Structural pharmacology and therapeutic potential of 5-methoxytryptamines.

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders1-3. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT2A (ref. 4). However, 5-HT1A also plays a part in the behavioural effects of tryptamine hallucinogens5, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads6. Although 5-HT1A is a validated therapeutic target7,8, little is known about how psychedelics engage 5-HT1A and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT1A, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT1A and 5-HT2A enable the characterization of molecular determinants of 5-HT1A signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT1A agonists. We show that a 5-HT1A-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.

GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents.

The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.

A Congenital Tongue Mass.

A 13-month-old male presents with a firm left anterior tongue mass noted since birth that has increased proportionally with the child's growth. What is your diagnosis?

CTNNB1 and APC Mutations in Sinonasal Myxoma : Expanding the Spectrum of Tumors Driven By WNT/ß-catenin Pathway.

Sinonasal myxoma (SNM) is a rare, benign mesenchymal neoplasm with distinct clinicopathologic features and aberrant nuclear localization of ß-catenin by immunohistochemistry. The molecular underpinnings have been linked to that of a "myxoid variant" of desmoid fibromatosis. Herein, we describe a series of 8 cases of SNM and propose clinical and biologic differences compared with desmoid fibromatosis. Our patient cohort is comprised of 5 males and 3 females (age range: 10 mo to 12 y), 6 of whom are aged less than or equal to 24 months. All presented with facial swelling, reflecting lesions involving the maxillary bone, and all underwent resection. All tumors were variably cellular and comprised of bland spindled to stellate cells in a profusely myxoid background with diffuse nuclear ß-catenin expression. All cases of SNM were analyzed by next-generation sequencing using the Oncopanel assay. Three cases failed sequencing, 2 of 5 successful cases exhibited exon 3 CTNNB1 alterations involving the ubiquitin recognition motif, and 3 had adenomatous polyposis coli ( APC ) deletions. One patient had APC germline testing which was negative. No germline testing was available for the remaining 7 patients. Follow-up data over a range of 1 month to 23 years was available for 7 of the 8 SNMs. One case patient had local recurrence, and all were alive without evidence of disease. This is in contrast to the high recurrence rate typically seen in desmoid fibromatosis, particularly after resection. Our findings expand the spectrum of tumors with underlying WNT/ß-catenin pathway and highlight the histologic, clinical, and genetic differences of SNM compared with desmoid fibromatosis. APC deletion raises the possibility of underlying germline alteration and familial adenomatous polyposis.

Juvenile Nasopharyngeal Angiofibroma: Outcomes Analysis Based Upon Hospital Volume.

OBJECTIVE: To evaluate the management of juvenile nasopharyngeal angiofibroma (JNA) from a national perspective with outcomes comparison based on hospital volume. STUDY DESIGN: Ten-year Pediatric Health Information Systems (PHIS) data analysis. METHODS: The PHIS database was queried for the diagnosis of JNA. Data regarding demographics, surgical approach, embolization, length of stay, charges, readmission, and revision surgery was collected and analyzed. Hospitals were classified as low volume if fewer than 10 cases and high volume if greater than or equal to 10 cases during the study period. A random effects model compared outcomes based on hospital volume. RESULTS: A total of 287 JNA patients were identified with a mean age of 13.8 (± 2.7) years. Nine hospitals were classified as high volume, accounting for a total of 121 patients. The mean length of hospitalization, blood transfusion rate, and 30-day readmissions did not differ significantly by hospital volume. Patients cared for at high-volume institutions were less likely to require postoperative mechanical ventilation (8.3% vs. 25.0%; adjusted RR = 0.32; 95% CI 0.14-0.73; p < 0.01) or return to the operating room for residual disease than patients admitted to low-volume hospitals (7.4% vs. 20.5%; adjusted RR = 0.38; 95% CI 0.18-0.79; p = 0.01). CONCLUSIONS: The management of JNA is complex from both an operative and perioperative management standpoint. Over the past decade, nearly half (42.2%) of JNA patients have been managed at nine institutions in the United States. These centers have significantly lower rates of postoperative mechanical ventilation and the need for revision surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3216-3220, 2023.

Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs.

Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinson's disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown. Here, we report a detailed examination of the in vitro and in vivo pharmacology of Ariadne and its analogs, and propose a molecular hypothesis for the lack of hallucinogenic effects and the therapeutic potential of this compound class. We also provide a summary of previous clinical and preclinical results to contextualize the molecular signaling data. Our results show that Ariadne is a serotonin 5-HT2 receptor agonist, exhibits modest selectivity over 5-HT1 receptors, has no relevant activity at 5-HT4,5,7 and other aminergic receptors, and no substantial affinity at plasma membrane monoamine transporters. Compared to DOM, Ariadne shows lower signaling potency and efficacy in multiple signaling pathways examined (Gq, G11, and ß-arrestin2) coupled to 5-HT2A receptors. We confirmed the shift in signaling for an α-propyl analog and provide a molecular docking rationale for the progressive decrease in signaling potency with the growing length of the α-substituent. Ariadne versus DOM exhibits no apparent change in the relative preference between Gq/11 activation and ß-arrestin2 recruitment; instead, there is a small but consistent drop in efficacy in these signaling channels. Ariadne acts as a 5-HT2A agonist in vivo in mice and shows markedly attenuated head twitch response (HTR) in comparison to its hallucinogenic analogs, consistent with previous studies in rabbits, cats, and dogs. Hence, we propose the lower 5-HT2A receptor signaling efficacy of this compound class as an explanatory model for the lack of hallucinogenic effects of Ariadne in humans and the dramatically attenuated hallucinosis-like effects in animals (5-HT2A signaling efficacy hypothesis). In terms of reverse translation of the noted clinical therapeutic effects, we used an auxilin knockout model of Parkinson's disease where Ariadne rescued severe motor deficits in this mouse line, on par with the effects of l-DOPA, a notable finding considering Ariadne's lack of activity at dopamine receptors and transporters. Ariadne emerges as a prototype of a new drug class, non-hallucinogenic 5-HT2A agonists, with considerable therapeutic potential across psychiatric and neurological indications.

Management of Intracranial Sinusitis Complications in Children and Adolescents: Similarities and Differences Among Otolaryngology Subspecialists.

The purpose of this study was to compare the management of intracranial sinusitis complications in pediatric patients between members of the American Rhinologic Society (ARS) and the American Society of Pediatric Otolaryngology (ASPO). A cross-sectional web-based survey was distributed twice to the ASPO and ARS membership over an 8-month period. The overall survey response rate was 12.1% (7.5% of ARS members and 17.3% of ASPO members). Recommended management was similar with respect to the use of intravenous antibiotics, nasal saline irrigations, topical decongestants, and nasal steroid sprays. Recommendations diverged with regards to systemic steroid use and urgent/emergent endoscopic sinus surgery (ESS). ARS members were more likely to recommend systemic corticosteroids. ASPO members were more likely to recommend immediate ESS. Based on survey responses, we found differences in practice patterns among subspecialists, which indicates additional collaborative research between societies is necessary to develop and disseminate evidence-based guidelines for these patients. Level of Evidence: 4.

Charles F. Ferguson, MD: America's first full time pediatric otolaryngologist.

This historical review highlights the career of Charles F. Ferguson, MD for whom the annual clinical science awards bestowed by the American Society of Pediatric Otolaryngology are named. Dr. Ferguson was the first full time pediatric otolaryngologist in the United States. His career at Boston Children's Hospital spanned almost four decades. Disorders of the larynx, trachea and bronchi were his principal professional focus, with a specific expertise in bronchoesophagology. His pioneering work in pediatric airway endoscopy and the development of techniques to diagnose congenital airway malformations led to his receipt of the Chevalier Jackson Award from the American Bronchoesophagological Association, and the James Newcomb Award from the American Laryngological Society. He notably edited the first Pediatric Otolaryngology textbook in 1972. His life's work help set the foundation for the creation of the American Society of Pediatric Otolaryngology in 1984, six years following his retirement. The Charles Ferguson Clinical Science Awards were established to sustain his legacy.

Postoperative Disposition Following Pediatric Sistrunk Procedures: A National Database Query.

OBJECTIVE/HYPOTHESIS: Variability exists in the postoperative disposition of children following Sistrunk procedures. Management options include discharge home versus overnight observation, with the latter allowing monitoring for immediate postoperative complications, presumably reducing the need for subsequent readmission. This study investigates the association between overnight observation and ambulatory management of children undergoing Sistrunk procedures and relevant postoperative complication and revisit rates to clarify best practice for these patients. METHODS: This was a retrospective database review using the Pediatric Health Information System database from 2007 to 2016. RESULTS: The cited dataset identified 6,434 qualifying patients, categorized into ambulatory versus overnight observation cohorts. The overall 30-day revisit rate was 4.9%; the revisit rate with overnight observation (6.1%) was higher than for ambulatory patients (3.8%, adjusted odds ratio (OR) 1.60; 95% confidence interval (CI): 1.21, 2.12). Revisit rates were significantly higher in patients 2 years of age or younger compared to older patients (6.7% vs. 4.3%). The rates of return to the operating room for the observation versus ambulatory groups were 1.8% and 0.5%, respectively. Cervical fluid collection and neck swelling were among the most common revisit indications in both groups, with a mean time to presentation of 9 days. CONCLUSIONS: This study demonstrates that ambulatory management following a Sistrunk procedure is not associated with increased rates of common postoperative complications, readmission, or need for secondary surgical intervention. A Sistrunk procedure may be safely performed on an ambulatory basis in select cases. LEVEL OF EVIDENCE: IV Laryngoscope, 131:E2352-E2355, 2021.

Utility of DNA barcoding in native Oreochromis species.

The importance of Oreochromis in worldwide aquaculture and regional fisheries motivates the study of their genetic diversity in their native range. In this article, all mitochondrial cytochrome c oxidase subunit I gene (COI) sequences of Oreochromis species are retrieved from Barcode of Life Data system to quantify the available DNA barcoding information from wild individuals collected within the native ranges of the respective species. It is found that 70% of the known species in the genus still lack a COI barcode, and only 15% of the available sequences are from within the respective native ranges. Many of the available sequences have been produced from specimens acquired from aquaculture and introduced, naturalized populations, making the assessment of variation within the original native range challenging. Analyses of the wild-collected fraction of available sequences indicated the presence of cryptic lineages within Nile tilapia Oreochromis niloticus and O. schwebischi, the occurrence of potential introgressive hybridization between O. niloticus and blue tilapia O. aureus, and potential ancestral polymorphism between Karonga tilapia O. karongae and black tilapia O. placidus. This article also reports a case of misidentification of O. mweruensis as longfin tilapia O. macrochir. These results stress the importance of improving the knowledge of genetic variation within the native ranges of Oreochromis species for better-informed conservation of these natural resources.

Contemporary Management of Vascular Anomalies of the Head and Neck-Part 1: Vascular Malformations: A Review.

Importance: Vascular anomalies of the head and neck are relatively rare lesions. Management is challenging because of the high likelihood of involvement of functionally critical structures. Multiple modalities of treatment exist for vascular anomalies of the head and neck, including medical therapies, sclerotherapy and embolization procedures, and surgery. This review focuses on the accurate diagnosis and the relative roles of the various therapeutic options. Observations: Vascular anomalies are classified by the International Society for the Study of Vascular Anomalies into 2 major groups: vascular tumors and vascular malformations. Vascular tumors encompass proliferative lesions ranging from infantile and congenital hemangiomas to kaposiform hemangioendothelioma. Alternatively, vascular malformations are embryologic errors in vasculogenesis. This article focuses on the management of vascular malformations. The 3 primary vascular malformation subclassifications are lymphatic, venous, and arteriovenous. The burden of disease, diagnosis, and current management options are discussed in detail for each subtype. Conclusions and Relevance: Most vascular malformations of the head and neck require a multidisciplinary approach. Available medical, interventional radiologic, and surgical interventions are constantly evolving. Optimization of function and cosmesis must be balanced with minimization of treatment-associated morbidity. Otolaryngologists-head and neck surgeons must remain up to date regarding options for diagnosis and management of these lesions.

COVID19: a case report of thrombus in transit.

BACKGROUND: The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused significant morbidity and mortality, not only through devastating lung injury, but also due to multiple malfunctions in the cardiovascular system. The primary aetiology is believed to be mediated through lung alveolar injury; however, a few published reports have linked SARS-CoV-2 to significant organ dysfunction, venous thrombo-embolism, and coagulopathy. In view of the fact that the utility of tissue plasminogen activator in this population is not well studied, we present this case of rapid improvement in oxygenation after successful lytic therapy for thrombus in transit in this patient with SARS-CoV-2. CASE SUMMARY: We discuss a patient admitted with SARS-CoV-2 pneumonia. Due to the development of dramatic hypoxia, he underwent echocardiography which demonstrated extensive thrombus in transit. He received successful thrombolytic therapy with tissue plasminogen activator, with subsequent improvement in oxygenation. The patient was successfully discharged home on 2 L of oxygen via nasal cannula, and continues to improve at follow-up with his cardiologist and primary care physician. CONCLUSION: This case not only highlights embolic causes of hypoxia in SARS-CoV-2, but demonstrates the important utility of an echocardiogram and tissue plasminogen activator in this population.

Theoretical Framework of a Polydisperse Cell Filtration Model.

Filtration via a porous medium is a ubiquitous process where high-fidelity physical models are needed. The classical cell model oversimplifies the filtration medium and results in biased and inaccurate predictions of the filter performance. This paper presents the discrete framework of a polydisperse cell model that can incorporate any measured pore size distribution. A new equation connecting the polydisperse cell efficiencies and the medium efficiency is derived from first principles. For ceramic filters, the discrete model demonstrates a generic prediction capability of the filtration efficiency with a root-mean-squared difference of 5.4%, while the counterpart of the classical cell model is 26.4%. In addition, the discrete model eliminates the biased predictions of the classical cell model on sub-100 nm particles.

International Pediatric Otolaryngology group (IPOG) consensus on the diagnosis and management of pediatric obstructive sleep apnea (OSA).

OBJECTIVE: To develop an expert-based consensus of recommendations for the diagnosis and management of pediatric obstructive sleep apnea. METHODS: A two-iterative Delphi method questionnaire was used to formulate expert recommendations by the members of the International Pediatric Otolaryngology Group (IPOG). RESULTS: Twenty-six members completed the survey. Consensus recommendations (>90% agreement) are formulated for 15 different items related to the clinical evaluation, diagnosis, treatment, postoperative management and follow-up of children with OSA. CONCLUSION: The recommendations formulated in this IPOG consensus statement may be used along with existing clinical practice guidelines to improve the quality of care and to reduce variation in care for children with OSA.

Pediatric Subperiosteal Abscess Secondary to Acute Sinusitis: A Systematic Review and Meta-analysis.

OBJECTIVES/HYPOTHESIS: The surgical versus medical management of subperiosteal abscess can be controversial. The purpose of this study was to summarize current literature and provide pooled analyses to help direct management decisions. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Patients <18 years old with subperiosteal abscess secondary to acute sinusitis were reviewed, and a meta-analysis was conducted. Studies including five or more patients written in English were the primary search focus. RESULTS: Thirty-eight studies met inclusion criteria for the systematic review, and seven studies contained sufficient data for the meta-analysis. A total of 1,167 patients between the ages of 10 days and 18 years were included. Eleven sign/symptom categories were identified, with restricted ocular motility (n = 289, 45.9%), proptosis (n = 277, 44%), and fever (n = 223, 35.4%) being most frequent. Staphylococcus aureus was the most common pathogen isolated from cultures. Patients with abscess volume greater than the threshold specified in each individual study were over three times more likely to require surgical intervention compared to those with smaller abscess volume (pooled risk ratio [RR] = 3.61, 95% confidence interval [CI]: 2.40-5.44). Proptosis and gaze restriction also significantly predicted surgical intervention (pooled RR = 1.65: 95% CI: 1.29-2.12 for proptosis/pooled RR = 1.90; 95% CI: 1.20-3.00 for gaze restriction). CONCLUSIONS: Approximately half of patients with a subperiosteal abscess undergo surgical drainage. Abscess volume appears to be the most significant predictive risk factor. Detailed data from future studies regarding radiologic and ophthalmologic parameters are needed to provide more definitive values predictive of which patients are likely to fail medical therapy. LEVEL OF EVIDENCE: 2a Laryngoscope, 2020.

Advanced practice providers and children's hospital-based pediatric otolarynology practices.

INTRODUCTION: Advanced practice providers (APPs), including nurse practitioners and physician assistants, have been deployed in children's hospital-based academic pediatric otolaryngology practices for many years. However, this relationship in terms of prevalence, roles, financial consequences and satisfaction has not been examined. The objective of this study is to explore how APPs impact healthcare delivery in this setting. METHODS: Pediatric otolaryngology chiefs of all academic children's hospitals in the US were electronically surveyed about the ways APPs intersected clinically and financially in their respective practice. RESULTS: A total of 29 of 36 children's hospital-based pediatric otolaryngology practices completed the survey, of which 26 practices (90%) utilized APP. There were large variances within the APP practice cohort in faculty size (mean/median/range = 9.4/8.5/3-29); annual patient visits (mean/median = 18,373/17,600); number of practice site (mean/median/range = 4.3/4/2-9) and number of outpatient APP (mean/median/range = 6.3/5/1-30). No factors (faculty size, annual visits and number of practice sites) differentiated between the APP and non-APP practices. Among APP practices, significant correlation (p<.00001) was observed between size of APP cohort to faculty size and annual visits. 69% of the practices did not differentiate job functions of nurse practitioners and physician assistants. 85% of the practices utilized APPs in all practice sites and 19% utilized APPs in the operating room. 77% of APPs billed independently and 46% had on-site supervision. The most prevalent APP salary bracket based on 0-5, 6-10 and > 11 years of tenure were $76-100K (65%), $100-150K (77%) and $100-150K (86%), respectively. In 46% of the practices, APPs were able to generate enough revenue to cover more than 75% of their salary and 23% of practices generated a profit. 81% of the chiefs ranked the effectiveness of APPs as high (4 and 5) on a 5-point Likert scale. DISCUSSION: The majority of academic pediatric otolaryngology practices employed APPs. Despite the diversity seen in practice complexity, APP functionality and financial impact, most found the APP model to be beneficial in improving patient care, patient access and faculty productivity.

To drain or not to drain following a Sistrunk procedure: A dual institutional experience.

INTRODUCTION: A Sistrunk procedure is the standard operative management of patients with thyroglossal duct cysts. Drain placement is commonly employed with the goal of reducing postoperative complications. This study investigates the association between drain use and relevant postoperative complications following pediatric Sistrunk procedures. METHODS: Retrospective cohort study evaluating 295 pediatric patients treated between 2007 and 2016 at two tertiary care children's hospitals. RESULTS: The mean age of the study population was 5.6 years (SD 4.0). A drain was utilized in 234 cases (79.3%). The mean procedural duration was 108 min (SD 48), and significantly longer in patients receiving a drain. Early postoperative complications included seroma (5.8%), secondary infection (3.4%), wound breakdown (2.0%) and hematoma (0.3%). The risk of such complications did not significantly differ between patients without drain placement (9.8%) versus those who underwent surgical drain placement (12.0%) after accounting for age and history of preoperative infection (adjusted RR = 0.86; 95% CI: 0.37, 1.98; p = 0.72). In the subgroup analysis, findings were consistent across institutions, age category, history of infection, and primary versus secondary procedure. CONCLUSION: This dual institutional study found drain placement during a Sistrunk procedure may not reduce rates of common postoperative complications, even in longer duration cases in which a drain is more frequently placed. This data suggests a Sistrunk procedure may be safely performed without drain placement in select cases.

Balloon Sinuplasty Utilization in the Pediatric Population: A National Database Perspective.

OBJECTIVE: Balloon sinuplasty (BS) is a surgical management option in the treatment of chronic rhinosinusitis. The purpose of this study was to examine BS utilization among children with a national database. STUDY DESIGN: Retrospective review. SETTING: National pediatric database. SUBJECTS AND METHODS: All cases of children aged ≤18 years who underwent BS or traditional endoscopic sinus surgery (ESS) 5 years before and after the introduction of BS billing codes were studied with the Pediatric Health Information System database. We evaluated overall trends, demographics, performing physicians, readmissions, and cost data. RESULTS: A total of 14,079 patients met inclusion criteria: 13,555 underwent traditional ESS and 524 had a BS procedure. There was no significant increase in BS rates between 2011 and 2016. BS was more commonly performed among younger children than ESS (median age [interquartile range], 6 years [4-10] vs 9 years [6-13]; P < .001). There were 23 (4.4%) readmissions within 30 days in the balloon cohort versus 474 (3.5%) in the ESS cohort. The median cost of balloon maxillary antrostomy (US $6560 [$5420-$8250]) was higher than that of traditional maxillary antrostomy (US $5630 [$4130-$7700], P < .001). Physicians who performed BS had a larger volume of ESS procedures when compared with those who did not perform BS. CONCLUSION: Rates of BS performance in the pediatric population have not increased over time. Results showed no difference in readmission rates between BS and ESS. BS was associated with higher costs as compared with ESS. The role of BS in the pediatric chronic rhinosinusitis population remains unclear.