Multivalent GU-rich oligonucleotides sequester TDP-43 in the nucleus by inducing high molecular weight RNP complexes.

TDP-43 nuclear clearance and cytoplasmic aggregation are hallmarks of TDP-43 proteinopathies. We recently demonstrated that binding to endogenous nuclear GU-rich RNAs sequesters TDP-43 in the nucleus by restricting its passive nuclear export. Here, we tested the feasibility of synthetic RNA oligonucleotide-mediated augmentation of TDP-43 nuclear localization. Using biochemical assays, we compared the ability of GU-rich oligonucleotides to engage in multivalent, RRM-dependent binding with TDP-43. When transfected into cells, (GU)16 attenuated TDP-43 mislocalization induced by transcriptional blockade or RanGAP1 ablation. Clip34nt and (GU)16 accelerated TDP-43 nuclear re-import after cytoplasmic mislocalization. RNA pulldowns confirmed that multivalent GU-oligonucleotides induced high molecular weight RNP complexes, incorporating TDP-43 and possibly other GU-binding proteins. Transfected GU-repeat oligos disrupted TDP-43 cryptic exon repression, likely by diverting TDP-43 from endogenous RNAs, except for Clip34nt that contains interspersed A and C. Thus, exogenous multivalent GU-RNAs can promote TDP-43 nuclear localization, though pure GU-repeat motifs impair TDP-43 function.

Conceptualizing Fit in Surgical Residency Selection: The Experience in Otolaryngology-Head and Neck Surgery.

OBJECTIVE: Fit is a crucial factor in surgical residency selection, but how this abstract concept is applied in practice is poorly understood. Person-environment (PE) fit theory suggests that there are multiple fit domains that can clarify usage: person-job, person-organization, and person-workgroup fit. We used PE fit theory to explore how otolaryngology residency selection committee (RSC) members operationalize the concept of fit. DESIGN: One-hour focus groups were conducted in November 2022. Interview questions explored participants' definitions and uses of fit in the resident selection process. Transcripts were analyzed using directed qualitative content analysis to generate themes and evaluate how these align with PE fit domains. SETTING: Society of University Otolaryngologists Annual Meeting breakout session in November 2022. PARTICIPANTS: 21 RSC members from 20 different otolaryngology-head and neck surgery departments participated in three seven-person focus groups. RESULTS: Participants described aspects of fit that aligned with PE fit domains. Person-job included how applicants fit as both surgeons and residents. Person-organization included how applicants fit with the program's characteristics, program's mission, and the local community. Person-workgroup emphasized how applicants fit with current residents. Various challenges in the selection process limited the extent to which PE fit was operationalized, including 1) ambiguous uses of fit, 2) unique features of the match process, 3) lack of outcomes data for selection decisions, and 4) interactions with diversity, equity, and inclusion goals. CONCLUSIONS: Fit manifests in various ways during the surgical residency selection process that parallel domains of PE fit theory. Recommendations are made to assist programs in using fit in resident selection, including clearly articulating definitions of fit to increase transparency in conversations. Further work on selection challenges is needed to maximize the utility of fit in practice.

Angioembolization for splenic injuries: does it help? Retrospective evaluation of grade III-V splenic injuries at two level I trauma centers.

Background: Splenic angioembolization (SAE) has increased in utilization for blunt splenic injuries. We hypothesized lower SAE usage would not correlate with higher rates of additional intervention or mortality when choosing initial non-operative management (NOM) or surgery. Study design: Trauma registries from two level I trauma centers from 2010 to 2020 were used to identify patients aged >18 years with grade III-V blunt splenic injuries. Results were compared with the National Trauma Data Bank (NTDB) for 2018 for level I and II centers. Additional intervention or failure was defined as any subsequent SAE or surgery. Mortality was defined as death during admission. Results: There were 266 vs 5943 patients who met inclusion/exclusion criteria at Stanford/Santa Clara Valley Medical Center (SCVMC) versus the NTDB. Initial intervention differed significantly between cohorts with the use of SAE (6% vs 17%, p=0.000). Failure differed significantly between cohorts (1.5% vs 6.5%, p=0.005). On multivariate analysis, failure in NOM was significantly associated with NTDB cohort status, age 65+ years, more than one comorbidity, mechanism of injury, grade V spleen injury, and Injury Severity Score (ISS) 25+. On multivariate analysis, failure in SAE was significantly associated with Shock Index >0.9 and 10+ units blood in 24 hours. On multivariate analysis, a higher risk of mortality was significantly associated with NTDB cohort status, age 65+ years, no private insurance, more than one comorbidity, mechanism of injury, ISS 25+, 10+ units blood in 24 hours, NOM, more than one hospital complications, anticoagulant use, other Abbreviated Injury Scale ≥3 abdominal injuries. Conclusions: Compared with national data, our cohort had less SAE, lower rates of additional intervention, and had lower risk-adjusted mortality. Shock Index >0.9, grade V splenic injuries, and increased transfusion requirements in the first 24 hours may signal a need for surgical intervention rather than SAE or NOM and may reduce mortality in appropriately selected patients. Level of evidence: Level II/III.

Utilizing augmented reality for reconstruction of fractured, fragmented and damaged craniofacial remains in forensic anthropology.

Forensic anthropologists are often confronted with human remains that have been damaged due to trauma, fire, or postmortem taphonomic alteration, frequently resulting in the fracture and fragmentation of skeletal elements. The augmented reality (AR) technology introduced in this paper builds on familiar 3D visualization methods and utilizes them to make three dimensional holographic meshes of skeletal fragments that can be manipulated, tagged, and examined by the user. Here, CT scans, neural radiance fields (NeRF) artificial intelligence software, and Unreal Engine production software are utilized to construct a three-dimensional holographic image that can be manipulated with HoloLens™ technology to analyze the fracture margin and reconstruct craniofacial elements without causing damage to fragile remains via excessive handling. This allows forensic anthropologists a means of assessing aspects of the biological profile and traumatic injuries without risking further damage to the skeleton. It can also be utilized by students and professional anthropologists to practice refitting before reconstructing craniofacial fragments if refitting is necessary. Additionally, the holographic images can be used to explain complicated concepts in a courtroom without the emotional response related to using bony elements as courtroom exhibits.

Multivalent GU-rich oligonucleotides sequester TDP-43 in the nucleus by inducing high molecular weight RNP complexes.

TDP-43 nuclear clearance and cytoplasmic aggregation are hallmarks of TDP-43 proteinopathies. We recently demonstrated that binding to endogenous nuclear GU-rich RNAs sequesters TDP-43 in the nucleus by restricting its passive nuclear export. Here, we tested the feasibility of synthetic RNA oligonucleotide-mediated augmentation of TDP-43 nuclear localization. Using biochemical assays, we compared the ability of GU-rich oligonucleotides to engage in multivalent, RRM-dependent binding with TDP-43. When transfected into cells, (GU)16 attenuated TDP-43 mislocalization induced by transcriptional blockade or RanGAP1 ablation. Clip34nt and (GU)16 accelerated TDP-43 nuclear re-import after cytoplasmic mislocalization. RNA pulldowns confirmed that multivalent GU-oligonucleotides induced high molecular weight RNP complexes, incorporating TDP-43 and possibly other GU-binding proteins. Transfected GU-repeat oligos disrupted TDP-43 cryptic exon repression, likely by diverting TDP-43 from endogenous RNAs, except for Clip34nt which contains interspersed A and C. Thus, exogenous multivalent GU-RNAs can promote TDP-43 nuclear localization, though pure GU-repeat motifs impair TDP-43 function.

PANGEA: a new gene set enrichment tool for Drosophila and common research organisms.

Gene set enrichment analysis (GSEA) plays an important role in large-scale data analysis, helping scientists discover the underlying biological patterns over-represented in a gene list resulting from, for example, an 'omics' study. Gene Ontology (GO) annotation is the most frequently used classification mechanism for gene set definition. Here we present a new GSEA tool, PANGEA (PAthway, Network and Gene-set Enrichment Analysis; https://www.flyrnai.org/tools/pangea/), developed to allow a more flexible and configurable approach to data analysis using a variety of classification sets. PANGEA allows GO analysis to be performed on different sets of GO annotations, for example excluding high-throughput studies. Beyond GO, gene sets for pathway annotation and protein complex data from various resources as well as expression and disease annotation from the Alliance of Genome Resources (Alliance). In addition, visualizations of results are enhanced by providing an option to view network of gene set to gene relationships. The tool also allows comparison of multiple input gene lists and accompanying visualisation tools for quick and easy comparison. This new tool will facilitate GSEA for Drosophila and other major model organisms based on high-quality annotated information available for these species.

PANGEA: A New Gene Set Enrichment Tool for Drosophila and Common Research Organisms.

Gene set enrichment analysis (GSEA) plays an important role in large-scale data analysis, helping scientists discover the underlying biological patterns over-represented in a gene list resulting from, for example, an 'omics' study. Gene Ontology (GO) annotation is the most frequently used classification mechanism for gene set definition. Here we present a new GSEA tool, PANGEA (PAthway, Network and Gene-set Enrichment Analysis; https://www.flyrnai.org/tools/pangea/ ), developed to allow a more flexible and configurable approach to data analysis using a variety of classification sets. PANGEA allows GO analysis to be performed on different sets of GO annotations, for example excluding high-throughput studies. Beyond GO, gene sets for pathway annotation and protein complex data from various resources as well as expression and disease annotation from the Alliance of Genome Resources (Alliance). In addition, visualisations of results are enhanced by providing an option to view network of gene set to gene relationships. The tool also allows comparison of multiple input gene lists and accompanying visualisation tools for quick and easy comparison. This new tool will facilitate GSEA for Drosophila and other major model organisms based on high-quality annotated information available for these species.

Are We Undertreating Pain-A Review of the CDC 2022 Opioid Prescription Guidelines in the Context of Otolaryngology.

This Viewpoint discusses the 2022 Centers for Disease Control and Prevention guidelines for opioid prescription in the context of otolaryngology.

Flipping the Otolaryngology Didactics Curriculum: Results of a Novel Resident Course Structure.

OBJECTIVE: To assess the impact of a novel flipped-classroom (FC) otolaryngology resident didactic curriculum on resident learning. METHODS: Based on the preferences elicited in a survey of preferred learning styles of residents, a hybrid web-based and in-person FC otolaryngology didactic curriculum was implemented over a 6-month period in 2020-2021. Resident reactions to the new curriculum were assessed via a second survey. Kruskal Wallis tests were used to compare mean stanine scores on the Otolaryngology Training Examination (OTE) exam for topics taught in the new format with topics delivered in the old format. RESULTS: After instituting the curriculum reform, engagement in at least a moderate amount of the pre-didactic work and synchronous case discussions was reported by 67% and 88% of the residents, respectively. After the curriculum change, residents in years PGY2 and above reported statistically significant increases in self-reported ability to retain information from didactics, to feel prepared for the OTE, and to feel confident in fund of knowledge (p < 0.001, p = 0.004, and p = 0.004, respectively). Compared to the prior year, mean stanine increased on OTE scores for residents in years PGY2-PGY5 to a statistically significant degree (5.45 vs. 4.41, p = 0.001) for the topics delivered in the new format compared to topics delivered in the traditional format (5.13 vs. 4.70, p = 0.07). CONCLUSION: By organizing a didactic curriculum through online modules that incorporate pre-recorded lectures and external resources, residents reported and demonstrated improved knowledge retention. LEVEL OF EVIDENCE: NA Laryngoscope, 133:2129-2134, 2023.

Financial impact of the COVID-19 pandemic on an academic otolaryngology department.

Objective: To quantify the financial impact of the coronavirus disease (COVID-19) pandemic on an academic otolaryngology department. Methods: A year-over-year comparison was used to compare department revenue from April 2020 and April 2021 as a percentage of baseline April 2019 activity. Results: At the onset of the COVID-19 pandemic in April 2020, total department charges decreased by 83.4%, of which outpatient clinic charges were affected to the greatest extent. One year into pandemic recovery, department charges remained down 6.7% from baseline, and outpatient clinic charges remained down 9.9%. The reduction in outpatient clinic charges was mostly driven by a decrease in in-office procedure charges. Conclusion: Given that precautions to mitigate the risk of viral transmission in the health care setting are likely to be long-lived, it is important to consider the vulnerabilities of our specialty to mitigate financial losses going forward.

Isolated Otologic Involvement of IgG4 Related Disease: A Case Report and Review of Literature.

Immunoglobulin G4 related disease (IgG4-RD) is a systemic autoimmune disease process that classically presents with multi-organ involvement; however isolated involvement of various structures within the body has also been described. Histopathologic examination is considered the gold standard for diagnosis. Glucocorticoids are well established as first-line treatment, but relapses are common, and consultation with rheumatology, immunology, and/or oncology teams is almost always warranted for proper medical management and disease maintenance. Given the relative infancy of IgG4-RD as an accepted diagnosis and the overall rarity of the disease, much still needs to be learned about this variable disease process. We present this case of isolated otologic and lateral skull base involvement of IgG4-RD to contribute to the understanding of this exceedingly rare clinical entity.

Transoral management of pharyngeal ballistics.

OBJECTIVE: To present a case of a ballistic foreign body in the pharynx after a gunshot wound to the maxillofacial area, an accompanying review of relevant literature, and our approach to management. METHOD: A 68-year-old male with no prior medical history presented to our trauma center with gunshot wounds to the left chin, left wrist, right chest, and sternum. A CT Angiogram of the neck revealed a bullet fragment left neck and additional fragment adjacent to the L hypopharynx at the level of the hyoid. The patient was taken to the operating room for direct laryngoscopy with foreign body removal and esophagoscopy. RESULTS: We document our workup and successful surgical removal of the pharyngeal ballistic foreign body via our video abstract, compiling preoperative imaging, intraoperative imaging, and video. Literature review of the subject accompanying our video abstract highlights the extensive complications that can occur from a retained foreign body in this area, supporting surgical removal of the foreign body if safely possible. CONCLUSION: Given the demonstrated feasibility and success of endoscopic foreign body removal from the pharyngoepiglottic space, in addition to overwhelming support for removal in the literature we recommend surgical extraction of ballistic foreign bodies located in the upper aerodigestive tract in stable patients to avoid early and long-term complications that can impact swallowing function, airway stability and the vital structures contained within the neck.

The Association of Frontal Alopecia with a History of Facial and Scalp Surgical Procedures.

INTRODUCTION: The prevalence of frontal fibrosing alopecia (FFA) is increasing worldwide, though the pathogenesis remains unknown. Anecdotal reports describe alopecia occurring in an FFA pattern following facial surgical procedures, but this potential link remains unexplored. OBJECTIVE: The objective of this study is to determine if a significant association exists between the diagnosis of FFA and a history of facial and scalp surgical procedures. METHODS: This retrospective study comparing data from frontal alopecia patients to controls was conducted at a tertiary medical center. Additionally, a literature review was conducted on scarring alopecias occurring from scalp procedures. RESULTS: Fifty percent of frontal alopecia patients (n = 54) reported a history of facial surgical procedures compared to 9.8% of controls (n = 51) (OR: 7.8 [95% CI: 2.77-25.98, p < 0.001]). Although no significant differences were observed in current daily facial sunscreen use, sunscreen use prior to alopecia onset was significantly higher in frontal alopecia (p = 0.295; p = 0.021). Sunscreen use was not a significant modifier in the association between frontal alopecia and facial surgical procedures (p = 0.89). CONCLUSIONS: A significant association exists between frontal alopecia clinically consistent with FFA and a history of facial surgery, the nature of which is unclear. The role of sunscreen use and frontal alopecia development in this setting needs to be better elucidated.

Dysphagia and Swallowing Disorders.

Dysphagia, defined as impairment of the swallowing process, is a common symptom and can be a significant source of morbidity and mortality in the general population. This article summarizes the causes of the condition, its prevalence, and the consequences and costs of untreated dysphagia. The aim of this article is to provide a framework for the general internist in assessing, diagnosing, and managing dysphagia in an adult patient. Basic diagnostic screening procedures and techniques for management are emphasized. A basic treatment pathway based on cause is provided for reference.

Surgical Treatment of Sinonasal Mucosal Melanoma in Patients Treated with Systemic Immunotherapy.

Objective Surgical resection is widely accepted as a critical component for definitive treatment of sinonasal mucosal melanoma. Systemic immunotherapy, including multiple newer agents, has been used to treat metastatic or unresectable disease. In this study, we examine its efficacy in locoregional control when used in conjunction with surgical resection for primary mucosal lesions. Design Present study is a retrospective review of all patients at a tertiary academic medical center with primary sinonasal mucosal melanoma and distant metastatic disease. Results A total of four patients were identified. In all cases, patients were treated with a combination of surgical resection of the primary tumor and systemic immunotherapy. Three patients were initially treated with surgery at the primary site followed by immunotherapy for distant metastases. Response to immunotherapy at the sites of primary and metastatic disease was seen in two patients. All four patients developed progression or recurrence at the primary site following initiation of immunotherapy for which they underwent surgical resection. One patient remains in follow-up without evidence of disease 20 months after initial treatment; three succumbed to the disease at 135, 37, and 16 months after initial treatment. Conclusion Surgical resection for local control plays a critically important role in the treatment of sinonasal mucosal melanoma regardless of the presence of metastases and whether immunotherapy will be given. This case series suggests that, though immunotherapy may demonstrate efficacy in managing distant disease, surgery should remain the first-line treatment for the primary site.

Evaluation of an interactive virtual surgical rotation during the COVID-19 pandemic.

OBJECTIVE: To evaluate medical student and attending surgeon experiences with a novel interactive virtual Otolaryngology - Head and Neck Surgery (OHNS) medical student elective during the COVID-19 pandemic. STUDY DESIGN: A virtual OHNS elective was created, with three components: (1) interactive virtual operating room (OR) experience using live-stream video-conferencing, (2) telehealth clinic, (3) virtual didactics. SETTING: OHNS Department at the University of Pennsylvania (May 2020 to June 2020). METHODS: Six medical students from the University of Pennsylvania; five attending otolaryngologists. Two surveys were designed and distributed to participating medical students and attending surgeons. Surveys included 5-point Likert scale items, with 1 indicating "not at all" and 5 indicating "very much so". RESULTS: Response rate was 100% for both surveys. Students on average rated the educational value of the telehealth experience as 4.2 ± 1.2, and the virtual OR experience as 4.0 ± 0.6. Most students (n = 5, 83%) indicated that they had enough exposure to faculty they met on this rotation to ask for a letter of recommendation (LOR) for residency if needed, while attending surgeons had an average response of 3.0 ± 1.0 when asked how comfortable they would feel writing a LOR for a student they met through the rotation. A majority of students (n = 4, 67%) felt they connected enough with faculty during the rotation to ask for mentorship. Half the students (n = 5, 50%) indicated that the rotation allowed them to evaluate the department's culture either "extremely well" or "somewhat well". CONCLUSIONS: Overall, participating students described this innovative virtual surgical rotation as an educationally and professionally valuable experience. With the continued suspension of visiting student rotations due to the COVID-19 pandemic, this virtual model may have continued relevance to medical education.

The Effect of Conflict on Obstetric and Non-Obstetric Surgical Needs and Operative Mortality in Fragile States.

BACKGROUND: Médecins Sans Frontières (MSF) provides surgical care in fragile states, which are more vulnerable to conflict. The primary objective of this study was to compare the indications for operative intervention in surgical projects in fragile states during periods of active conflict (CON) and non-conflict (NON-CON). In addition, risk factors for non-obstetric and obstetric operative mortality were identified. METHODS: This was a retrospective analysis of MSF surgical projects in fragile states January 1, 2008-December 31, 2017. Variables considered in the analysis include age, gender, American Society of Anesthesiology physical status, emergency status, re-intervention status, indication for surgical intervention, and conflict/non-conflict time period. RESULTS: There were 30 surgical projects in 13 fragile states with 87,968 surgical interventions in 68,667 patients. Obstetric needs were the most common indication for surgical intervention (n = 28,060, 31.9%) but were more common during NON-CON (n = 23,142, 35.7%) compared to CON periods (n = 4,918, 21.2%, p < 0.001). Trauma was more common during CON (42.0%) compared to NON-CON (23.0%) periods (p < 0.001). Non-obstetric operative mortality was similar during CON (0.2%) compared to NON-CON (0.2%, p = 0.920), but obstetric operative mortality was higher (0.5%) during CON compared to NON-CON (0.2%, p < 0.001) periods. Risk factors for obstetric and non-obstetric mortality included age ≥ 30 years, ASA greater than 1, and emergency intervention. CONCLUSION: Humanitarian surgeons working in fragile states should be prepared to treat a range of surgical needs including trauma and obstetrics during conflict and non-conflict periods. The mortality in obstetric patients was higher during conflict periods, and further research to understand ways to protect this vulnerable group is needed.

Predictors of success in hypoglossal nerve stimulator implantation for obstructive sleep apnea.

OBJECTIVE: Current guidelines for hypoglossal nerve stimulator (HGNS) implantation eligibility include drug-induced sleep endoscopy (DISE) findings and other patient characteristics but lead to highly variable rates of surgical success across institutions. Our objective was to determine whether additional factors seen on preoperative evaluation could be used as predictors of surgical success. STUDY DESIGN: Retrospective chart review. SETTING: Single-institution academic tertiary care medical center. SUBJECTS: and Methods:This study included patients with obstructive sleep apnea (OSA) who underwent HGNS implantation between 2015 and 2018. Surgical success was defined as a postoperative apnea-hypopnea index (AHI) of less than 20 events per hour and an AHI reduction of at least 50%. Preoperative polysomnogram (PSG) results, DISE findings, and physical parameters were compared between surgical successes and failures. RESULTS: A total of 68 patients were included in the analysis. The overall surgical success rate was 79.4% (54/68). Elevated preoperative AHI was associated with an increased likelihood of treatment failure, with an AHI of (36.9 ± 16.8) events/hour in the success group compared to (49.4 ± 19.6) events/hour in the failure group (P = 0.05). Patients observed to have partial lateral oropharyngeal collapse on DISE was more frequently associated with the treatment failure group than in the success group (P = 0.04). CONCLUSION: Patients who underwent HGNS implantation overall had a very high treatment response rate at our institution. Factors that may predispose patients to surgical failure included the presence of lateral oropharyngeal collapse and a significantly elevated preoperative AHI. These should be considered when determining surgical candidacy for HGNS implantation.

Creation of an Interactive Virtual Surgical Rotation for Undergraduate Medical Education During the COVID-19 Pandemic.

OBJECTIVE: During the coronavirus 2019 pandemic, medical student involvement in direct patient care has been severely limited. Rotations mandatory not only for core curricula but also for informing decisions regarding specialty choice have been postponed during a critical window in the application cycle. Existing virtual rotations are largely observational or lack patient-facing components. SETTING: A virtual Otolaryngology - Head and Neck Surgery rotation at the University of Pennsylvania (Philadelphia, Pennsylvania) was implemented for medical students, comprising interactive live-streamed surgeries, outpatient telehealth visits, and virtual small group didactics. RESULTS: Medical students enrolled in the virtual surgical rotation were able to engage with attending surgeons and operating room staff while remotely viewing surgical procedures captured with first-person audiovisual technology. Students participated in several different aspects of care delivery in both the inpatient and outpatient setting, similar to their typical responsibilities of an in-person rotation. CONCLUSIONS: The authors will continue to develop the virtual surgical education methodology to further disseminate an interactive video-based medical student elective to other procedural specialties and institutions.