Longer upper airway lengths in Robin Sequence: A case-control study using computed tomography.

BACKGROUND: Direct laryngoscopy and intubation are often difficult in children with Robin Sequence. Previous research characterizing anatomic airway differences has focused on parameters influencing airway patency; there is a paucity of data pertaining to intubation trajectories and depth. Such information could impact airway management approaches and decrease the incidence of endotracheal tube malpositioning. AIM: The study goal was to examine whether longitudinal airway parameters pertaining to intubation are different in children with Robin Sequence compared with age-matched controls. METHOD: This case-control study compared patients with RS <4 years of age who had computed tomography scans of the head and neck to age- and sex-matched controls. Measurements were made of the nasopharynx, oropharynx, hypopharynx, tongue, hyoid, and the front teeth to vocal cord, nares to vocal cord, and nasion-basion distances. Statistical analysis was performed using multiple ANCOVA models with the categorical predictor of Robin Sequence vs control and potential covariates including subject height/length, weight, and age. RESULTS: Thirty-three patients with Robin Sequence and 33 control subjects were included. After controlling for subject height/length, mean front teeth to vocal cord distance was 1.2 cm longer (95% CI: 0.9 to 1.6 cm, P < .001) and mean nares to vocal cord distance was 0.8 cm longer (95% CI: 0.4 to 1.2 cm, P < .001) in patients with Robin Sequence than in controls. The tongue was positioned on average 0.5 cm higher (95% CI: 0.3 to 0.8, P < .001) and 0.9 cm more posterior (95% CI: 0.6 to 1.0 cm, P < .001) in cases than in controls. Moreover, in patients with Robin Sequence, the hyoid was positioned on average 0.5 cm more inferiorly (95% CI: 0.2 to 0.8 cm, P < .001) and 0.2 cm more posteriorly (95% CI: 0.1 to 0.4 cm, P < .01) than controls. CONCLUSION: In patients with Robin Sequence under 4 years of age, the mean front teeth to vocal cord distance was found to be 1.2 cm longer while the mean nares to vocal cord distance was found to be 0.8 cm longer controlling for subject length. Clinicians should account for these differences when selecting and placing endotracheal tubes, particularly those with a preformed bend.

Enrollment challenges in multicenter, international studies: The example of the GAS trial.

INTRODUCTION: Randomized trials are important for generating high-quality evidence, but are perceived as difficult to perform in the pediatric population. Thus far there has been poor characterization of the barriers to conducting trials involving children, and the variation in these barriers between countries remains undescribed. The General Anesthesia compared to Spinal anesthesia (GAS) trial, conducted in seven countries between 2007 and 2013, provides an opportunity to explore these issues. METHODS: We undertook a descriptive analysis to evaluate the reasons for variation in enrollment between countries in the GAS trial, looking specifically at the number of potential subjects screened, and the subsequent application of four exclusion criteria that were applied in a hierarchical order. RESULTS: A total of 4023 patients were screened by 28 centers in seven countries. Australia and the USA screened the most subjects, accounting for 84% of all potential trial participants. The percentage of subjects eliminated from the screened pool by each exclusion criterion varied between countries. Exclusion due to a predefined condition (H1) eliminated only 5% of potential subjects in Italy and the UK, but 37% in Canada. Exclusions due to a contraindication or a physician's refusal most impacted enrollment in Australia and the USA. The patient being "too large for spinal anesthesia" was the most commonly cited by anesthetists who refused to enroll a patient (64% of anesthetist refusals). The majority of surgeon refusals came from the USA, where surgeons preferred the patient to receive a general anesthetic. The percentage of approached parents refusing to consent ranged from a low of 3% in Italy to a high of 70% in the USA and Netherlands. The most frequently cited reason for parent refusal in all countries was a preference for general anesthesia (median: 43%, range: 32%-67%). However, a sizeable proportion of parents in all countries had a contrasting preference for spinal anesthesia (median: 25%, range: 13%-31%), and 23% of U.S. parents expressed concern about randomization. CONCLUSION: The GAS trial highlights enrollment challenges that can occur when conducting multicenter, international, pediatric studies. Investigators planning future trials should be aware of potential differences in screening processes across countries, and that exclusions by anesthetists and surgeons may vary in reason, in frequency, and by country. Furthermore, investigators should be aware that the U.S. centers encountered particularly high surgeon and parental refusal rates and that U.S. parents were uniquely concerned about randomization. Planning trials that address these difficulties should increase the likelihood of successfully recruiting subjects in pediatric trials.

Endoscopic Versus Open Repair for Craniosynostosis in Infants Using Propensity Score Matching to Compare Outcomes: A Multicenter Study from the Pediatric Craniofacial Collaborative Group.

BACKGROUND: The North American Pediatric Craniofacial Collaborative Group (PCCG) established the Pediatric Craniofacial Surgery Perioperative Registry to evaluate outcomes in infants and children undergoing craniosynostosis repair. The goal of this multicenter study was to utilize this registry to assess differences in blood utilization, intensive care unit (ICU) utilization, duration of hospitalization, and perioperative complications between endoscopic-assisted (ESC) and open repair in infants with craniosynostosis. We hypothesized that advantages of ESC from single-center studies would be validated based on combined data from a large multicenter registry. METHODS: Thirty-one institutions contributed data from June 2012 to September 2015. We analyzed 1382 infants younger than 12 months undergoing open (anterior and/or posterior cranial vault reconstruction, modified-Pi procedure, or strip craniectomy) or endoscopic craniectomy. The primary outcomes included transfusion data, ICU utilization, hospital length of stay, and perioperative complications; secondary outcomes included anesthesia and surgical duration. Comparison of unmatched groups (ESC: N = 311, open repair: N = 1071) and propensity score 2:1 matched groups (ESC: N = 311, open repair: N = 622) were performed by conditional logistic regression analysis. RESULTS: Imbalances in baseline age and weight are inherent due to surgical selection criteria for ESC. Quality of propensity score matching in balancing age and weight between ESC and open groups was assessed by quintiles of the propensity scores. Analysis of matched groups confirmed significantly reduced utilization of blood (26% vs 81%, P < .001) and coagulation (3% vs 16%, P < .001) products in the ESC group compared to the open group. Median blood donor exposure (0 vs 1), anesthesia (168 vs 248 minutes) and surgical duration (70 vs 130 minutes), days in ICU (0 vs 2), and hospital length of stay (2 vs 4) were all significantly lower in the ESC group (all P < .001). Median volume of red blood cell administered was significantly lower in ESC (19.6 vs 26.9 mL/kg, P = .035), with a difference of approximately 7 mL/kg less for the ESC (95% confidence interval for the difference, 3-12 mL/kg), whereas the median volume of coagulation products was not significantly different between the 2 groups (21.2 vs 24.6 mL/kg, P = .73). Incidence of complications including hypotension requiring treatment with vasoactive agents (3% vs 4%), venous air embolism (1%), and hypothermia, defined as <35°C (22% vs 26%), was similar between the 2 groups, whereas postoperative intubation was significantly higher in the open group (2% vs 10%, P < .001). CONCLUSIONS: This multicenter study of ESC versus open craniosynostosis repair represents the largest comparison to date. It demonstrates striking advantages of ESC for young infants that may result in improved clinical outcomes, as well as increased safety.

A Minimal Functional Complex of Cytochrome P450 and FBD of Cytochrome P450 Reductase in Nanodiscs.

Structural interactions that enable electron transfer to cytochrome-P450 (CYP450) from its redox partner CYP450-reductase (CPR) are a vital prerequisite for its catalytic mechanism. The first structural model for the membrane-bound functional complex to reveal interactions between the full-length CYP450 and a minimal domain of CPR is now reported. The results suggest that anchorage of the proteins in a lipid bilayer is a minimal requirement for CYP450 catalytic function. Akin to cytochrome-b5 (cyt-b5 ), Arg 125 on the C-helix of CYP450s is found to be important for effective electron transfer, thus supporting the competitive behavior of redox partners for CYP450s. A general approach is presented to study protein-protein interactions combining the use of nanodiscs with NMR spectroscopy and SAXS. Linking structural details to the mechanism will help unravel the xenobiotic metabolism of diverse microsomal CYP450s in their native environment and facilitate the design of new drug entities.

Perioperative Outcomes and Management in Pediatric Complex Cranial Vault Reconstruction: A Multicenter Study from the Pediatric Craniofacial Collaborative Group.

BACKGROUND: The Pediatric Craniofacial Collaborative Group established the Pediatric Craniofacial Surgery Perioperative Registry to elucidate practices and outcomes in children with craniosynostosis undergoing complex cranial vault reconstruction and inform quality improvement efforts. The aim of this study is to determine perioperative management, outcomes, and complications in children undergoing complex cranial vault reconstruction across North America and to delineate salient features of current practices. METHODS: Thirty-one institutions contributed data from June 2012 to September 2015. Data extracted included demographics, perioperative management, length of stay, laboratory results, and blood management techniques employed. Complications and outlier events were described. Outcomes analyzed included total blood donor exposures, intraoperative and perioperative transfusion volumes, and length of stay outcomes. RESULTS: One thousand two hundred twenty-three cases were analyzed: 935 children aged less than or equal to 24 months and 288 children aged more than 24 months. Ninety-five percent of children aged less than or equal to 24 months and 79% of children aged more than 24 months received at least one transfusion. There were no deaths. Notable complications included cardiac arrest, postoperative seizures, unplanned postoperative mechanical ventilation, large-volume transfusion, and unplanned second surgeries. Utilization of blood conservation techniques was highly variable. CONCLUSIONS: The authors present a comprehensive description of perioperative management, outcomes, and complications from a large group of North American children undergoing complex cranial vault reconstruction. Transfusion remains the rule for the vast majority of patients. The occurrence of numerous significant complications together with large variability in perioperative management and outcomes suggest targets for improvement.

Informed consent in pediatric anesthesiology.

BACKGROUND: Informed consent for pediatric anesthesia is unique because it is (1) obtained from surrogates (ie, parents) rather than from the patient and (2) sought after parents have authorized the surgical intervention. There are limited data on how pediatric anesthesia informed and consent discussions are conducted. The purpose of this study was to characterize the content of preanesthesia informed consent discussions and assess their impact on parent recall and understanding. METHODS: We conducted a cross-sectional observational study at a tertiary pediatric hospital. We audio-recorded and transcribed preanesthesia consent discussions between pediatric anesthesia providers and parents of children undergoing elective surgery. Parents were recruited on the day of surgery and completed a survey postdiscussion to assess their recall and perceived understanding. We used directed content analysis to identify 7 informed consent elements: (i) description of the plan; mention of (ii) alternatives, (iii) risks, and (iv) benefits; (v) discussion of uncertainties; (vi) assessment of comprehension; and (vii) solicitation of a decision. We used multivariable logistic regression to explore the association between discussions that included 3 informed consent elements (description of plan, mention of risks, and mention of benefits) and parent recall and understanding of these elements. RESULTS: We analyzed 97 discussions involving 41 different anesthesia providers. The element most frequently included in preanesthesia discussions was a description of the plan (100%); the least frequently included was decision solicitation (18%). Seventy-one percent of discussions included ≥5 informed consent elements and 70% included a description of the plan, mention of risks, and mention of benefits. Parental recall of these 3 informed consent elements was associated with their inclusion in the preanesthesia discussion (75% vs 34%), and more parents understood all 3 elements if they had reported (vs not reported) recall of all 3 elements (97% vs 53%). CONCLUSION: Most pediatric preanesthesia discussions include ≥5 informed consent elements and describe the plan, mention risks, and mention benefits. Inclusion of these latter 3 consent elements was associated with parental recall of these elements but not understanding.

Stabilization of α-Synuclein Fibril Clusters Prevents Fragmentation and Reduces Seeding Activity and Toxicity.

Protein misfolding results in the accumulation of aggregated ß-sheet-rich structures in Parkinson's disease (PD) and Alzheimer's disease. The toxic oligomer hypothesis stipulates that prefibrillar assemblies, such as soluble oligomers or protofibrils, are responsible for the poor prognosis of these diseases. Previous studies demonstrated that a small molecule related to the natural compound orcein, O4, directly binds to amyloid-ß fibrils and stabilizes them, accelerating the formation of end-stage mature fibrils. Here we demonstrate a similar phenomenon during O4 treatment of α-synuclein (αsyn) aggregates, the protein responsible for PD pathology. While the drug did not change the kinetics of aggregate formation as measured by the amyloidophilic dye thioflavin T, O4 depleted αsyn oligomers and promoted the formation of sodium dodecyl sulfate and proteinase K resistant aggregates consisting of large fibril clusters. These fibril clusters exhibited reduced toxicity to human neuronal model cells and reduced seeding activity in vitro. The effectiveness of O4 decreased when it was added at later points in the αsyn aggregation pathway, which suggests that the incorporation of O4 into fibril assemblies stabilizes them against chemical, enzymatic, and mechanic degradation. These findings suggest that small molecules, which stabilize amyloid fibrils, can prevent fibril fragmentation and seeding and consequently prevent prion-like replication of misfolded αsyn. Inhibiting prion replication by fibril stabilization could thus be a therapeutic strategy for PD.

Esophageal Bronchus-the Hidden Link. A Case Report.

An esophageal bronchus is a subtype of congenital bronchopulmonary foregut malformations in which a lobar bronchus arises directly from the esophagus, creating a communication between the esophagus and lung tissue. Early diagnosis is crucial to prevent worsening pulmonary sequelae but is challenging due to the rarity of the anomaly and nonspecific respiratory symptoms. We present a child whose esophageal bronchus was identified incidentally during preanesthetic assessment for craniosynostosis repair and discuss the role an anesthesiologist can play in identifying and managing this diagnosis.

Early developmental exposure to volatile anesthetics causes behavioral defects in Caenorhabditis elegans.

BACKGROUND: Mounting evidence from animal studies shows that anesthetic exposure in early life leads to apoptosis in the developing nervous system. This loss of neurons has functional consequences in adulthood. Clinical retrospective reviews have suggested that multiple anesthetic exposures in early childhood are associated with learning disabilities later in life as well. Despite much concern about this phenomenon, little is known about the mechanism by which anesthetics initiate neuronal cell death. Caenorhabditis elegans, a powerful genetic animal model, with precisely characterized neural development and cell death pathways, affords an excellent opportunity to study anesthetic-induced neurotoxicity. We hypothesized that exposing the nematode to volatile anesthetics early in life would induce neuron cell death, producing a behavioral defect that would be manifested in adulthood. METHODS: After synchronization and hatching, larval worms were exposed to volatile anesthetics at their 95% effective concentration for 4 hours. On day 4 of life, exposed and control worms were tested for their ability to sense and move to an attractant (i.e., to chemotax). We determined the rate of successful chemotaxis using a standardized chemotaxis index. RESULTS: Wild-type nematodes demonstrated striking deficits in chemotaxis indices after exposure to isoflurane (ISO) or sevoflurane (SEVO) in the first larval stage (chemotaxis index: untreated, 85 ± 2; ISO, 52 ± 2; SEVO, 47 ± 2; P < 0.05 for both exposures). The mitochondrial mutant gas-1 had a heightened effect from the anesthetic exposure (chemotaxis index: untreated, 71 ± 2; ISO, 29 ± 12; SEVO, 24 ± 13; P < 0.05 for both exposures). In contrast, animals unable to undergo apoptosis because of a mutation in the pathway that mediates programmed cell death (ced-3) retained their ability to sense and move toward an attractant (chemotaxis index: untreated, 76 ± 10; ISO, 73 ± 9; SEVO, 76 ± 10). Furthermore, we discovered that the window of greatest susceptibility to anesthetic neurotoxicity in nematodes occurs in the first larval stage after hatching (L1). This coincides with a period of neurogenesis in this model. All values are means ± SD. CONCLUSION: These data indicate that anesthetics affect neurobehavior in nematodes, extending the range of phyla in which early exposure to volatile anesthetics has been shown to cause functional neurological deficits. This implies that anesthetic-induced neurotoxicity occurs via an ancient underlying mechanism. C elegans is a tractable model organism with which to survey an entire genome for molecules that mediate the toxic effects of volatile anesthetics on the developing nervous system.

Acupuncture therapy for infants: a preliminary report on reasons for consultation, feasibility, and tolerability.

OBJECTIVES/AIMS: The aim of this retrospective review was to determine the feasibility, safety, and potential therapeutic effects of acupuncture in an inpatient infant population and to obtain data that would support the design of a randomized, controlled trial of acupuncture in infants. BACKGROUND: Hospitalized infants are often exposed to sedative and analgesic medications to facilitate intensive and invasive medical care. With increasing concern about the potential neurotoxic effects of common analgesic and sedative medications, minimizing an infant's exposure to such agents is desirable. Acupuncture can be therapeutic in adults and children, but data in infants are lacking. METHODS/MATERIALS: We performed a retrospective chart review of infants who received acupuncture during hospitalizations between 2008 and 2010. Demographic data, diagnoses, reason for acupuncture consult, ventilator settings, sedative/analgesic medication regimens, details of acupuncture therapy, and adverse effects were among data collected. RESULTS: Ten infants were identified in this review, seven of whom had agitation issues, two of whom had feeding difficulties, and one had both symptoms. Six of the eight infants with agitation had a decrease in the use of sedative and analgesic medications over the acupuncture therapy period, and four of five initially requiring mechanical ventilation were successfully weaned. One of the three infants with oral aversion transitioned rapidly to oral intake. Acupuncture therapy was well tolerated, and there were no complications observed. CONCLUSIONS: In this small group of hospitalized infants, acupuncture was found to be safe, well tolerated, and therapeutic. More studies are warranted to define the role of acupuncture in this population.

Bioacoustics in cognitive research: Applications, considerations, and recommendations.

The multifaceted ability to produce, transmit, receive, and respond to acoustic signals is widespread in animals and forms the basis of the interdisciplinary science of bioacoustics. Bioacoustics research methods, including sound recording and playback experiments, are applicable in cognitive research that centers around the processing of information from the acoustic environment. We provide an overview of bioacoustics techniques in the context of cognitive studies and make the case for the importance of bioacoustics in the study of cognition by outlining some of the major cognitive processes in which acoustic signals are involved. We also describe key considerations associated with the recording of sound and its use in cognitive applications. Based on these considerations, we provide a set of recommendations for best practices in the recording and use of acoustic signals in cognitive studies. Our aim is to demonstrate that acoustic recordings and stimuli are valuable tools for cognitive researchers when used appropriately. In doing so, we hope to stimulate opportunities for innovative cognitive research that incorporates robust recording protocols. This article is categorized under: Neuroscience > Cognition Psychology > Theory and Methods Neuroscience > Behavior Neuroscience > Cognition.

Noise-induced vocal plasticity in urban white-crowned sparrows does not involve adjustment of trill performance components.

Background noise can interfere with acoustic communication and subsequently influence signaling behavior. Immediate signaling flexibility (ISF) is a context-dependent form of behavioral plasticity that allows animals to temporarily change their acoustic behavior in response to noise fluctuations and potentially improve the chances of successful communication in noisy environments. The adaptive value of ISF is ultimately contingent on the response of the intended receiver, and there are differential effects on receiver response depending on which signal component is modified. However, there is scant research on whether ISF involves modification of a signal component specifically linked to mate attraction or territory defense. Our study addresses this knowledge gap and provides important insight into whether males employ short-term signal modification in a manner that could affect mate pairing success in birds. Specifically, we explore the maladaptive potential of ISF in the San Francisco, California population of Zonotrichia leucophrys nuttalli by testing for changes in trill bandwidth and rate-the specific trill structure components known to influence the receiver's perception of vocal performance in this species-before and during noise broadcast experiments. Although Zonotrichia leucophrys nuttalli are capable of ISF, we found no evidence that noise induces temporary adjustment of the trill structure traits used by receivers to assess vocal performance.

Probing protein-protein and protein-substrate interactions in the dynamic membrane-associated ternary complex of cytochromes P450, b5, and reductase.

Cytochrome P450 (cytP450) interacts with two redox partners, cytP450 reductase and cytochrome-b5, to metabolize substrates. Using NMR, we reveal changes in the dynamic interplay when all three proteins are incorporated into lipid nanodiscs in the absence and presence of substrates.