Pediatric liver transplant following near catastrophic head bleed: Lessons learned.

Evaluation for liver transplant candidacy is a multidisciplinary effort that involves all aspects of clinical care including social work, nutrition, and a multitude of medical specialties. The prognosis of a pretransplant clinical condition is integrated into the decision to list a patient. Herein, we report a successful liver transplant and recovery of a 3-month-old male following a large right hemispheric subdural hematoma related to acute coagulopathy secondary to undiagnosed end-stage liver disease. On presentation with jaundice, lethargy, and unequal pupils, a CT scan was obtained which demonstrated a large right subdural hematoma with herniation. Once his coagulopathy was corrected, he went for decompressive craniectomy. He survived with medically controlled seizures and improving L-sided neglect and extremity weakness. Six weeks later, given his continued neurologic recovery and worsening liver function, the decision was made to list him for liver transplantation. One month later, he underwent orthotopic liver transplant. His post-operative hospital course was complicated by DVTs and heparin-induced thrombocytopenia, but no neurologic decline, and he was eventually discharged from the hospital on post-op day 26. Three years later, he has a well-functioning allograft and no clinically evident neurologic deficits. The prognosis following pediatric neurologic trauma remains somewhat unclear as recovery and neurologic examinations can be influenced by numerous extrinsic factors. This is one of the first reports of near full neurologic recovery of a pediatric liver transplant recipient following a large subdural hematoma with herniation.

Eculizumab therapy for atypical haemolytic uraemic syndrome due to a gain-of-function mutation of complement factor B.

BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is caused by dysregulated complement activation. A humanised anti-C5 monoclonal antibody has recently become available for treatment of this condition CASE-DIAGNOSIS/TREATMENT: We present the first description of an infant with an activating mutation of complement factor B successfully treated with eculizumab. On standard doses she had evidence of ongoing C5 cleavage despite a good clinical response. CONCLUSIONS: Eculizumab is effective therapy for aHUS associated with factor B mutations, but recommended doses may not be adequate for all patients.

Community-Engaged Needs Assessment of Deaf American Sign Language Users in Florida, 2018.

OBJECTIVES: Deaf American Sign Language (ASL) users comprise a linguistic and cultural minority group that is understudied and underserved in health education and health care research. We examined differences in health risk behaviors, concerns, and access to health care among Deaf ASL users and hearing English speakers living in Florida. METHODS: We applied community-engaged research methods to develop and administer the first linguistically accessible and contextually tailored community health needs assessment to Deaf ASL users living in Florida. Deaf ASL users (n = 92) were recruited during a 3-month period in summer 2018 and compared with a subset of data on hearing English speakers from the 2018 Florida Behavioral Risk Factor Surveillance System (n = 12 589). We explored prevalence and adjusted odds of health behavior, including substance use and health care use. RESULTS: Mental health was the top health concern among Deaf participants; 15.5% of participants screened as likely having a depressive disorder. Deaf people were 1.8 times more likely than hearing people to engage in binge drinking during the past month. In addition, 37.2% of participants reported being denied an interpreter in a medical facility in the past 12 months. CONCLUSION: This study highlights the need to work with Deaf ASL users to develop context-specific health education and health promotion activities tailored to their linguistic and cultural needs and ensure that they receive accessible health care and health education.

Eosinophilic Granulomatosis With Polyangiitis: An Unusual Case of Pediatric Subglottic Stenosis.

Systemic disease is an uncommon cause of subglottic stenosis (SGS). We report a case of severe SGS due to underlying eosinophilic granulomatosis with polyangiitis (EGPA) in a child presenting with isolated stridor. EGPA is a rare systemic vasculitis with very limited cases reported in the pediatric population. While surgical intervention was required given the degree of stenosis in this case, medical management of the underlying systemic disease process is critical when there is clinical suspicion of SGS in the context of systemic vasculitis. Laryngoscope, 131:656-659, 2021.

Quality of Deaf and Hard-of-Hearing Mobile Apps: Evaluation Using the Mobile App Rating Scale (MARS) With Additional Criteria From a Content Expert.

BACKGROUND: The spread of technology and dissemination of knowledge across the World Wide Web has prompted the development of apps for American Sign Language (ASL) translation, interpretation, and syntax recognition. There is limited literature regarding the quality, effectiveness, and appropriateness of mobile health (mHealth) apps for the deaf and hard-of-hearing (DHOH) that pose to aid the DHOH in their everyday communication and activities. Other than the star-rating system with minimal comments regarding quality, the evaluation metrics used to rate mobile apps are commonly subjective. OBJECTIVE: This study aimed to evaluate the quality and effectiveness of DHOH apps using a standardized scale. In addition, it also aimed to identify content-specific criteria to improve the evaluation process by using a content expert, and to use the content expert to more accurately evaluate apps and features supporting the DHOH. METHODS: A list of potential apps for evaluation was generated after a preliminary screening for apps related to the DHOH. Inclusion and exclusion criteria were developed to refine the master list of apps. The study modified a standardized rating scale with additional content-specific criteria applicable to the DHOH population for app evaluation. This was accomplished by including a DHOH content expert in the design of content-specific criteria. RESULTS: The results indicate a clear distinction in Mobile App Rating Scale (MARS) scores among apps within the study's three app categories: ASL translators (highest score=3.72), speech-to-text (highest score=3.6), and hard-of-hearing assistants (highest score=3.90). Of the 217 apps obtained from the search criteria, 21 apps met the inclusion and exclusion criteria. Furthermore, the limited consideration for measures specific to the target population along with a high app turnover rate suggests opportunities for improved app effectiveness and evaluation. CONCLUSIONS: As more mHealth apps enter the market for the DHOH population, more criteria-based evaluation is needed to ensure the safety and appropriateness of the apps for the intended users. Evaluation of population-specific mHealth apps can benefit from content-specific measurement criteria developed by a content expert in the field.

Prep-Along Facilitated Posterior Crown Preparation in the Preclinical Dental Setting: A Multimedia Approach.

Introduction: Dental students often seek visual aids and demonstrations when attempting to perform new procedures. This video resource provides an adjunctive teaching tool for a crown preparation on an ivorine molar using the "prep-along" method. This method teaches crown preparation in a uniform, step-by-step manner while providing feedback to students after each step. Methods: Prior to the daily simulation clinic session, a calibration session was held for faculty. Following didactic instruction-including principles, criteria, and grading rubric-students participated in the laboratory portion of the course. During this laboratory portion, students viewed a segment of the video, the video was paused, and students attempted that portion of the preparation. The project continued in stages until it was completed. Upon completion, using an electronic grading system, each student performed a self-evaluation, the instructor then performed a blind evaluation, and both student and instructor compared assessments. Results: To obtain feedback, an electronic survey was sent to 285 third- and fourth-year dental students. Ninety-four students completed the survey; 94% responded favorably to this method of instruction. Individual comments were also predominantly positive. Discussion: Preclinical faculty at the Midwestern University College of Dental Medicine-Arizona use this prep-along for instruction of direct and indirect tooth preparations and restorations. Students participate in this step-by-step process while receiving feedback. Faculty are allowed a structured environment in which to give feedback and instruction at each segment of the preparation. The faculty found that this method of instruction created efficiency and excellence in training surgical hand skills.

The diagnostic role of triple endoscopy in pediatric patients with chronic cough.

OBJECTIVE/HYPOTHESIS: Multi-disciplinary aero-digestive centers provide high quality health care through improved outcomes and treatment costs over separate sub specialty clinics. These outcomes are often the result of a common investigative tool known as triple endoscopy: a rigid bronchoscopy performed by an otolaryngologist, flexible bronchoscopy and lavage obtained by a pulmonologist, and an endoscopy with guided biopsies performed by a gastroenterologist. Combining such procedures into one 'triple endoscopy' allows for diagnoses which otherwise might have been missed with just one procedure. The goal of our study was to describe the efficacy of the triple endoscopy procedure in diagnosing recalcitrant aero-digestive conditions, specifically chronic cough. STUDY DESIGN: Retrospective chart review METHODS: Multiple charts from children who underwent the triple endoscopy for chronic cough were retrospectively reviewed from 2005 and 2017. Complete data from the triple procedure was gathered on 243 patients, including findings by sub specialty (otolaryngology, pulmonology, and gastroenterology). RESULTS: Of the 243 patients with complete data who underwent triple endoscopy, 203 (83.5%) children had at least one positive finding. Of these children, 101 (41.5%) had one specialty specific diagnosis, and 102 (42%) had multiple cross specialty diagnoses. When describing the diagnoses, 63 children had gastro esophageal reflux (GER), 14 had eosinophilic esophagitis (EoE), 118 had tracheomalacia, 54 had laryngeal clefts, and 102 children had positive bronchoalveolar lavages. Outcome data was available on 226 patients (93%), of these patients, 188 patients had a diagnosis from the triple scope. Of those patients with a diagnosis and outcome data, 144 (76.6%) children had an improved outcome as a result of a treatment plan targeting that diagnosis, while 16 of the 37 patients without a diagnosis improved. This difference was significant by chi square analysis (p<0.0001). CONCLUSION: The triple scope procedure is a useful investigative tool for patients with recalcitrant aero-digestive complaints like chronic cough. In particular, triple scope can yield more than one specialty specific diagnosis, normally missed by one procedure. The triple scope also leads to improved parental satisfaction by improved cost and healthcare outcomes.

Assessment of the feeding Swallowing Impact Survey as a quality of life measure in children with laryngeal cleft before and after repair.

OBJECTIVE: To cross-validate the Feeding Swallowing Impact Survey (FSIS), a quality of life instrument, specifically to a subpopulation of children who aspirate due to laryngeal cleft. INTRODUCTION: The FSIS is a recently validated instrument used to describe caregiver quality of life (QOL) in children with aspiration due to various causes. To cross-validate the FSIS specifically to the subpopulation of children who aspirate due to laryngeal cleft, we tested the hypotheses that caregivers would report significant different scores form baseline if their children improved at the one year mark postintervention due to either successful conservative or surgical measures (discriminant validity) and would not report significant differences in their FSIS reporting if there was no change in their child's aspiration at the one year mark post intervention (convergent validity). METHODS: The FSIS was administered to the caregivers of 35 children (19 male, 16 female; age range: 5-79 months) who aspirate secondary to known laryngeal cleft (diagnosed by suspension laryngoscopy and inspection). All children had a baseline VFSS demonstrating aspiration and documenting what feeding plan to follow and caregivers completed the FSIS at this point as well. All children regardless of whether they were treated by conservative or surgical intervention underwent a follow-up VFSS at the one year post-intervention mark and the caregivers completed a FSIS at this time point as well. RESULTS: Among two distinct sub-populations of children who underwent either successful conservative or surgical treatment for their laryngeal cleft and demonstrated improvement at the one year mark (as defined by a VFSS documented decreased need for thickener by at least one consistency or more) and where we hypothesized that FSIS scores would not be significantly different, the caregivers reported no significant differences in FSIS scores cleft repair (mean FSIS scores 2.45 (SD 0.88)/2.1 (SD 0.94); p = 0.28). Moreover, as another test to convergent validity, for children who underwent either unsuccessful conservative treatment (and subsequently went on to need surgery) or who were not successfully surgically treated for their laryngeal cleft and demonstrated no significant improvement at the one year mark (as defined by a VFSS documented decreased need for thickener by at least one consistency or more), the caregivers reported no significant differences in FSIS scores cleft repair (mean FSIS scores 2.8(SD 0.79)/2.5(SD 0.88); p = 0.69). For divergent validity, two distinct sub-populations of children who underwent either successful or not successful surgical treatment for their laryngeal cleft (demonstrated by either improvement or lack of improvement at the one year mark VFSS as defined by a decreased need for thickener by at least one consistency or more) revealed significant differences in caregiver FSIS scores cleft repair (mean FSIS scores 1.38 (SD 0.32); 32.8 (SD 0.79); p=<0.0002). DISCUSSION: This results of this study provide convergent and divergent validity supporting the cross-validation of the FSIS instrument to be utilized as a validated QOL instrument to evaluate children with aspiration specifically due laryngeal cleft as another tool with which to evaluate the outcomes of medical or surgical interventions for this disorder.

Time-driven activity-based costing to estimate cost of care at multidisciplinary aerodigestive centers.

OBJECTIVES/HYPOTHESIS: Providing high-value healthcare to patients is increasingly becoming an objective for providers including those at multidisciplinary aerodigestive centers. Measuring value has two components: 1) identify relevant health outcomes and 2) determine relevant treatment costs. Via their inherent structure, multidisciplinary care units consolidate care for complex patients. However, their potential impact on decreasing healthcare costs is less clear. The goal of this study was to estimate the potential cost savings of treating patients with laryngeal clefts at multidisciplinary aerodigestive centers. STUDY DESIGN: Retrospective chart review. METHODS: Time-driven activity-based costing was used to estimate the cost of care for patients with laryngeal cleft seen between 2008 and 2013 at the Massachusetts Eye and Ear Infirmary Pediatric Aerodigestive Center. Retrospective chart review was performed to identify clinic utilization by patients as well as patient diet outcomes after treatment. Patients were stratified into neurologically complex and neurologically noncomplex groups. RESULTS: The cost of care for patients requiring surgical intervention was five and three times as expensive of the cost of care for patients not requiring surgery for neurologically noncomplex and complex patients, respectively. Following treatment, 50% and 55% of complex and noncomplex patients returned to normal diet, whereas 83% and 87% of patients experienced improved diets, respectively. Additionally, multidisciplinary team-based care for children with laryngeal clefts potentially achieves 20% to 40% cost savings. CONCLUSIONS: These findings demonstrate how time-driven activity-based costing can be used to estimate and compare patient costs in multidisciplinary aerodigestive centers. LEVEL OF EVIDENCE: 2c. Laryngoscope, 127:2152-2158, 2017.

Inhibition of prenylated KRAS in a lipid environment.

RAS mutations lead to a constitutively active oncogenic protein that signals through multiple effector pathways. In this chemical biology study, we describe a novel coupled biochemical assay that measures activation of the effector BRAF by prenylated KRASG12V in a lipid-dependent manner. Using this assay, we discovered compounds that block biochemical and cellular functions of KRASG12V with low single-digit micromolar potency. We characterized the structural basis for inhibition using NMR methods and showed that the compounds stabilized the inactive conformation of KRASG12V. Determination of the biophysical affinity of binding using biolayer interferometry demonstrated that the potency of inhibition matches the affinity of binding only when KRAS is in its native state, namely post-translationally modified and in a lipid environment. The assays we describe here provide a first-time alignment across biochemical, biophysical, and cellular KRAS assays through incorporation of key physiological factors regulating RAS biology, namely a negatively charged lipid environment and prenylation, into the in vitro assays. These assays and the ligands we discovered are valuable tools for further study of KRAS inhibition and drug discovery.

Type 1 laryngeal cleft: establishing a functional diagnostic and management algorithm.

OBJECTIVES: To report our experience with all patients diagnosed with type 1 laryngeal cleft over a period of 3 years in our referral practice and to describe a functional diagnostic and management algorithm for children with this disorder. METHODS: A prospective longitudinal study in a tertiary care referral center. Twenty pediatric patients diagnosed with type 1 laryngeal cleft in a 3-year period (5/1/2002-5/1/2005) were included in this study. The incidence, presenting symptoms, diagnostic procedures, medical and surgical interventions performed, and clinical outcomes were evaluated. RESULTS: The incidence of type 1 laryngeal cleft was 7.6%. Among the 20 patients in this study, aspiration with thin liquids was the most common presenting symptom (18 patients, 90%). Three patients underwent modified barium swallow (MBS) alone, 3 patients underwent functional endoscopic evaluation of swallow (FEES) alone, and 11 patients underwent both MBS and FEES prior to intraoperative endoscopic evaluation. Four patients (20%) were successfully treated with conservative therapy. Sixteen patients (80%) required endoscopic surgical repair after failing a course of conservative measures. The success rate of surgical repair was 94% (15 out of 16 patients). CONCLUSIONS: Type 1 laryngeal cleft can be challenging diagnostically. We propose a functional diagnostic and management algorithm that includes MBS, FEES, suspension laryngoscopy with bimanual interarytenoid palpation, and a trial of conservative therapy, as a way to diagnose and manage type 1 laryngeal cleft prior to consideration of surgical repair. If conservative therapy fails, then surgical intervention is indicated.

RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation.

ATP competitive inhibitors of the BRAF(V600E) oncogene paradoxically activate downstream signaling in cells bearing wild-type BRAF (BRAF(WT)). In this study, we investigate the biochemical mechanism of wild-type RAF (RAF(WT)) activation by multiple catalytic inhibitors using kinetic analysis of purified BRAF(V600E) and RAF(WT) enzymes. We show that activation of RAF(WT) is ATP dependent and directly linked to RAF kinase activity. These data support a mechanism involving inhibitory autophosphorylation of RAF's phosphate-binding loop that, when disrupted either through pharmacologic or genetic alterations, results in activation of RAF and the mitogen-activated protein kinase (MAPK) pathway. This mechanism accounts not only for compound-mediated activation of the MAPK pathway in BRAF(WT) cells but also offers a biochemical mechanism for BRAF oncogenesis.

Eosinophilic esophagitis in children: a pathologic or clinicopathologic diagnosis?

OBJECTIVE: To determine the accuracy of histopathologic diagnosis in distinguishing eosinophilic esophagitis (EE) from gastroesophageal reflux disease (GERD) in children with upper aerodigestive symptoms. DESIGN: Masked review of esophageal biopsy findings and comparison with each child's established clinical diagnosis. SETTING: A tertiary care multidisciplinary aerodigestive center. PATIENTS: Children were selected from a longitudinal database of all children referred for upper aerodigestive symptoms who underwent a comprehensive evaluation between September 1, 2004, and September 1, 2007. Three groups were recognized based on clinical presentation, initial histologic review, and therapeutic response: children with EE, GERD, or neither. INTERVENTION: Review of esophageal biopsy findings by a pathologist masked to the child's clinical or previous pathologic diagnosis. MAIN OUTCOME MEASURE: Masked histopathologic diagnosis of EE, GERD, or neither. RESULTS: Medical records from 31 patients were reviewed (11 children with EE, 10 with GERD, and 10 with neither). Diagnostic concurrence between the masked pathologic diagnosis and the established clinicopathologic diagnosis was 64% in children with EE, 70% in children with GERD, and 100% in children with neither. The 4 cases of EE that did not concur were misclassified as GERD when esophageal specimens were evaluated by histopathologic means alone. A clinicopathologic schema for EE developed by gastroenterologists accurately identified 82% of children with EE. CONCLUSIONS: The distinction between EE and GERD cannot be reliably made on histopathologic evidence alone in children with upper aerodigestive symptoms. Despite the recent gastroenterology consensus statement regarding the clinicopathologic diagnosis of EE, children with primary airway symptoms in whom EE is suspected represent a diagnostic dilemma.

Fragmented tissue factor pathway inhibitor (TFPI) and TFPI C-terminal peptides eliminate serum-resistant Escherichia coli from blood cultures.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) is a major regulator of blood clotting. Receipt of recombinant TFPI (rTFPI) protected animals from death in Escherichia coli-induced severe sepsis models and is under evaluation in a phase III clinical trial involving patients with severe community-acquired pneumonia. Because the mechanism of action of rTFPI in acute bacterial infection is not well understood, we sought to identify and map rTFPI peptides that have antimicrobial activity against E. coli. METHODS: Fragmented rTFPI and C-terminal TFPI peptide activities against pathogenic E. coli strains were measured in ex vivo blood cultures and in serum. RESULTS: The C-terminal peptides exhibited complement-dependent antibacterial activity and directly interacted with the bacterial cell surface of E. coli. Both complement-mediated killing and cell-surface binding were reversed by low amounts of heparin. CONCLUSIONS: Our investigation revealed a previously unidentified mechanism of antibacterial activity for TFPI. C-terminal rTFPI fragments kill serum-resistant E. coli though the complement pathway of the innate immune system, suggesting a multimodal mechanism of action of rTFPI that may assist in reducing mortality in animal models of severe sepsis and contribute to therapeutic effectiveness.

Morphological Stability of a Cylinder.

The stability of the shape of a solid cylinder crystallizing in a supercooled liquid is treated. The effects of solute diffusion, slightly anisotropic surface tension and interface kinetics are included. The resulting stability equations are applied to the specific case of ice cylinders.

Heat shock protein and high-dose aspirin: effects on random skin flap survival in a rat model.

The heat shock response is known to have a protective effect against flap ischemia. It has been shown that heat shock protein (hsp) expression can be augmented in vivo with the administration of high-dose aspirin before heat treatment. The authors hypothesized that administration of aspirin before hsp induction through heat stress would enhance further the protective effects of the heat shock response against skin flap ischemia. They used a random dorsal skin flap model in 32 rats divided into four groups (N = 8 each): control, heat shock, aspirin plus heat shock, and aspirin. Before surgery, rats in the two heat shock groups were placed in a 45 degrees C water bath until core body temperature measured 42 degrees C, and they were maintained at 42 degrees C for 15 minutes. Rats in the two aspirin groups received a single oral dose of aspirin (100 mg per kilogram) 1 hour before heat bath or surgery. Immunohistochemistry confirmed hsp expression in the two heat groups. Skin flap survival was improved significantly (p < 0.05) in the heat shock (55%), aspirin plus heat shock (58%), and aspirin (60%) groups when compared with controls (45%). Contrary to their hypothesis, aspirin combined with hsp induction did not offer greater protection from ischemia than hsp induction alone (p > 0.05). However, high-dose aspirin administration alone did improve skin flap survival when compared with controls. Future studies are needed to investigate further the role of pharmacological therapy combined with hsp induction in improving skin flap survival and to delineate the dose-response relationship between aspirin and hsp.