Advanced Therapies for Severe Tracheobronchomalacia: A Review of the Use of 3D-Printed, Patient-Specific, Externally Implanted, Bioresorbable Airway Splints.

Tracheobronchomalacia is a condition of dynamic collapse of the trachea and mainstem bronchi. The clinical significance of tracheobronchomalacia depends on its severity. Mild cases may be medically managed with limited symptomology, while severe cases require advanced therapies, lengthy hospital stays, and carry significant morbidity and mortality. Current therapies for severe tracheobronchomalacia include tracheostomy with prolonged mechanical ventilation, aortopexy, tracheobronchopexy, and intraluminal metallic, silicone, or bioresorbable stents. Three-dimensional (3D)-printed, patient-specific, bioresorbable airway splinting is a novel treatment option that is undergoing investigation in a cohort of critically ill children with severe tracheobronchomalacia. At the time of our last review of our data, 29 splints had been implanted in 15 children with intrathoracic tracheobronchomalacia. The median follow-up was 8.5 months. There were 12 long-term survivors, and all but one lived at home. This article discusses the details of our institution's development and use of 3D-printed, patient-specific, bioresorbable splints for treatment of severe tracheobronchomalacia in the pediatric population.

Development and Multidisciplinary Preliminary Validation of a 3-Dimensional-Printed Pediatric Airway Model for Emergency Airway Front-of-Neck Access Procedures.

BACKGROUND: Pediatric-specific difficult airway guidelines include algorithms for 3 scenarios: unanticipated difficult tracheal intubation, difficult mask ventilation, and cannot intubate/cannot ventilate. While rare, these instances may require front-of-neck access (FONA) to secure an airway until a definitive airway can be established. The aim of this study was to develop a pediatric FONA simulator evaluated by both anesthesiology and otolaryngology providers, promoting multidisciplinary airway management. METHODS: A 3-dimensional-printed tracheal model was developed using rescaled, anatomically accurate dimensions from a computerized tomography scan using computer-aided design software. The medical grade silicone model was incorporated into a mannequin to create a low-cost, high-fidelity simulator. A multidisciplinary team of anesthesiology, otolaryngology, and simulation experts refined the model. Experts in airway management were recruited to rate the realism of the model's characteristics and features and their own ability to complete specific FONA-related tasks. RESULTS: Six expert raters (3 anesthesiology and 3 otolaryngology) were identified for multidisciplinary evaluation of model test content validity. Analysis of response data shows null variance within 1 or both specialties for a majority of the content validity tool elements. High and consistent absolute ratings for each domain indicate that the tested experts perceived this trainer as a realistic and highly valuable tool in its current state. CONCLUSIONS: The ability to practice front-of-neck emergency airway procedures safely and subsequently demonstrate proficiency on a child model has great implications regarding both quality of physician training and patient outcomes. This model may be incorporated into curricula to teach needle cricothyroidotomy and other FONA procedures to providers across disciplines.

PLZF-expressing CD4 T cells show the characteristics of terminally differentiated effector memory CD4 T cells in humans.

We show the presence of lymphoid tissue-resident PLZF+ CD45RA+ RO+ CD4 T cells in humans. They express HLA-DR, granzyme B, and perforin and are low on CCR7 like terminally differentiated effector memory (Temra) cells and are likely generated from effector T cells (Te) or from central (Tcm) or effector (Tem) memory T (Tcm) cells during immune responses. Tn, Naïve T cells.

Atypical phenotypes associated with pathogenic CHD7 variants and a proposal for broadening CHARGE syndrome clinical diagnostic criteria.

CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary anomalies, and Ear malformations, including deafness and vestibular disorders) is a genetic condition characterized by a specific and recognizable pattern of features. Heterozygous pathogenic variants in the chromodomain helicase DNA-binding protein 7 (CHD7) are the major cause of CHARGE syndrome, and have been identified in 70-90% of individuals fulfilling clinical diagnostic criteria. Since 2004, when CHD7 was discovered as the causative gene for CHARGE syndrome, the phenotypic spectrum associated with pathogenic CHD7 variants has expanded. Predicted pathogenic CHD7 variants have been identified in individuals with isolated features of CHARGE including autism and hypogonadotropic hypogonadism. Here, we present genotype and phenotype data from a cohort of 28 patients who were considered for a diagnosis of CHARGE syndrome, including one patient with atypical presentations and a pathogenic CHD7 variant. We also summarize published literature on pathogenic CHD7 variant positive individuals who have atypical clinical presentations. Lastly, we propose a revision to current clinical diagnostic criteria, including broadening of the major features associated with CHARGE syndrome and addition of pathogenic CHD7 variant status as a major criterion.

Duplication 2p25 in a child with clinical features of CHARGE syndrome.

CHARGE syndrome is a dominant disorder characterized by ocular colobomata, heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear abnormalities including deafness and vestibular disorders. The majority of individuals with CHARGE have pathogenic variants in the gene encoding CHD7, a chromatin remodeling protein. Here, we present a 15-year-old girl with clinical features of CHARGE syndrome and a de novo 6.5 Mb gain of genomic material at 2p25.3-p25.2. The duplicated region contained 24 genes, including the early and broadly expressed transcription factor gene SOX11. Analysis of 28 other patients with CHARGE showed no SOX11 copy number changes or pathogenic sequence variants. To our knowledge, this child's chromosomal abnormality is unique and represents the first co-occurrence of duplication 2p25 and clinical features of CHARGE syndrome. We compare our patient's phenotype to ten previously published patients with isolated terminal duplication 2p, and elaborate on the clinical diagnosis of CHARGE in the context of atypical genetic findings.

A human homeotic transformation resulting from mutations in PLCB4 and GNAI3 causes auriculocondylar syndrome.

Auriculocondylar syndrome (ACS) is a rare, autosomal-dominant craniofacial malformation syndrome characterized by variable micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic "question-mark" ear malformation. Careful phenotypic characterization of severely affected probands in our cohort suggested the presence of a mandibular patterning defect resulting in a maxillary phenotype (i.e., homeotic transformation). We used exome sequencing of five probands and identified two novel (exclusive to the patient and/or family studied) missense mutations in PLCB4 and a shared mutation in GNAI3 in two unrelated probands. In confirmatory studies, three additional novel PLCB4 mutations were found in multigenerational ACS pedigrees. All mutations were confirmed by Sanger sequencing, were not present in more than 10,000 control chromosomes, and resulted in amino-acid substitutions located in highly conserved protein domains. Additionally, protein-structure modeling demonstrated that all ACS substitutions disrupt the catalytic sites of PLCB4 and GNAI3. We suggest that PLCB4 and GNAI3 are core signaling molecules of the endothelin-1-distal-less homeobox 5 and 6 (EDN1-DLX5/DLX6) pathway. Functional studies demonstrated a significant reduction in downstream DLX5 and DLX6 expression in ACS cases in assays using cultured osteoblasts from probands and controls. These results support the role of the previously implicated EDN1-DLX5/6 pathway in regulating mandibular specification in other species, which, when disrupted, results in a maxillary phenotype. This work defines the molecular basis of ACS as a homeotic transformation (mandible to maxilla) in humans.

Digital music exposure reliably induces temporary threshold shift in normal-hearing human subjects.

OBJECTIVES: One of the challenges for evaluating new otoprotective agents for potential benefit in human populations is the availability of an established clinical paradigm with real-world relevance. These studies were explicitly designed to develop a real-world digital music exposure that reliably induces temporary threshold shift (TTS) in normal-hearing human subjects. DESIGN: Thirty-three subjects participated in studies that measured effects of digital music player use on hearing. Subjects selected either rock or pop music, which was then presented at 93 to 95 (n = 10), 98 to 100 (n = 11), or 100 to 102 (n = 12) dBA in-ear exposure level for a period of 4 hr. Audiograms and distortion product otoacoustic emissions (DPOAEs) were measured before and after music exposure. Postmusic tests were initiated 15 min, 1 hr 15 min, 2 hr 15 min, and 3 hr 15 min after the exposure ended. Additional tests were conducted the following day and 1 week later. RESULTS: Changes in thresholds after the lowest-level exposure were difficult to distinguish from test-retest variability; however, TTS was reliably detected after higher levels of sound exposure. Changes in audiometric thresholds had a "notch" configuration, with the largest changes observed at 4 kHz (mean = 6.3 ± 3.9 dB; range = 0-14 dB). Recovery was largely complete within the first 4 hr postexposure, and all subjects showed complete recovery of both thresholds and DPOAE measures when tested 1 week postexposure. CONCLUSIONS: These data provide insight into the variability of TTS induced by music-player use in a healthy, normal-hearing, young adult population, with music playlist, level, and duration carefully controlled. These data confirm the likelihood of temporary changes in auditory function after digital music-player use. Such data are essential for the development of a human clinical trial protocol that provides a highly powered design for evaluating novel therapeutics in human clinical trials. Care must be taken to fully inform potential subjects in future TTS studies, including protective agent evaluations, that some noise exposures have resulted in neural degeneration in animal models, even when both audiometric thresholds and DPOAE levels returned to pre-exposure values.

Campomelic dysplasia: airway management in two patients and an update on clinical-molecular correlations in the head and neck.

Campomelic dysplasia is a rare and historically lethal skeletal dysplasia with a variable but recognizable phenotype; it affects the long bones and is associated with a variety of head and neck anomalies. Mutations in or around the SOX9 gene have been identified as the molecular origin in most patients. We briefly present 2 children who meet the diagnostic criteria for campomelic dysplasia to illustrate the various clinical manifestations. Many patients with campomelic dysplasia have airway obstruction at multiple levels. We describe our approach to managing the airway in these patients, and review recent advances in understanding how SOX9 mutations lead to the spectrum of abnormalities seen in the head and neck.

Modified Minerva Cervical Thoracic Orthosis for Postoperative Management of Cricotracheal Resection.

The worst complication of cricotracheal resection (CTR) is anastomotic dehiscence, and to limit it, postoperative management at Michigan Medicine included the use of a modified Minerva cervical-thoracic orthosis (MMCTO). To date, there has been no analysis of the risks and benefits of the brace's use following CTR. We analyze this with our retrospective study. A search with the keywords "cricotracheal resection" and "laryngotracheal reconstruction" was performed in the Electronic Medical Record Search Engine to identify patients retrospectively. The Statistical Package for Social Sciences was used for analysis; t test, χ2, and Fisher exact tests were used to analyze data. Fifteen males and 13 females with a median age of 4 years were identified, and almost 2/3 had a supra- and/or infrahyoid release performed. Postoperatively, 12 had a Grillo stitch and an MMCTO for a mean of 7 days. Most had no complications, but the most common complications were agitation due to brace discomfort and skin irritation. The worst complication was stroke. Our MMCTO's design allowed for better head and neck control with relative comfortability, and most patients had no complications with its short-term use. Our modification may be useful adjunct in the postoperative management.

Evaluating Directional Dependency of Selective Laser Sintered Patient Specific Biodegradable Devices to Improve Predictive Modeling and Design Verification.

Additive manufacturing, or 3D printing, of the bioresorbable polymer [Formula: see text]-polycaprolactone (PCL) is an emerging tissue engineering solution addressing patient specific anatomies. Predictively modeling the mechanical behavior of 3D printed parts comprised of PCL improves the ability to develop patient specific devices that meet design requirements while reducing the testing of extraneous design variants and development time for emergency devices. Predicting mechanical behavior of 3D-printed devices is limited by the variability of effective material moduli that are determined in part by the 3D printing manufacturing process. Powder fusion methods, specifically laser sintering, are known to produce parts with internal porosity ultimately impacting the mechanical performance of printed devices. This study investigates the role of print direction and part size on the material and structural properties of laser sintered PCL parts. Solid PCL cylinders were printed in the XY (perpendicular to laser) and Z direction (parallel to laser), scanned using microcomputed tomography, and mechanically tested under compression. Compositional, structural, and functional properties of the printed parts were evaluated with differential scanning calorimetry, gel permeation chromatography, microcomputed tomography, and mechanical testing. Computational models of printed and scanned cylinders were fit to experimental data to derive effective moduli. Effective moduli were used to predict the mechanical behavior of splints used for emergency repair of severe tracheobronchomalacia. Laser sintering did not cause significant differences in polymer material properties compared to unmanufactured powder. Effective moduli (Eeff) were greater for larger part sizes (p < 0.01) and for parts oriented in the XY direction compared to the Z direction (p < 0.001). These dependencies were congruent with the differences in void volumes associated with the print direction (p < 0.01) and part size (p < 0.01). Finite element models of splint parallel compression tests utilizing the Eeff dependent on print direction and size agreed with experimental closed compression tests of splints. Evaluating the microstructural properties of printed parts and selecting effective moduli for finite element models based on manufacturing parameters allows accurate prediction of device performance. These findings allow testing of a greater number of device design variants in silico to accomodate patient specific anatomies towards providing higher quality parts while lowering overall time and costs of manufacturing and testing.

Addressing the Pandemic Training Deficiency: Filling the Void with Simulation in Facial Reconstruction.

OBJECTIVE/HYPOTHESIS: To assess the use of a three-dimensional (3D) printed, multilayer facial flap model for use in trainee education as an alternative method of teaching surgical techniques of facial reconstruction. STUDY DESIGN: Cohort study. METHODS: A 3D printed facial flap simulator was designed from a computed tomography scan and manufactured out of silicone for low-cost, high-fidelity simulation. This simulator was tested by a group of Otolaryngology-Head and Neck Surgery trainees at a single institution. The simulator group was compared to a control group who completed an exercise on a traditional paper facial flap exercise. Both groups underwent didactic lectures prior to completing their respective exercises. Pre- and post-exercise Likert scale surveys measuring experience, understanding, effectiveness, and realism were completed by both groups. Central tendency, variability, and confidence intervals were measured to evaluate the outcomes. RESULTS: Trainees completing the facial flap simulator reported a statistically significant (p < 0.05) improvement in overall expertise in facial flap procedures, design of facial flaps, and excision of standing cutaneous deformities. No statistically significant improvement was seen in the control group. CONCLUSIONS: Trainees found the facial flap simulator to be an effective and useful training tool with a high level of realism in surgical education of facial reconstruction. Surgical simulators can serve as an adjunct to trainee education, especially during extraordinary times such as the novel coronavirus disease 2019 pandemic, which significantly impacted surgical training. LEVEL OF EVIDENCE: NA Laryngoscope, 131:E2444-E2448, 2021.

Competency-Based Assessment Tool for Pediatric Esophagoscopy: International Modified Delphi Consensus.

OBJECTIVES/HYPOTHESIS: Create a competency-based assessment tool for pediatric esophagoscopy with foreign body removal. STUDY DESIGN: Blinded modified Delphi consensus process. SETTING: Tertiary care center. METHODS: A list of 25 potential items was sent via the Research Electronic Data Capture database to 66 expert surgeons who perform pediatric esophagoscopy. In the first round, items were rated as "keep" or "remove" and comments were incorporated. In the second round, experts rated the importance of each item on a seven-point Likert scale. Consensus was determined with a goal of 7 to 25 final items. RESULTS: The response rate was 38/64 (59.4%) in the first round and returned questionnaires were 100% complete. Experts wanted to "keep" all items and 172 comments were incorporated. Twenty-four task-specific and 7 previously-validated global rating items were distributed in the second round, and the response rate was 53/64 (82.8%) with questionnaires returned 97.5% complete. Of the task-specific items, 9 reached consensus, 7 were near consensus, and 8 did not achieve consensus. For global rating items that were previously validated, 6 reached consensus and 1 was near consensus. CONCLUSIONS: It is possible to reach consensus about the important steps involved in rigid esophagoscopy with foreign body removal using a modified Delphi consensus technique. These items can now be considered when evaluating trainees during this procedure. This tool may allow trainees to focus on important steps of the procedure and help training programs standardize how trainees are evaluated. LEVEL OF EVIDENCE: 5. Laryngoscope, 131:1168-1174, 2021.

Delivery system can vary ventilatory parameters across multiple patients from a single source of mechanical ventilation.

BACKGROUND: Current limitations in the supply of ventilators during the Covid19 pandemic have limited respiratory support for patients with respiratory failure. Split ventilation allows a single ventilator to be used for more than one patient but is not practicable due to requirements for matched patient settings, risks of cross-contamination, harmful interference between patients and the inability to individualize ventilator support parameters. We hypothesized that a system could be developed to circumvent these limitations. METHODS AND FINDINGS: A novel delivery system was developed to allow individualized peak inspiratory pressure settings and PEEP using a pressure regulatory valve, developed de novo, and an inline PEEP 'booster'. One-way valves, filters, monitoring ports and wye splitters were assembled in-line to complete the system and achieve the design targets. This system was then tested to see if previously described limitations could be addressed. The system was investigated in mechanical and animal trials (ultimately with a pig and sheep concurrently ventilated from the same ventilator). The system demonstrated the ability to provide ventilation across clinically relevant scenarios including circuit occlusion, unmatched physiology, and a surgical procedure, while allowing significantly different pressures to be safely delivered to each animal for individualized support. CONCLUSIONS: In settings of limited ventilator availability, systems can be developed to allow increased delivery of ventilator support to patients. This enables more rapid deployment of ventilator capacity under constraints of time, space and financial cost. These systems can be smaller, lighter, more readily stored and more rapidly deployable than ventilators. However, optimizing ventilator support for patients with individualized ventilation parameters will still be dependent upon ease of use and the availability of medical personnel.

Competency-Based Assessment Tool for Pediatric Tracheotomy: International Modified Delphi Consensus.

OBJECTIVES/HYPOTHESIS: Create a competency-based assessment tool for pediatric tracheotomy. STUDY DESIGN: Blinded, modified, Delphi consensus process. METHODS: Using the REDCap database, a list of 31 potential items was circulated to 65 expert surgeons who perform pediatric tracheotomy. In the first round, items were rated as "keep" or "remove," and comments were incorporated. In the second round, experts were asked to rate the importance of each item on a seven-point Likert scale. Consensus criteria were determined a priori with a goal of 7 to 25 final items. RESULTS: The first round achieved a response rate of 39/65 (60.0%), and returned questionnaires were 99.5% complete. All items were rated as "keep," and 137 comments were incorporated. In the second round, 30 task-specific and seven previously validated global rating items were distributed, and the response rate was 44/65 (67.7%), with returned questionnaires being 99.3% complete. Of the Task-Specific Items, 13 reached consensus, 10 were near consensus, and 7 did not achieve consensus. For the 7 previously validated global rating items, 5 reached consensus and two were near consensus. CONCLUSIONS: It is feasible to reach consensus on the important steps involved in pediatric tracheotomy using a modified Delphi consensus process. These items can now be considered to create a competency-based assessment tool for pediatric tracheotomy. Such a tool will hopefully allow trainees to focus on the important aspects of this procedure and help teaching programs standardize how they evaluate trainees during this procedure. LEVEL OF EVIDENCE: 5 Laryngoscope, 130:2700-2707, 2020.

Obesity and risk of peri-operative complications in children presenting for adenotonsillectomy.

BACKGROUND: Adenotonsillectomy (T&A) is a very common surgical procedure in children. With the rising prevalence of childhood overweight and obesity, our goal was to describe the prevalence of overweight/obesity in children presenting for T&A in our institution. We also sought to compare the frequency of peri-operative complications and the likelihood of being admitted following T&A between overweight/obese and normal weight children. METHODS: We examined our peri-operative database and extracted clinical, demographic and anthropometric information on 2170 children who underwent T&A between January 2005 and February 2008. Children were classified into normal weight, overweight and obese using published body mass index (BMI) criteria. The incidences of peri-operative complications were compared between the BMI categories. We also examined factors contributing to the likelihood of admission following T&A. RESULTS: The overall prevalence of overweight and obese was 20.7%. Overweight/obese children were more likely to have intra-operative desaturation (p=0.004), multiple attempts at laryngoscopy (p<0.001), difficult mask ventilation (p=0.001), and post-induction and post-anesthesia care unit (PACU) upper airway obstruction (p<0.001). Additionally, overweight and obese children were more likely to be admitted following T&A. BMI showed a moderate positive correlation with post-operative length of stay (LOS). Multiple logistic regression analysis showed that BMI and presence of medical co-morbidities were independent predictors of LOS. CONCLUSION: Overweight and obese children presenting for T&A have a higher incidence of peri-operative complications and are more likely to be admitted and stay for longer than their healthy weight peers.

Innovations in Airway Surgery.

The management of pediatric airway stenosis has evolved considerably over time. At the outset, dilation was the mainstay of management. In the 1900s, open surgery in the form of cricoid expansion procedures or resection procedures was the primary treatment with subsequent development of the slide tracheoplasty. Now in the twenty-first century, advances in endoscopic management, balloon dilation, and stenting, along with the advent of external scaffolds and tissue replacement continue to advance pediatric airway surgery.

3D-printed, externally-implanted, bioresorbable airway splints for severe tracheobronchomalacia.

OBJECTIVES/HYPOTHESIS: To report the clinical safety and efficacy of three-dimensional (3D)-printed, patient-specific, bioresorbable airway splints in a cohort of critically ill children with severe tracheobronchomalacia. STUDY DESIGN: Case series. METHODS: From 2012 to 2018, 15 subjects received 29 splints on their trachea, right and/or left mainstem bronchi. The median age at implantation was 8 months (range, 3-25 months). Nine children were female. Five subjects had a history of extracorporeal membrane oxygenation (ECMO), and 11 required continuous sedation, six of whom required paralytics to maintain adequate ventilation. Thirteen were chronically hospitalized, unable to be discharged, and seven were hospitalized their entire lives. At the time of splint implantation, one subject required ECMO, one required positive airway pressure, and 13 subjects were tracheostomy and ventilator dependent, requiring a median positive end-expiratory pressure (PEEP) of 14 cm H2 O (range, 6-20 cm H2 0). Outcomes collected included level of respiratory support, disposition, and splint-related complications. RESULTS: At the time of discharge from our institution, at a median of 28 days postimplantation (range, 10-56 days), the subject on ECMO was weaned from extracorporeal support, and the subjects who were ventilated via tracheostomy had a median change in PEEP (discharge-baseline) of -2.5 cm H2 O (range, -15 to 2 cm H2 O, P = .022). At median follow-up of 8.5 months (range, 0.3-77 months), all but one of the 12 surviving subjects lives at home. Of the 11 survivors who were tracheostomy dependent preoperatively, one is decannulated, one uses a speaking valve, six use a ventilator exclusively at night, and three remain ventilator dependent. CONCLUSIONS: This case series demonstrates the initial clinical efficacy of the 3D-printed bioresorbable airway splint device in a cohort of critically ill children with severe tracheobronchomalacia. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1763-1771, 2019.