maximize bed capacity. The success of this intense collaborative effort offers an opportunity for ongoing teamwork to enhance efficient, effective, and high-quality patient care.

OBJECTIVE: To develop an interfacility transfer handoff intervention by applying the person-based approach method. METHODS: We conducted a qualitative study that used nominal group technique (NGT) and focus groups to apply the person-based approach for intervention development. NGT methods were used to determine prioritized pediatric transfer handoff elements to design the initial intervention prototype. Five focus group sessions were then held to solicit feedback on the intervention, perceptions on implementing the intervention, and outcomes for evaluating the intervention. Data were analyzed by using content analysis. Iterative improvements were made to the intervention prototype as data emerged. RESULTS: Forty-two clinical providers in total participated in NGT and focus group sessions, including physicians, advanced practitioners, nurses, and a respiratory therapist. The initial intervention prototype was a handoff mnemonic tool, “SHARING” (short introduction, how the patient appeared, action taken, responses and results, interpretation, next steps, gather documents). Perceived benefits of the intervention included clarifying handoff expectations, reducing handoff deficits, supporting less experienced clinical providers, and setting the stage for ongoing effective communication. Outcomes perceived to be meaningful were related to triage appropriateness, workflow and use, and communication and information sharing. The final version of the intervention consisted of a SHARING reference card and a SHARING electronic medical record note template. CONCLUSIONS: Using qualitative methods to apply the person-based approach to intervention development, we developed a transfer handoff intervention. Future research is needed to examine impacts of this tool; outcomes can include those identified as meaningful by participants in our present study.

Hundreds of dominant-negative myosin mutations have been identified that lead to hypertrophic cardiomyopathy, and the biomechanical link between mutation and disease is heterogeneous across this patient population. To increase the therapeutic feasibility of treating this diverse genetic population, we investigated the ability of locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) to selectively knock down mutant myosin transcripts by targeting single-nucleotide polymorphisms (SNPs) that were found to be common in the myosin heavy chain 7 (MYH7) gene. We identified three SNPs in MYH7 and designed ASO libraries to selectively target either the reference or alternate MYH7 sequence. We identified ASOs that selectively knocked down either the reference or alternate allele at all three SNP regions. We also show allele-selective knockdown in a mouse model that was humanized on one allele. These results suggest that SNP-targeting ASOs are a promising therapeutic modality for treating cardiac pathology. Keywords: antisense oligonucleotides, myosin, cardiac hypertrophy, cardiomyopathy, nucleic acid, RNA degradation

Multisystem inflammatory syndrome in children (MIS-C) is a novel disease that was identified during the COVID-19 pandemic and is characterised by systemic inflammation following SARS-CoV-2 infection. Early detection of MIS-C is a challenge given its clinical similarities to Kawasaki disease and other acute febrile childhood illnesses. We aimed to develop and validate an artificial intelligence algorithm that can distinguish among MIS-C, Kawasaki disease, and other similar febrile illnesses and aid in the diagnosis of patients in the emergency department and acute care setting.In this retrospective model development and validation study, we developed a deep-learning algorithm called KIDMATCH (Kawasaki Disease vs Multisystem Inflammatory Syndrome in Children) using patient age, the five classic clinical Kawasaki disease signs, and 17 laboratory measurements. All features were prospectively collected at the time of initial evaluation from patients diagnosed with Kawasaki disease or other febrile illness between Jan 1, 2009, and Dec 31, 2019, at Rady Children's Hospital in San Diego (CA, USA). For patients with MIS-C, the same data were collected from patients between May 7, 2020, and July 20, 2021, at Rady Children's Hospital, Connecticut Children's Medical Center in Hartford (CT, USA), and Children's Hospital Los Angeles (CA, USA). We trained a two-stage model consisting of feedforward neural networks to distinguish between patients with MIS-C and those without and then those with Kawasaki disease and other febrile illnesses. After internally validating the algorithm using stratified tenfold cross-validation, we incorporated a conformal prediction framework to tag patients with erroneous data or distribution shifts. We finally externally validated KIDMATCH on patients with MIS-C enrolled between April 22, 2020, and July 21, 2021, from Boston Children's Hospital (MA, USA), Children's National Hospital (Washington, DC, USA), and the CHARMS Study Group consortium of 14 US hospitals.1517 patients diagnosed at Rady Children's Hospital between Jan 1, 2009, and June 7, 2021, with MIS-C (n=69), Kawasaki disease (n=775), or other febrile illnesses (n=673) were identified for internal validation, with an additional 16 patients with MIS-C included from Connecticut Children's Medical Center and 50 from Children's Hospital Los Angeles between May 7, 2020, and July 20, 2021. KIDMATCH achieved a median area under the receiver operating characteristic curve during internal validation of 98·8% (IQR 98·0-99·3) in the first stage and 96·0% (95·6-97·2) in the second stage. We externally validated KIDMATCH on 175 patients with MIS-C from Boston Children's Hospital (n=50), Children's National Hospital (n=42), and the CHARMS Study Group consortium of 14 US hospitals (n=83). External validation of KIDMATCH on patients with MIS-C correctly classified 76 of 81 patients (94% accuracy, two rejected by conformal prediction) from 14 hospitals in the CHARMS Study Group consortium, 47 of 49 patients (96% accuracy, one rejected by conformal prediction) from Boston Children's Hospital, and 36 of 40 patients (90% accuracy, two rejected by conformal prediction) from Children's National Hospital.KIDMATCH has the potential to aid front-line clinicians to distinguish between MIS-C, Kawasaki disease, and other similar febrile illnesses to allow prompt treatment and prevent severe complications.US Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Heart, Lung, and Blood Institute, US Patient-Centered Outcomes Research Institute, US National Library of Medicine, the McCance Foundation, and the Gordon and Marilyn Macklin Foundation.

Background: Despite the recognized benefits of telemedicine use for pediatric emergency consultations, there are barriers to the widespread uptake of this technology. Quality improvement methods can be used to rapidly test implementation strategies. Our objective was to test telemedicine implementation strategies in real-world application using quality improvement methods. Our quality improvement aim was to achieve high rates of telemedicine use for pediatric transfer consultations. Methods: A multidisciplinary multisite improvement team identified that key drivers of increasing telemedicine use included telemedicine resource awareness, streamlined telemedicine workflow, provider buy-in, and data transparency. Interventions focused on telemedicine trainings, disseminating telemedicine uptake data, telemedicine reminders, telemedicine test calls, and preparing for telemedicine use for every transfer consultation. The outcome measure was percentage of pediatric emergency transfer consultations that used telemedicine. The balancing measure was time (minutes) from the initial transfer center call to completion of the consultation. Results: Multiple plan-do-study-act cycles were associated with special cause variation, with an upward shift in mean percentage of telemedicine use from 5% to 22%. Time from initial call to consultation completion remained unchanged. Conclusion: Our study supports the use of quality improvement methods to test telemedicine implementation strategies for pediatric telemedicine emergency consultations.

BACKGROUND AND OBJECTIVES:Safety event reporting systems facilitate identification of system-level targets to improve patient safety. Resident physicians report few safety events despite their role as frontline providers and the frequent occurrence of events. The objective of this study is to increase the number of pediatric resident safety event submissions from METHODS:We conducted an iterative quality improvement process with 39 pediatric residents at a children’s hospital. Interventions focused on 4 key drivers: user-friendly event submission process, resident buy-in, nonpunitive safety culture, and data transparency. The primary outcome measure of number of pediatric resident event submissions was analyzed by using statistical process control. Balancing measures included time from submission to feedback, duplicate submissions, and nonevent submissions. As a control, the primary outcome measure was monitored for nonpediatric residents during the same period.RESULTS:The mean number of pediatric resident event submissions increased from 0.9 to 5.7 submissions per 14 days. Impactful interventions included a designated space in the resident workroom to list safety events to submit, monthly project updates, and an interresident competition. There were no duplicate submissions or nonevent submissions in the postintervention period. Time to feedback in the postintervention period had both upward and downward shifts, with >8 consecutive points above and below the baseline period’s centerline. The control group showed no sustained change in event submissions.CONCLUSIONS:Our improvement process was associated with significant increase in pediatric resident safety event submissions without an increase in the number of submissions categorized as duplicates or nonevents.

SARS-CoV-2, the novel coronavirus causing coronavirus disease 2019 (COVID-19), is now a global pandemic. Human-to-human transmission has been documented to occur through respiratory secretions, feces, aerosols, and contaminated environmental surfaces. Pediatric patients present a unique challenge as they may have minimal symptoms and yet transmit disease. Endoscopists face risk for infection with viruses like SARS-CoV-2, as the aerosol generating nature of endoscopy diffuses respiratory disease that can be spread via an airborne and droplet route. We describe our center's methodology for pediatric patient risk stratification to facilitate responsible use of endoscopic resources during this crisis. We also describe our recommendations for use of personal protective equipment by endoscopists, with the goal of ensuring the safety of ourselves, our anesthesiology and endoscopy staff, and our patients.

Background Ventilator-associated pneumonia (VAP) increases morbidity, mortality, and health care costs. Objective To reduce the VAP rate in the pediatric/cardiac intensive care unit to fewer than 2 events per 1000 ventilator days within 2 years and to sustain a rate near 0 for the next 5 years. Methods An evidence-based VAP prevention bundle was developed and implemented by an interprofessional team using the Six Sigma Define, Measure, Analyze, Improve, Control methodology. The mixed unit's 5-element VAP prevention bundle consisted of age-appropriate oral care, proper airway suction technique, maintenance of safe endotracheal-tube cuff pressures, aspiration precautions, and head-of-bed elevation. Knowledge and practice were reinforced through multidisciplinary education and one-on-one teaching. Practice compliance was monitored through regular, unannounced bedside audits linked to just-in-time teaching. Results Within 2 years, the annual VAP rate fell from 7.86 to 1.16 events per 1000 ventilator days; VAP bundle-element compliance ranged from 86% to 99%. There were no VAP events during a 10-quarter period in 2012 through 2014. Conclusions Development, implementation, and revision of a VAP prevention strategy using the Define, Measure, Analyze, Improve, Control methodology was associated with marked, sustained reduction in VAP rates, notably during the unit's expansion from 16 to 24 beds, the opening of a pediatric cardiothoracic unit, and the hiring of more than 80 new nurses. After 7 years, the VAP rate continues to be low at 0.86 for 2016 and 0 through June 2017.

We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as α7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective α7 nAChR partial agonist, N‐(6‐methyl‐1,3‐benzoxazol‐2‐yl)‐3′,5′‐dihydro‐4‐azaspiro[bicyclo[2.2.2]octane‐2,4′‐imidazole]‐2′‐amine (BMS-910731, 16), was identified. This compound induced immediate early genes c-fos and Arc in a preclinical rodent model of α7 nAChR-derived cellular activation and plasticity. Importantly, the ability to incorporate selectivity for the α7 nACh receptor over the 5-HT3A receptor in this series suggested a significant difference in steric requirements between the two receptors.

Ventilator-associated pneumonia (VAP) increases morbidity, mortality, and health care costs.To reduce the VAP rate in the pediatric/cardiac intensive care unit to fewer than 2 events per 1000 ventilator days within 2 years and to sustain a rate near 0 for the next 5 years.An evidence-based VAP prevention bundle was developed and implemented by an interprofessional team using the Six Sigma Define, Measure, Analyze, Improve, Control methodology. The mixed unit's 5-element VAP prevention bundle consisted of age-appropriate oral care, proper airway suction technique, maintenance of safe endotracheal-tube cuff pressures, aspiration precautions, and head-of-bed elevation. Knowledge and practice were reinforced through multidisciplinary education and one-on-one teaching. Practice compliance was monitored through regular, unannounced bedside audits linked to just-in-time teaching.Within 2 years, the annual VAP rate fell from 7.86 to 1.16 events per 1000 ventilator days; VAP bundle-element compliance ranged from 86% to 99%. There were no VAP events during a 10-quarter period in 2012 through 2014.Development, implementation, and revision of a VAP prevention strategy using the Define, Measure, Analyze, Improve, Control methodology was associated with marked, sustained reduction in VAP rates, notably during the unit's expansion from 16 to 24 beds, the opening of a pediatric cardiothoracic unit, and the hiring of more than 80 new nurses. After 7 years, the VAP rate continues to be low at 0.86 for 2016 and 0 through June 2017.

To compare current analgesia and sedation management practices between critically ill children with pre-existing cognitive impairment and critically ill neurotypical children, including possible indicators of therapeutic efficacy.This study used secondary analysis of prospective data from the RESTORE clinical trial, with 2449 children admitted to the pediatric intensive care unit and receiving mechanical ventilation for acute respiratory failure. Subjects with a baseline Pediatric Cerebral Performance Category ≥3 were defined as subjects with cognitive impairment, and differences between groups were explored using regression methods accounting for pediatric intensive care unit as a cluster variable.This study identified 412 subjects (17%) with cognitive impairment. Compared with neurotypical subjects, subjects with cognitive impairment were older (median, years, 6.2 vs 1.4; P .001) with more severe pediatric acute respiratory distress syndrome (40% vs 33%; P = .009). They received significantly lower cumulative doses of opioids (median, mg/kg, 14.2 vs 16.2; P .001) and benzodiazepines (10.6 vs 14.4; P .001). Three nonverbal subjects with cognitive impairment received no analgesia or sedation. Subjects with cognitive impairment were assessed as having more study days awake and calm and fewer study days with an episode of pain. They were less likely to be assessed as having inadequate pain/sedation management or unplanned endotracheal/invasive tube removal. Subjects with cognitive impairment had more documented iatrogenic withdrawal symptoms than neurotypical subjects.Subjects with cognitive impairment in this study received less medication, but it is unclear whether they have authentically lower analgesic and/or sedative requirements or are vulnerable to inadequate assessment of discomfort because of the lack of validated assessment tools. We recommend the development of pain and sedation assessment tools specific to this patient population.

OBJECTIVES:To compare patient factors and outcomes among children admitted to PICUs from referring versus children’s hospital emergency departments (EDs).METHODS:Pediatric patients (RESULTS:Of 80 045 children from 109 PICUs, 35.6% were admitted from referring EDs and 64.4% were admitted from children’s hospital EDs. Children from referring EDs had higher illness severity (Pediatric Index of Mortality, version 2–predicted risk of mortality, 3.1% vs 2.2%, P < .001), were more likely to be mechanically ventilated within their first hour in the PICU (28.4% vs 23.4%, P < .001), and had higher observed mortality (3.3% vs 2.1%, P < .001). Once adjusted for illness severity and other confounders in a multivariable logistic regression model, there was no difference in the odds of mortality between children from referring and children’s hospital EDs (odds ratio: 0.90; 95% confidence interval: 0.79 to 1.02, P = .09)CONCLUSIONS:Children transferred to PICUs from referring EDs had higher illness severity on arrival compared with children admitted from children’s hospital EDs. Variations in patient selection for transfer or pretransfer treatment at referring EDs may contribute to the greater illness severity of transferred children. Referring hospitals may benefit from leveraging existing resources to improve patient stabilization before transfer.

Super-refractory status epilepticus is a life-threatening condition. Resistance to benzodiazepine and barbiturate treatment for this disorder is thought to be due to internalization of synaptic γ-aminobutyric acid (GABA)A receptors, and withdrawal of benzodiazepines and barbiturates during treatment often triggers seizure recurrence. The neurosteroid allopregnanolone acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. Here we describe the use of allopregnanolone in 2 pediatric patients with super-refractory status epilepticus. This treatment allowed the general anesthetic infusions to be weaned with resolution of status epilepticus. This is the first report of allopregnanolone use to treat status epilepticus in children.

Acrylamide (S)-6, a potent and efficacious KCNQ2 (Kv7.2) opener, demonstrated significant activity in two models of neuropathic pain and in the formalin test, suggesting that KCNQ2 openers may be useful in the treatment of neuropathic pain including diabetic neuropathy.

To describe the differences in goals for their usual practice for various medical therapies from a number of international centers for children with severe traumatic brain injury.A survey of the goals from representatives of the international centers.Thirty-two pediatric traumatic brain injury centers in the United States, United Kingdom, France, and Spain.None.None.A survey instrument was developed that required free-form responses from the centers regarding their usual practice goals for topics of intracranial hypertension therapies, hypoxia/ischemia prevention and detection, and metabolic support. Cerebrospinal fluid diversion strategies varied both across centers and within centers, with roughly equal proportion of centers adopting a strategy of continuous cerebrospinal fluid diversion and a strategy of no cerebrospinal fluid diversion. Use of mannitol and hypertonic saline for hyperosmolar therapies was widespread among centers (90.1% and 96.9%, respectively). Of centers using hypertonic saline, 3% saline preparations were the most common but many other concentrations were in common use. Routine hyperventilation was not reported as a standard goal and 31.3% of centers currently use PbO(2) monitoring for cerebral hypoxia. The time to start nutritional support and glucose administration varied widely, with nutritional support beginning before 96 hours and glucose administration being started earlier in most centers.There were marked differences in medical goals for children with severe traumatic brain injury across our international consortium, and these differences seemed to be greatest in areas with the weakest evidence in the literature. Future studies that determine the superiority of the various medical therapies outlined within our survey would be a significant advance for the pediatric neurotrauma field and may lead to new standards of care and improved study designs for clinical trials.

© 2016 American College of Emergency Physicians Study objective Among children requiring hospital admission or transfer, we seek to determine whether insurance is associated with the decision to either admit locally or transfer to another hospital. Methods This cross-sectional study used Healthcare Cost and Utilization Project 2012 Nationwide Emergency Department Sample. Pediatric patients receiving care in emergency departments (EDs) who were either admitted or transferred were included. Clinical Classifications Software was used to categorize patients into noninjury diagnostic cohorts. Multivariable logistic regression models adjusting for potential confounders, including severity of illness and comorbidities, and incorporating nationally representative weights were used to determine the association between insurance and the odds of transfer relative to admission. Results A total of 240,620 noninjury pediatric ED events met inclusion criteria. Patient and hospital characteristics, including older age and nonteaching hospitals, were associated with greater odds of transfer relative to admission. Patients who were uninsured or had self-pay had higher odds of transfer (odds ratio [OR] 3.84; 95% confidence interval [CI] 2.08 to 7.09) relative to admission compared with those with private insurance. Uninsured and self-pay patients also had higher odds of transfer across all 13 diagnostic categories, with ORs ranging from 2.96 to 12.00. Patients with Medicaid (OR 1.05; 95% CI 0.90 to 1.22) and other insurances (OR 1.14; 95% CI 0.87 to 1.48) had similar odds of transfer compared with patients with private insurance. Conclusion Children without insurance and those considered as having self-pay are more likely to be transferred to another hospital than to be admitted for inpatient care within the same receiving hospital compared with children with private insurance. This study reinforces ongoing concerns about disparities in the provision of pediatric ED and inpatient care.

The design and synthesis of a series of quinuclidine-containing spirooxazolidines (“spiroimidates”) and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT3A receptor. Modification of the N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N-isoquinolin-3-yl)-4′H-4-azaspiro[bicyclo[2.2.2]octane-2,5′oxazol]-2′-amine (BMS-902483), a potent α7 partial agonist, which improved cognition in preclinical rodent models.

Editorials institutions and by examining more closely the temporal evo- lution of EEG characteristics in order to further improve prog- nostic accuracy. This accumulating evidence will further strengthen the case that EEG monitoring for prognostication following pediatric cardiac arrest is indeed “ready for prime time.” REFERENCES 1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart dis- ease and stroke statistics–2013 update: A report from the American Heart Association. Circulation 2013; 127:e6–e245 2. Atkins DL, Everson-Stewart S, Sears GK, et al; Resuscitation Outcomes Consortium Investigators: Epidemiology and outcomes from out-of-hos- pital cardiac arrest in children: The Resuscitation Outcomes Consortium Epistry-Cardiac Arrest. Circulation 2009; 119:1484–1491 3. Girotra S, Spertus JA, Li Y, et al; American Heart Association Get With the Guidelines–Resuscitation Investigators: Survival trends in pediatric in-hospital cardiac arrests: An analysis from Get With the Guidelines-Resuscitation. Circ Cardiovasc Qual Outcomes 2013; 4. van Zellem L, Buysse C, Madderom M, et al: Long-term neuropsy- chological outcomes in children and adolescents after cardiac arrest. Intensive Care Med 2015; 41:1057–1066 5. Sharbrough FW, Messick JM Jr, Sundt TM Jr: Correlation of continu- ous electroencephalograms with cerebral blood flow measurements during carotid endarterectomy. Stroke 1973; 4:674–683 6. Topjian AA, Sanchez SM, Shults J, et al: Early Electroencephalographic Background Features Predict Outcomes in Children Resuscitated From Cardiac Arrest. Pediatr Crit Care Med 2016; 17:547–557 7. Murray DM, Boylan GB, Ryan CA, et al: Early EEG findings in hypoxic- ischemic encephalopathy predict outcomes at 2 years. Pediatrics 2009; 124:e459–e467 8. Abend NS, Dlugos DJ, Hahn CD, et al: Use of EEG monitoring and management of non-convulsive seizures in critically ill patients: A sur- vey of neurologists. Neurocrit Care 2010; 12:382–389 9. Gavvala J, Abend N, LaRoche S, et al; Critical Care EEG Monitoring Research Consortium (CCEMRC): Continuous EEG monitoring: A survey of neurophysiologists and neurointensivists. Epilepsia 2014; 10. Herman ST, Abend NS, Bleck TP, et al; Critical Care Continuous EEG Task Force of the American Clinical Neurophysiology Society: Consensus statement on continuous EEG in critically ill adults and children, part I: Indications. J Clin Neurophysiol 2015; 32:87–95 PICU Readmissions: Not Just Output but Patient Throughput* JoAnne E. Natale, MD, PhD James P. Marcin, MD, MPH Department of Pediatrics University of California Davis School of Medicine Sacramento, CA P rognostication has traditionally been identified as one of the chief skills of the intensivist. One very important aspect of prognostication is the ability to safely predict which patients are ready for to discharge, whether to a lower level of care or to home. As demand for limited intensive care resources grows, discharge decision making is often influenced by external nonclinical factors, sometimes resulting in unin- tended risks for the patient and the healthcare system. Among both adult and pediatric patients, a predominant risk of dis- charge is unplanned readmission—a factor known to be asso- ciated with adverse patient outcomes, a measure of potentially preventable utilization, and a frequently referenced indicator of quality (1–7). In this issue of Pediatric Critical Care Medi- cine, Kotsakis et al (8) contribute to the growing literature *See also p. 558. Key Words: patient readmission; pediatric critical care; quality indicators; risk factors The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000764 Pediatric Critical Care Medicine specifically focused on discharge and unplanned readmission from the perspective of the pediatric intensivist. Their finding that 2.5% of patients discharged from their pediatric cardiac and medical/surgical ICUs are readmitted within 48 hours and that such patients are at increased risk for mortality is gener- ally consistent with previous reports analyzing large groups of patients (3, 4, 6). They also identify several clinical factors, including potentially modifiable ones, which are associated with an increased risk of readmission to the PICU. In so doing, they successfully responded to a 2013 editorial calling for data describing patient physiologic status and clinical interventions immediately before discharge and applying a standard 48-hour follow-up period for readmission (9). In considering how to apply these findings to make discharge decisions safer, a pediatric intensivist could ask how successful available patient-level information is in predicting readmission. Such a question is traditionally assessed by considering an algo- rithm’s sensitivity, specificity, discrimination, and positive and negative predictive values. The epidemiologic understanding of tradeoffs between sensitivity and sensitivity acknowledges that the goal of zero readmissions may not be either possible or desirable as it would have the effect of increasing length of stay and decreasing the availability of PICU resources. Put succinctly, the ability to prognosticate for individual patients confronts the inevitable challenge of whether to prefer false positives (patients discharged from the PICU with a high risk of unplanned readmission) or false negatives (patients retained in the PICU when PICU resources are not needed). Although the impressive analyses of Kotsakis et al (8) improve our understanding of factors associated with PICU www.pccmjournal.org Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. Unauthorized reproduction of this article is prohibited

Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. Objectives: To compare the severity of illness and outcomes among children admitted to a children's hospital PICU from referring emergency departments with and without access to a pediatric critical care telemedicine program. Design: Retrospective cohort study. Setting: Tertiary academic children's hospital PICU. Patients: Pediatric patients admitted directly to the PICU from referring emergency departments between 2010 and 2014. Interventions: None. Measurements: Demographic factors, severity of illness, and clinical outcomes among children receiving care in emergency departments with and without access to pediatric telemedicine, as well as a subcohort of children admitted from emergency departments before and after the implementation of telemedicine. Main Results: Five hundred eighty-two patients from 15 emergency departments with telemedicine and 524 patients from 60 emergency departments without telemedicine were transferred and admitted to the PICU. Children admitted from emergency departments using telemedicine were younger (5.6 vs 6.9 yr; p< 0.001) and less sick (Pediatric Risk of Mortality III score, 3.2 vs 4.0; p < 0.05) at admission to the PICU compared with children admitted from emergency departments without telemedicine. Among transfers from emergency departments that established telemedicine programs during the study period, children arrived significantly less sick (mean Pediatric Risk of Mortality III scores, 1.2 units lower; p = 0.03) after the implementation of telemedicine (n = 43) than before the implementation of telemedicine (n = 95). The observed-to-expected mortality ratios of posttelemedicine, pretelemedicine, and no-telemedicine cohorts were 0.81 (95% CI, 0.53-1.09), 1.07 (95% CI, 0.53-1.60), and 1.02 (95% CI, 0.71-1.33), respectively. Conclusions: The implementation of a telemedicine program designed to assist in the care of seriously ill children receiving care in referring emergency departments was associated with lower illness severity at admission to the PICU. This study contributes to the body of evidence that pediatric critical care telemedicine programs assist referring emergency departments in the care of critically ill children and could result in improved clinical outcomes.

Levetiracetam (LEV) has antiepileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients was unknown. We report pharmacokinetics of TBI subjects≥6years with high PTE risk treated with LEV 55mg/kg/day orally, nasogastrically or intravenously for 30days starting ≤8h after injury in a phase II safety and pharmacokinetic study. Forty-one subjects (26 adults and 15 children) were randomized to PK studies on treatment days 3 and 30. Thirty-six out of forty-one randomized subjects underwent PK study on treatment day 3, and 24/41 subjects underwent PK study on day 30. On day 3, mean T(max) was 2.2h, C(max) was 60.2μg/ml and AUC was 403.7μg/h/ml. T(max) was longer in the elderly than in children and non-elderly adults (5.96h vs. 1.5h and 1.8h; p=0.0001). AUC was non-significantly lower in children compared with adults and the elderly (317.4μg/h/ml vs. 461.4μg/h/ml and 450.2μg/h/ml; p=0.08). C(max) trended higher in i.v.- versus tablet- or n.g.-treated subjects (78.4μg/ml vs. 59μg/ml and 48.2μg/ml; p=0.07). AUC of n.g. and i.v. administrations was 79% and 88% of AUC of oral administration. There were no significant PK differences between days 3 and 30. Treatment of TBI patients with high PTE risk with 55mg/kg/day LEV, a dose with antiepileptogenic effect in animals, results in plasma LEV levels comparable to those in animal studies.

We sought to assess the attitudes of pediatric intensive care unit medical directors in California regarding the need for, the validity of, and the potential impact of benchmarking, public reporting, and pay-for-performance on pediatric critical care.Cross-sectional survey.Pediatric intensive care units in California.Medical directors of pediatric intensive care units.None.Self-administered questionnaire and a semi-structured phone interview from 16 pediatric intensive care unit medical directors. All data were anonymized before review. Standard methods for identifying and agreeing on themes in transcribed interviews were applied. Seventy-three percent of California pediatric intensive care unit medical directors agree that benchmarking improves patient outcomes but are undecided whether public reporting and pay-for-performance improve healthcare quality. They are wary of the validity of data used to generate these performance measures and are discouraged by the time and costs required to collect data for standard performance outcomes (severity-adjusted pediatric intensive care unit mortality). Leadership opinions appear potentially "dynamic" in multiple domains and across each of the measures assessed.Pediatric intensive care unit medical directors sometimes express contradictory opinions about the merits of shared benchmarking efforts and express concerns across a range of logistic, methodological, and policy issues. These findings raise fundamental questions about how to create clinical performance standards that facilitate quality improvement in the face of a seriously divided constituency. Further, we propose that pediatric intensive care unit medical directors play more active roles in the development, implementation, and communication of shared state-wide data collection.

Objective: To reduce direct parental referral of low acuity ill pediatric patients to the outpatient facilities of a nation’s only pediatric referral hospital. Patients and Methods: Longitudinal monitoring of outpatient visits at Orotta Children’s Hospital (OCH) and primary health facilities (PHFs) following implementation of an intervention designed in response to information provided by parents and health-care providers. Parental surveys were undertaken before and after exposure to the intervention to assess effects on knowledge, attitudes, and behavioral intentions. Results: We analyzed 5,639 visits between baseline and follow-up, documenting a decline in parental referral among OCH outpatients from 95% to approximately 80%. Educational intervention increased the proportion of parents intending to use PHF for future outpatient care from 28% to 82%. Staff of the PHFs responded enthusiastically to this intervention program and requested further activities. Conclusions: Self-referral to tertiary care hospital was reduced following a modest program of parental education designed and implemented by residents in training.

Compared to adults, immature metallothionein I & II knockout (MT−/−) mice incur greater neuronal loss and a more rapid rate of microglia accumulation following target deprivation-induced injury. Since minocycline has been proposed to inhibit microglial activation and associated production of neuroinflammatory factors, we investigated its ability to promote neuronal survival in the immature, metallothionein-deficient brain. Following ablation of the visual cortex, 10-day-old MT−/− mice were treated with minocycline or saline and sacrificed 24 or 48 hours after injury. Using stereological methods, the number of microglia and neurons were estimated in the ipsilateral dorsal lateral geniculate nucleus (dLGN) by an investigator blinded to the treatment. No effect on neuronal survival was observed at 24 hours, but 48 hours after injury an unanticipated but significant minocycline-mediated increase in neuronal loss was detected. Further, while failing to inhibit microglial accumulation, minocycline treatment increased the proportion of amoeboid microglia in the ipsilateral dLGN. To understand the molecular mechanisms underlying this neurotoxic response, we identified minocycline-mediated changes in the expression of three potentially pro-apoptotic/ inflammatory genes: growth arrest- and DNA damage-inducible gene 45γ (GADD45γ); interferon-inducible protein 1 (IFI1) and cytokine induced growth factor (CTGF). We also observed increased mitogen-activated protein kinase (MAPK) p38 phosphorylation with minocycline treatment. Although minocycline inhibited calpain activity at 12 hours post-injury, this effect was not sustained at 24 hours. Together, these results help to explain how minocycline has a deleterious effect on neuronal survival in this injury model.

Sepsis-related mortality results in part from immunodeficiency secondary to profound lymphoid apoptosis. The biological mechanisms responsible are not understood.Because recent evidence shows that platelets are involved in microvascular inflammation and that they accumulate in lymphoid microvasculature in sepsis, we hypothesized a direct role for platelets in sepsis-related lymphoid apoptosis.We studied megakaryocytes and platelets from a murine-induced sepsis model, with validation in septic children, which showed induction of the cytotoxic serine protease granzyme B.Platelets from septic mice induced marked apoptosis of healthy splenocytes ex vivo. Platelets from septic granzyme B null (-/-) mice showed no lymphotoxicity.Our findings establish a conceptual advance in sepsis: Septic megakaryocytes produce platelets with acutely altered mRNA profiles, and these platelets mediate lymphotoxicity via granzyme B. Given the contribution of lymphoid apoptosis to sepsis-related mortality, modulation of platelet granzyme B becomes an important new target for investigation and therapy.

Compound 8a (BMS-191011), an opener of the cloned large-conductance, Ca2+-activated potassium (maxi-K) channel, demonstrated efficacy in in vivo stroke models, which led to its nomination as a candidate for clinical evaluation. Its maxi-K channel opening properties were consistent with its structural topology, being derived by combining elements from other known maxi-K openers. However, 8a suffered from poor aqueous solubility, which complicated elucidation of SAR during in vitro evaluation. The activity of 8a in in vivo stroke models and studies directed toward improving its solubility are reported herein. Enhanced solubility was achieved by appending heterocycles to the 8a scaffold, and a notable observation was made that inclusion of a simple amino group (anilines 8k and 8l) yielded excellent in vitro maxi-K ion channel opening activity and enhanced brain-to-plasma partitioning compared to the appended heterocycles.

The clinical manifestations of inflicted traumatic brain injury in infancy most commonly result from intracranial hemorrhage, axonal stretch and disruption, and cerebral edema. Often hypoxia ischem...

O RIGINAL C ONTRIBUTION Relationship of Physician-identified Patient Race and Ethnicity to Use of Computed Tomography in Pediatric Blunt Torso Trauma JoAnne E. Natale, MD, PhD, Jill G. Joseph, MD, PhD, Alexander J. Rogers, MD, Michael Tunik, MD, David Monroe, MD, Benjamin Kerrey, MD, MS, Bema K. Bonsu, MD, Lawrence J. Cook, MStat, PhD, Kent Page, MStat, Kathleen Adelgais, MD, MPH, Kimberly Quayle, MD, Nathan Kuppermann, MD, MPH, and James F. Holmes, MD, MPH Abstract Objectives: The objective was to determine whether a child’s race or ethnicity as determined by the treating physician is independently associated with receiving abdominal computed tomography (CT) after blunt torso trauma. Methods: We performed a planned secondary analysis of a prospective observational cohort of children < 18 years old presenting within 24 hours of blunt torso trauma to 20 North American emergency departments (EDs) participating in a pediatric research network, 2007–2010. Treating physicians documented race/ethnicity as white non-Hispanic, black non-Hispanic, or Hispanic. Using a previously derived clinical prediction rule, we classified each child’s risk for having an intra-abdominal injury undergoing acute intervention to define injury severity. We performed multivariable analyses using generalized estimating equations to control for confounding and for clustering of children within hospitals. Results: Among 12,044 enrolled patients, treating physicians documented race/ethnicity as white non- Hispanic (n = 5,847, 54.0%), black non-Hispanic (n = 3,687, 34.1%), or Hispanic of any race (n = 1,291, 11.9%). Overall, 51.8% of white non-Hispanic, 32.7% of black non-Hispanic, and 44.2% of Hispanic children underwent abdominal CT imaging. After age, sex, abdominal ultrasound use, risk for intra- abdominal injury undergoing acute intervention, and hospital clustering were adjusted for, the likelihood of receiving an abdominal CT was lower (odds ratio [OR] = 0.8, 95% confidence interval [CI] = 0.7 to 0.9) for black non-Hispanic than for white non-Hispanic children. For Hispanic children, the likelihood of receiving an abdominal CT did not differ from that observed in white non-Hispanic children (OR = 0.9, 95% CI = 0.8 to 1.1). Conclusions: After blunt torso trauma, pediatric patients identified by the treating physicians as black non-Hispanic were less likely to receive abdominal CT imaging than those identified as white non- Hispanic. This suggests that nonclinical factors influence clinician decision-making regarding use of From the Department of Pediatrics (JEN, NK), the Betty Irene Moore School of Nursing (JGJ), and the Department of Emergency Medicine (NK, JFH), University of California at Davis, Sacramento, CA; the Departments of Emergency Medicine and Pediatrics, University of Michigan Medical Center and University of Michigan School of Medicine (AJR), Ann Arbor, MI; the Departments of Pediatrics and Emergency Medicine, New York University School of Medicine (MT), New York City, NY; Howard County General Hospital, Columbia (DM), MD; the Department of Pediatrics, Cincinnati Children’s Hospital, Cincinnati (BK), OH; the Department of Pediatrics, Nationwide Children’s Hospital (BKB), Columbus, OH; the Department of Pediatrics, University of California at San Diego (BKB), San Diego, CA; the University of Utah (LJC, KP), Salt Lake City, UT; the Department of Pediatrics and Emergency Medicine, University of Colorado (KA), Denver, CO; and the St. Louis Children’s Hospital, Washington University (KQ), St. Louis, MO. Participating centers and site investigators for the Pediatric Emergency Care Applied Research Network (PECARN) are listed in Appendix A. Received September 7, 2015; revision received December 2, 2015; accepted December 14, 2015. This work was presented in part at the Society for Academic Emergency Medicine Annual Meeting, Dallas, TX, May 2014. This work was supported by a grant from the Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, 1 R49CE00100201. The Pediatric Emergency Care Applied Research Network (PECARN) is supported by cooperative agreements U03MC00001, U03MC00003, U03MC00006, U03MC00007, U03MC00008, U03MC22684, and U03MC22685 from the EMSC program of the MCHB/HRSA. Supervising Editor: Jennifer D. H. Walthall, MD. Address for correspondence and reprints: JoAnne E. Natale, MD, PhD, FAAP; e-mail: jenatale@ucdavis.edu. ISSN 1069-6563 PII ISSN 1069-6563583 © 2016 by the Society for Academic Emergency Medicine doi: 10.1111/acem.12943

Microarray analysis of oligodendrocyte lineage cells purified by fluorescence-activated cell sorting (FACS) from 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP)–enhanced green fluorescent protein (EGFP) transgenic mice revealed Sox17 (SRY-box containing gene 17) gene expression to be coordinately regulated with that of four myelin genes during postnatal development. In CNP–EGFP-positive (CNP–EGFP+) cells, Sox17 mRNA and protein levels transiently increased between postnatal days 2 and 15, with white matter O4+preoligodendrocytes expressing greater Sox17 levels than Nkx2.2+(NK2 transcription factor related, locus 2) NG2+, or GalC+(galactocerebroside) cells. In spinal cord, Sox17 protein expression was undetectable in the primary motor neuron domain between embryonic days 12.5 and 15.5 but was evident in Nkx2.2+and CC1+cells. In cultured oligodendrocyte progenitor cells (OPCs), Sox17 levels were maximal in O4+cells and peaked during the phenotypic conversion from bipolar to multipolar. Parallel increases in Sox17 and p27 occurred before MBP protein expression, and Sox17 upregulation was prevented by conditions inhibiting differentiation. Sox17 downregulation with small interfering RNAs increased OPC proliferation and decreased lineage progression after mitogen withdrawal, whereas Sox17 overexpression in the presence of mitogen had opposite effects. Sox17 overexpression enhanced myelin gene expression in OPCs and directly stimulated MBP gene promoter activity. These findings support important roles for Sox17 in controlling both oligodendrocyte progenitor cell cycle exit and differentiation.

Clinical variability is common in inherited gene defects of the central nervous system in humans and in animal models of human disorders. Here, we used the homozygous spastic (spa) mutant mice, which resemble human hereditary hyperekplexia, to determine the molecular remodeling of the spinal cord through the course of the disease, and develop a model for clinical disparity between littermates. The spa mutation is an insertion of a LINE-1 element in the gene for the beta subunit of the glycine receptor, Glrb. The insertion causes aberrant splicing in the beta subunit of glycine receptor gene with a consequent important reduction of glycine receptors. At young ages, all homozygous spa animals were spastic, showed loss of glycine receptors, increased expression of vesicular glycine/GABA transporter and NMDA receptors, induction of activated caspase3, and preferential loss of glycinergic interneurons consistent with neurotransmitter toxicity model. Those littermates that recovered from symptoms showed strong over-expression of the glycine receptor alpha 1 subunit (Glra1), and increased myelination and synaptic plasticity. Littermates that showed a deteriorating clinical course failed to over-express Glra1, and also showed relative loss of gephyrin (receptor clustering). These molecular changes were associated with a preferential loss of GABAergic interneurons, and extensive motorneuron loss. These data suggest that functional recovery is likely due to expression of homomeric glycine receptors, rescue from excitotoxicity, and subsequent neuronal remodeling. We propose that human patients with hyperekplexia show remodeling similar to that of the recovering spa mice, as human patients also show a lessening of symptoms as a function of age.

Replacement of the morpholinyl moiety in (S,E)-N-[1-(3-morpholinophenyl)ethyl]-3-phenylacrylamide (1) with heteroaryl groups led to the identification of (S,E)-N-1-[3-(6-fluoropyridin-3-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (5) as a potent KCNQ2 potassium channel opener. Among this series of heteroaryl substituted acrylamides, (S,E)-N-1-[3-(1H-pyrazol-1-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (9) exhibits balanced potency and efficacy. The syntheses and the KCNQ2 opener activity of this series of acrylamides are described.

Both the immediate insult and delayed apoptosis contribute to functional deficits after brain injury. Secondary, delayed apoptotic death is more rapid in immature than in adult CNS neurons, suggesting the presence of age-dependent protective factors. To understand the molecular pathobiology of secondary injury in the context of brain development, we identified changes in expression of oxidative stress response genes during postnatal development and target deprivation-induced neurodegeneration. The antioxidants metallothionein I and II (MT I/II) were increased markedly in the thalamus of adult C57BL/6 mice compared to mice

Bioisosteric replacement studies led to the identification of N -(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide (( S )- 3 ) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)- N -[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide (( S )- 4 ), and N -[1-(2,3-dihydro-1 H -indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide (( S )- 5 ) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 μM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (±)- 3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds ( S )- 4 and ( S )- 5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.

Endocannabinoids, including 2-arachidonoylglycerol and anandamide ( N-arachidonoylethanolamine; AEA), have neuroprotective effects in the brain through actions at CB1 receptors. However, AEA also binds to vanilloid (VR1) receptors and induces cell death in several cell lines. Here we show that anandamide causes neuronal cell death in vitro and exacerbates cell loss caused by stretch-induced axonal injury or trophic withdrawal in rat primary neuronal cultures. Administered intracerebroventricularly, AEA causes sustained cerebral edema, as reflected by diffusion-weighted magnetic resonance imaging, regional cell loss, and impairment in long-term cognitive function. These effects are mediated, in part, through VR1 as well as through calpain-dependent mechanisms, but not through CB1 receptors or caspases. Central administration of AEA also significantly upregulates genes involved in proinflammatory/microglial-related responses. Thus, anandamide produces neurotoxic effects both in vitro and in vivo through multiple mechanisms independent of the CB1 receptor.

A new class of acrylamides was synthesized, and the effects of these analogues on outward potassium current were evaluated by using two electrode voltage clamp recordings from Xenopus laevis oocytes expressing cloned mKCNQ2 channels. SAR studies indicated that the pharmacophore of the acrylamide series includes the (S) absolute configuration at the (1-phenyl)ethyl moiety and the alpha,beta-unsaturated acrylamide functionality with a free NH. This study identified (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide ((S)-1) and (S)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-fluoro-phenyl)-acrylamide ((S)-2) as KCNQ2 openers for further electrophysiological evaluations. These two acrylamides demonstrated significant activity in the cortical spreading depression model of migraine as we reported previously.

(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-2) was identified as a potent and efficacious KCNQ2 opener. This compound demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices, and the inhibition mediated by (S)-2 was reversed by the KCNQ blocker linopirdine.

(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide (2) was synthesized as an orally bioavailable KCNQ2 potassium channel opener. In a rat model of migraine, 2 demonstrated significant oral activity in reducing the total number of cortical spreading depressions induced by potassium chloride.

Background: Ventilator-associated pneumonia (VAP), a leading cause of hospital acquired infection, increases morbidity, mortality and health care costs. Local problem: With a VAP rate at four times the National Healthcare Safety Network (NHSN) benchmark, the goal of this quality improvement project was to develop and implement a VAP prevention bundle to sustainably reduce VAP rate in a pediatric ICU to below NHSN benchmark over 5 years. Methods and interventions: Patient population included all patients …

In adults and children, head trauma can have long-term neuropathological and functional consequences. The thalamus is a major site of remote neurodegeneration after cortical damage in adult humans and experimental animals, but less is known about thalamic responses to cortical injury in the immature brain. This study introduces an in vivo model of axotomy/target deprivation-induced neuronal apoptosis in the dorsal lateral geniculate nucleus of the thalamus produced by unilateral ablation of the occipital cortex in the immature mouse. We specifically examined whether occipital cortex ablation in the immature brain causes apoptotic death of projection neurons in the dorsal lateral geniculate nucleus. After unilateral occipital cortex aspiration, 10-day-old C57BL/6 mice were recovered for up to 28 days. Fluorogold-prelabeled thalamocortical projection neurons were apoptotic at 36-48 h after ablation. The structural progression of apoptosis in the immature lateral geniculate nucleus reveals typical chromatolytic morphology by 18-24 h, followed by cytoplasmic shrinkage and chromatin condensation characteristic of end-stage apoptosis after 36-48 h. Electron microscopy confirmed the presence of apoptosis. This study shows internucleosomal DNA fragmentation and expression of cleaved caspase-3 occurs rapidly, being noted first at 18 h, well before the peak of apoptotic cell death occurring at 36 h after cortical damage in the immature brain. From these data we suggest that axotomy/target deprivation-induced cell death in the immature brain may: (1) differ from that previously reported in adult mice with respect to the time required for progression to cell death; (2) be mediated by caspase-3 activation.

A series of diphenyl-substituted heterocycles were synthesized and evaluated by electrophysiological techniques as openers of the cloned mammalian large-conductance, Ca(2+)-activated potassium (maxi-K) channel. The series was designed from deannulation of known benzimidazolone maxi-K opener NS-004 (2) thereby providing an effective template for obtaining structure-activity-related information. The triazolone ring system was the most studied wherein 4,5-diphenyltriazol-3-one 6d (maxi-K = 158%) was identified as the optimal maxi-K channel opener.

Super-refractory status epilepticus is a life-threatening condition. Resistance to benzodiazepine and barbiturate treatment for this disorder is thought to be due to internalization of synaptic γ-aminobutyric acid (GABA)A receptors, and withdrawal of benzodiazepines and barbiturates during treatment often triggers seizure recurrence. The neurosteroid allopregnanolone acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. Here we describe the use of allopregnanolone in 2 pediatric patients with super-refractory status epilepticus. This treatment allowed the general anesthetic infusions to be weaned with resolution of status epilepticus. This is the first report of allopregnanolone use to treat status epilepticus in children.

Letters The HVRN assembles home visiting stakeholders to set a na- tional research agenda, advance that agenda through innova- tion research methods, and translate research findings into policy and practice. 3 The HVRN identified the top 10 priorities for home visiting research with input from nearly 1800 individuals. 4 Now, the HVRN is building the Home Visiting Ap- plied Research Collaborative, a national practice-based re- search network of local home visiting programs to conduct field- initiated studies to address the research agenda’s priorities. We need to learn what works best for which families and under what circumstances and to translate this efficiently to policy and practice. The MIECHV Program’s state-level evalu- ative research, the Mother and Infant Home Visiting Program Evaluation, and the HVRN will substantially “clarify the evi- dence base” 1 related to home visiting investments to maxi- mize outcomes for children, families, and communities. Stake- holders are key participants in these efforts; they are eager to use results to ensure success in the adoption, adaptation, implementation, and sustainability of home visiting as part of the early childhood system of care and as part of efforts to pro- mote the foundations of health by enhancing the capacity of caregivers and communities. 5 Cynthia S. Minkovitz, MD, MPP Kay M. Gonsalves O’Neill, MSPH Anne K. Duggan, ScD Author Affiliations: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Corresponding Author: Cynthia S. Minkovitz, MD, MPP, Departments of Population, Family and Reproductive Health, and Pediatrics, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, E4636, Baltimore, MD 21205 (cminkovi@jhsph.edu). Conflict of Interest Disclosures: None reported. Funding/Support: Each of the authors is funded in part through home visiting research supported by grants or subcontracts as part of the Patient Protection and Affordable Care Act. Role of the Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Shonkoff JP. Changing the narrative for early childhood investment. JAMA Pediatr. 2014;168(2):105-106. 2. Michalpoulos C, Duggan A, Knox V, et al. ACF-OPRE Reports 2011-16: Design Options for the Home Visiting Evaluation: Draft Final Report. Washington, DC: US Dept of Health & Human Services; 2011. 3. Duggan A, Minkovitz CS, Chaffin M, et al. Creating a national home visiting research network. Pediatrics. 2013;132(suppl 2):S82-S89. 4. Home Visiting Research Network. Home visiting research agenda. http://www.hvrn.org/research-agenda.html. Accessed December 30, 2013. 5. Mistry KB, Minkovitz CS, Riley AW, et al. A new framework for childhood health promotion: the role of policies and programs in building capacity and foundations of early childhood health. Am J Public Health. 2012;102(9):1688-1696. Incorrect Classification in Articles About Traumatic Brain Injuries in Children With Minor Blunt Head Trauma To the Editor We are writing to make readers aware of an ana- lytic error that affected the data reported in 2 of our articles. 1,2 During recent preparation of another manuscript based on the same data, we discovered an error in construction of the final jamapediatrics.com analytic database for the entire cohort (an erroneous SQL [Structured Query Language] join statement) that led to the incorrect classification of the mechanism of injury as moder- ate, rather than severe, for 394 children in our cohort of 42 412 patients. Most of the erroneous classifications were among chil- dren aged 2 years or older. The first article affected by this erroneous classification was titled “Prevalence of Clinically Important Traumatic Brain In- juries in Children With Minor Blunt Head Trauma and Isolated Severe Injury Mechanisms.” 1 We have carefully examined the effects of this error on the entire published analysis. As previ- ously noted, the number of children with severe injury mecha- nism increased by 394, and the number of children with iso- lated severe injury mechanism increased from 3302 to 3630 as a result. These increased numbers led to numerous modifica- tions to data points in the article. However, the most impor- tant data points in the report are only slightly affected. The over- all incidence of severe injury mechanism increases by only a single percentage point in this population (from 14% to 15%) and the rates of clinically important traumatic brain injuries asso- ciated with isolated severe injury mechanism remain low, de- creasing by one-tenth of 1% among older children (from 0.6% to 0.5% for isolated severe mechanism and no other Pediatric Emergency Care Applied Research Network predictors and from 0.3% to 0.2% for isolated severe mechanism and no other pre- dictors in the expanded definition), with no change among younger children from the published report. The second article affected by the erroneous classifica- tion was titled “Cranial Computed Tomography Use Among Children With Minor Blunt Head Trauma: Association With Race/Ethnicity.” 2 Again, an erroneous SQL join statement led to the incorrect classification of the mechanism of injury as moderate, rather than severe, for 394 children in our cohort of 42 412 patients. This led to minor effects on the reported tabular data (Tables 1, 2, and 3), as well as minor differences in reported odds ratios/confidence intervals for association of black non-Hispanic or Hispanic race/ethnicity with cranial com- puted tomography in the emergency department (these data are reported in the abstract and the Results section of the text). We regret these errors but also believe unequivocally that the key findings and conclusions of the published papers firmly stand. The articles have been corrected and correction no- tices published. Nathan Kuppermann, MD, MPH JoAnne E. Natale, MD, PhD Lise E. Nigrovic, MD, MPH Author Affiliations: Department of Emergency Medicine, University of California, Davis School of Medicine, Sacramento (Kuppermann); Department of Pediatrics, University of California, Davis School of Medicine, Sacramento (Kuppermann, Natale); Division of Emergency Medicine, Boston Children’s Hospital, Boston, Massachusetts (Nigrovic). Corresponding Author: Nathan Kuppermann, MD, MPH, Departments of Emergency Medicine and Pediatrics, University of California, Davis Medical Center, 2315 Stockton Blvd, PSSB Bldg, Suite 2100, PSSB 2100, Sacramento, CA 95817 (nkuppermann@ucdavis.edu). Published Online: May 19, 2014. doi:10.1001/jamapediatrics.2014.651. Conflict of Interest Disclosures: None reported. JAMA Pediatrics June 2014 Volume 168, Number 6 Copyright 2014 American Medical Association. All rights reserved.

The mechanisms of injury-induced apoptosis of neurons within the CNS are not understood. We used a model of cortical injury in rat and mouse to induce retrograde neuronal apoptosis in thalamus. In this animal model, unilateral ablation of the occipital cortex causes unequivocal apoptosis of corticopetal projection neurons in the dorsal lateral geniculate nucleus (LGN) by 7 days postlesion. We tested the hypothesis that p53 and Bax regulate this retrograde neuronal apoptosis. We found, by using immunocytochemistry, that p53 accumulates in nuclei of neurons destined to undergo apoptosis. By immunoblotting, p53 levels increase (∼150% of control) in nuclear-enriched fractions of the ipsilateral LGN by 5 days after occipital cortex ablation. p53 is functionally activated in nuclear fractions of the ipsilateral LGN at 5 days postlesion, as shown by DNA binding assay (∼fourfold increase) and by immunodetection of phosphorylated p53. The levels of procaspase-3 increase at 4 days postlesion, and caspase-3 is activated prominently at 5 days postlesion. To identify whether neuronal apoptosis in the adult brain is dependent on p53 and Bax, cortical ablations were done on p53 and bax null mice. Neuronal apoptosis in the dorsal LGN is significantly attenuated (∼34%) in p53−/− mice. In lesioned p53+/+ mice, Bax immunostaining is enhanced in the ipsilateral dorsal LGN and Bax immunoreactivity accumulates at perinuclear locations in dorsal LGN neurons. The enhancement and redistribution of Bax immunostaining is attenuated in lesioned p53−/− mice. Neuronal apoptosis in the dorsal LGN is blocked completely in bax−/− mice. We conclude that neuronal apoptosis in the adult thalamus after cortical injury requires Bax and is modulated by p53. J. Comp. Neurol. 433:299–311, 2001. © 2001 Wiley-Liss, Inc.

a) To determine the risk factors for early hyperthermia after traumatic brain injury in children; b) to identify the contribution of early hyperthermia to neurologic status at pediatric intensive care unit (PICU) discharge and to PICU length of stay in head-injured children.Observational cohort study.PICU at a tertiary care, university medical center.Children (n = 117) admitted to a PICU from July 1995 to May 1997 with traumatic brain injury. These children had a median age of 5.4 yrs (3 wks to 15.2 yrs old), and 33.4% were girls.Early hyperthermia (temperature38.5 degrees C within the first 24 hrs of admission) occurred in 29.9% of patients admitted to the PICU with traumatic brain injury. Risk factors predicting early hyperthermia included Glasgow Coma Scale score in the emergency departmentor =8, pediatric trauma scoreor =8, cerebral edema or diffuse axonal injury on initial head computed tomography scan, admission blood glucose150 mg/dL (8.2 mmol/L), admission white cell count14,300 cells/mm3 (14.3 x 10(9) cells/L), and systolic hypotension. The presence of early hyperthermia significantly increased the risk for Glasgow Coma Scale score13 at PICU discharge (odds ratio [OR] 9.7, 95% confidence interval [CI] 2.8, 24.4) and PICU stayor =3 days (OR 13.8, CI 5.1, 37.5). When we used multiple logistic regression models including injury severity and hypotension, early hyperthermia remained an independent predictor of lower Glasgow Coma Scale score at PICU discharge (OR 4.7, CI 1.4, 15.6) and longer PICU length of stay (OR 8.5, CI 2.8, 25.6).Early hyperthermia is independently associated with a measure of early neurologic status and resource utilization in children with traumatic brain injury serious enough to require PICU admission. These results support the prevention of hyperthermia in the management of traumatic brain injury in children. Further research is required to understand the mechanisms of this response and to identify appropriate preventive or therapeutic interventions.