Rapid and accurate prediction of protein homo-oligomer symmetry with Seq2Symm.

The majority of proteins must form higher-order assemblies to perform their biological functions. Despite the importance of protein quaternary structure, there are few machine learning models that can accurately and rapidly predict the symmetry of assemblies involving multiple copies of the same protein chain. Here, we address this gap by training several classes of protein foundation models, including ESM-MSA, ESM2, and RoseTTAFold2, to predict homo-oligomer symmetry. Our best model named Seq2Symm, which utilizes ESM2, outperforms existing template-based and deep learning methods. It achieves an average PR-AUC of 0.48 and 0.44 across homo-oligomer symmetries on two different held-out test sets compared to 0.32 and 0.23 for the template-based method. Because Seq2Symm can rapidly predict homo-oligomer symmetries using a single sequence as input (~ 80,000 proteins/hour), we have applied it to 5 entire proteomes and ~ 3.5 million unlabeled protein sequences to identify patterns in protein assembly complexity across biological kingdoms and species.

A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation.

CD4+ T cells are central to adaptive immunity. Their role in cross-protection in viral infections such as influenza and severe acute respiratory syndrome (SARS) is well documented; however, molecular rules governing T cell receptor (TCR) engagement of peptide-human leukocyte antigen (pHLA) class II are less understood. Here, we exploit an aspect of HLA class II presentation, the peptide-flanking residues (PFRs), to "tune" CD4+ T cell responses within an in vivo model system of influenza. Using a recombinant virus containing targeted substitutions at immunodominant HLA-DR1 epitopes, we demonstrate limited weight loss and improved clinical scores after heterosubtypic re-challenge. We observe enhanced protection linked to lung-derived influenza-specific CD4+ and CD8+ T cells prior to re-infection. Structural analysis of the ternary TCR:pHLA complex identifies that flanking amino acids influence side chains in the core 9-mer peptide, increasing TCR affinity. Augmentation of CD4+ T cell immunity is achievable with a single mutation, representing a strategy to enhance adaptive immunity that is decoupled from vaccine modality.

Essential and virulence-related protein interactions of pathogens revealed through deep learning.

Identification of bacterial protein-protein interactions and predicting the structures of the complexes could aid in the understanding of pathogenicity mechanisms and developing treatments for infectious diseases. Here, we developed a deep learning-based pipeline that leverages residue-residue coevolution and protein structure prediction to systematically identify and structurally characterize protein-protein interactions at the proteome-wide scale. Using this pipeline, we searched through 78 million pairs of proteins across 19 human bacterial pathogens and identified 1923 confidently predicted complexes involving essential genes and 256 involving virulence factors. Many of these complexes were not previously known; we experimentally tested 12 such predictions, and half of them were validated. The predicted interactions span core metabolic and virulence pathways ranging from post-transcriptional modification to acid neutralization to outer membrane machinery and should contribute to our understanding of the biology of these important pathogens and the design of drugs to combat them.

Mucosal T-cell responses to chronic viral infections: Implications for vaccine design.

Mucosal surfaces that line the respiratory, gastrointestinal and genitourinary tracts are the major interfaces between the immune system and the environment. Their unique immunological landscape is characterized by the necessity of balancing tolerance to commensal microorganisms and other innocuous exposures against protection from pathogenic threats such as viruses. Numerous pathogenic viruses, including herpesviruses and retroviruses, exploit this environment to establish chronic infection. Effector and regulatory T-cell populations, including effector and resident memory T cells, play instrumental roles in mediating the transition from acute to chronic infection, where a degree of viral replication is tolerated to minimize immunopathology. Persistent antigen exposure during chronic viral infection leads to the evolution and divergence of these responses. In this review, we discuss advances in the understanding of mucosal T-cell immunity during chronic viral infections and how features of T-cell responses develop in different chronic viral infections of the mucosa. We consider how insights into T-cell immunity at mucosal surfaces could inform vaccine strategies: not only to protect hosts from chronic viral infections but also to exploit viruses that can persist within mucosal surfaces as vaccine vectors.

Generalized biomolecular modeling and design with RoseTTAFold All-Atom.

Deep-learning methods have revolutionized protein structure prediction and design but are presently limited to protein-only systems. We describe RoseTTAFold All-Atom (RFAA), which combines a residue-based representation of amino acids and DNA bases with an atomic representation of all other groups to model assemblies that contain proteins, nucleic acids, small molecules, metals, and covalent modifications, given their sequences and chemical structures. By fine-tuning on denoising tasks, we developed RFdiffusion All-Atom (RFdiffusionAA), which builds protein structures around small molecules. Starting from random distributions of amino acid residues surrounding target small molecules, we designed and experimentally validated, through crystallography and binding measurements, proteins that bind the cardiac disease therapeutic digoxigenin, the enzymatic cofactor heme, and the light-harvesting molecule bilin.

How Do Patients and Otolaryngologists Define Dizziness?

OBJECTIVE: To assess for differences in how patients and otolaryngologists define the term dizziness. METHODS: Between June 2020 and December 2022, otolaryngology clinicians and consecutive patients at 5 academic otolaryngology institutions across the United States were asked to define the term "dizziness" by completing a semantics-based questionnaire containing 20 common descriptors of the term within 5 symptom domains (imbalance-related, lightheadedness-related, motion-related, vision-related, and pain-related). The primary outcome was differences between patient and clinician perceptions of dizzy-related symptoms. Secondary outcomes included differences among patient populations by geographic location. RESULTS: Responses were obtained from 271 patients and 31 otolaryngologists. Patients and otolaryngologists selected 7.7 ± 3.5 and 7.1 ± 4.3 symptoms, respectively. Most patients (266, 98.2%) selected from more than 1 domain and 17 (6.3%) patients identified symptoms from all 5 domains. Patients and clinicians were equally likely to define dizziness using terms from the imbalance (difference, -2.3%; 95% CI, -13.2%, 8.6%), lightheadedness (-14.1%; -29.2%, 1.0%), and motion-related (9.4; -0.3, 19.1) domains. Patients were more likely to include terms from the vision-related (23.6%; 10.5, 36.8) and pain-related (18.2%; 10.3%, 26.1%) domains. There were minor variations in how patients defined dizziness based on geographic location. CONCLUSIONS: Patients and otolaryngologists commonly described dizziness using symptoms related to imbalance, lightheadedness, and motion. Patients were more likely to use vision or pain-related terms. Understanding of these semantic differences may enable more effective patient-clinician communication.

SNOT-22 subdomain outcomes following treatment for sinonasal malignancy: A prospective, multicenter study.

BACKGROUND: Patients with sinonasal malignancy (SNM) present with significant sinonasal quality of life (QOL) impairment. Global sinonasal QOL as measured by the 22-item Sinonasal Outcomes Test (SNOT-22) has been shown to improve with treatment. This study aims to characterize SNOT-22 subdomain outcomes in SNM. METHODS: Patients diagnosed with SNM were prospectively enrolled in a multi-center patient registry. SNOT-22 scores were collected at the time of diagnosis and through the post-treatment period for up to 5 years. Multivariable regression analysis was used to identify drivers of variation in SNOT-22 subdomains. RESULTS: Note that 234 patients were reviewed, with a mean follow-up of 22 months (3 months-64 months). Rhinologic, psychological, and sleep subdomains significantly improved versus baseline (all p < 0.05). Subanalysis of 40 patients with follow-up at all timepoints showed statistically significant improvement in rhinologic, extra-nasal, psychological, and sleep subdomains, with minimal clinically important difference met between 2 and 5 years in sleep and psychological subdomains. Adjuvant chemoradiation was associated with worse outcomes in rhinologic (adjusted odds ratio (5.22 [1.69-8.66])), extra-nasal (2.21 [0.22-4.17]) and ear/facial (5.53 [2.10-8.91]) subdomains. Pterygopalatine fossa involvement was associated with worse outcomes in rhinologic (3.22 [0.54-5.93]) and ear/facial (2.97 [0.32-5.65]) subdomains. Positive margins (5.74 [2.17-9.29]) and surgical approach-combined versus endoscopic (3.41 [0.78-6.05])-were associated with worse psychological outcomes. Adjuvant radiation (2.28 [0.18-4.40]) was associated with worse sleep outcomes. CONCLUSIONS: Sinonasal QOL improvements associated with treatment of SNM are driven by rhinologic, extra-nasal, psychological, and sleep subdomains.

Cognition and saccadic eye movement performance are impaired in chronic rhinosinusitis.

BACKGROUND: Patients with chronic rhinosinusitis (CRS) can experience cognitive dysfunction. The literature on this topic mostly reflects patient-reported measurements. Our goal was to assess cognitive function in patients with CRS using objective measures, including saccadic eye movements-a behavioral response reflecting cognitive and sensory information integration that is often compromised in conditions with impaired cognition. METHODS: Participants (N = 24 with CRS, N = 23 non-CRS healthy controls) enrolled from rhinology clinic underwent sinonasal evaluation, quality of life assessment (Sino-nasal Outcome Test 22 [SNOT-22]), and cognitive assessment with the Neuro-QOL Cognitive Function-Short Form, the Montreal Cognitive Assessment (MoCA), and recording of eye movements using video-oculography. RESULTS: Participants with CRS were more likely to report cognitive dysfunction (Neuro-QOL; 45.8% vs. 8.7%; p = 0.005) and demonstrate mild or greater cognitive impairment (MoCA; 41.7% vs. 8.7%; p = 0.005) than controls. Additionally, participants with CRS performed worse on the MoCA overall and within the executive functioning and memory domains (all p < 0.05) and on the anti-saccade (p = 0.014) and delay saccade (p = 0.044) eye movement tasks. Poorer performance on the MoCA (r = -0.422; p = 0.003) and the anti-saccade (r = -0.347; p = 0.017) and delay saccade (r = -0.419; p = 0.004) eye movement tasks correlated with worse CRS severity according to SNOT-22 scores. CONCLUSION: This study is the first to utilize objective eye movement assessments in addition to researcher-administered cognitive testing in patients with CRS. These patients demonstrated a high prevalence of cognitive dysfunction, most notably within executive functioning and memory domains, with the degree of dysfunction correlating with the severity of CRS.

Are you congested? A comparison of definitions between otolaryngologists and their patients.

OBJECTIVE: To assess for differences of intended meaning in the description of congestion-related symptoms among otolaryngology patients and clinicians. MATERIALS AND METHODS: Between June 2020 and October 2022, a questionnaire consisting of 16 common descriptors of congestion-related symptoms within four domains (obstructive-related, pressure-related, mucus-related, and other symptoms) was completed by patients and otolaryngologists at five tertiary otolaryngology practices. The primary outcome was to assess differences in patient and clinician perceptions of congestion-related symptoms. Differences based on geographic location was a secondary outcome. RESULTS: A total of 349 patients and 40 otolaryngologists participated. Patients selected a median of 6.8 (standard deviation [SD] 3.0) terms compared with 4.0 (SD 1.6) terms for otolaryngologists (p < 0.001). Otolaryngologists were more likely to select obstruction-related symptoms (difference 6.3%; 95% confidence interval [CI] 3.8%, 8.9%). Patients were more likely to describe congestion using pressure-related (-43.7%; -58.9%, -28.5%), mucus-related (-43.5%; -59.3%, -27.8%), and other symptoms (-44.2; -51.3%, -37.1%) compared with otolaryngologists. There were no significant differences identified based on geographic location with regard to symptom domains on multivariate analysis. CONCLUSIONS: There are differences between otolaryngologists and their patients in the interpretation of the symptoms of congestion. Clinicians tended to have a narrower interpretation of congestion that was limited to the obstruction-related symptom domain, while patients defined congestion more broadly. This has important counseling and communication implications for the clinician.

Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion.

Regulatory T (Treg) cells contribute to immune homeostasis but suppress immune responses to cancer. Strategies to disrupt Treg cell-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for treatment failure are poorly understood. By modeling Treg cell-targeted immunotherapy in mice, we find that CD4+ Foxp3- conventional T (Tconv) cells acquire suppressive function upon depletion of Foxp3+ Treg cells, limiting therapeutic efficacy. Foxp3- Tconv cells within tumors adopt a Treg cell-like transcriptional profile upon ablation of Treg cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppressive activity is enriched among CD4+ Tconv cells marked by expression of C-C motif receptor 8 (CCR8), which are found in mouse and human tumors. Upon Treg cell depletion, CCR8+ Tconv cells undergo systemic and intratumoral activation and expansion, and mediate IL-10-dependent suppression of antitumor immunity. Consequently, conditional deletion of Il10 within T cells augments antitumor immunity upon Treg cell depletion in mice, and antibody blockade of IL-10 signaling synergizes with Treg cell depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by Tconv cells released upon therapeutic Treg cell depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective Treg cell-targeted therapies.

Genetic manipulation of Patescibacteria provides mechanistic insights into microbial dark matter and the epibiotic lifestyle.

Patescibacteria, also known as the candidate phyla radiation (CPR), are a diverse group of bacteria that constitute a disproportionately large fraction of microbial dark matter. Its few cultivated members, belonging mostly to Saccharibacteria, grow as epibionts on host Actinobacteria. Due to a lack of suitable tools, the genetic basis of this lifestyle and other unique features of Patescibacteira remain unexplored. Here, we show that Saccharibacteria exhibit natural competence, and we exploit this property for their genetic manipulation. Imaging of fluorescent protein-labeled Saccharibacteria provides high spatiotemporal resolution of phenomena accompanying epibiotic growth, and a transposon-insertion sequencing (Tn-seq) genome-wide screen reveals the contribution of enigmatic Saccharibacterial genes to growth on their hosts. Finally, we leverage metagenomic data to provide cutting-edge protein structure-based bioinformatic resources that support the strain Southlakia epibionticum and its corresponding host, Actinomyces israelii, as a model system for unlocking the molecular underpinnings of the epibiotic lifestyle.

Inhibitory IL-10-producing CD4+ T cells are T-bet-dependent and facilitate cytomegalovirus persistence via coexpression of arginase-1.

Inhibitory CD4+ T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity. However, the mechanisms that underpin the development of these regulatory cells, especially in the context of ongoing antigen exposure, have remained obscure. To address this knowledge gap, we undertook a comprehensive functional, phenotypic, and transcriptomic analysis of interleukin (IL)-10-producing CD4+ T cells induced by chronic infection with murine cytomegalovirus (MCMV). We identified these cells as clonally expanded and highly differentiated TH1-like cells that developed in a T-bet-dependent manner and coexpressed arginase-1 (Arg1), which promotes the catalytic breakdown of L-arginine. Mice lacking Arg1-expressing CD4+ T cells exhibited more robust antiviral immunity and were better able to control MCMV. Conditional deletion of T-bet in the CD4+ lineage suppressed the development of these inhibitory cells and also enhanced immune control of MCMV. Collectively, these data elucidated the ontogeny of IL-10-producing CD4+ T cells and revealed a previously unappreciated mechanism of immune regulation, whereby viral persistence was facilitated by the site-specific delivery of Arg1.

Automatic summarization of endoscopic skull base surgical videos through object detection and hidden Markov modeling.

Endoscopic endonasal surgery is a medical procedure that utilizes an endoscopic video camera to view and manipulate a surgical site accessed through the nose. Despite these surgeries being video recorded, these videos are seldom reviewed or even saved in patient files due to the size and length of the video file. Editing to a manageable size may necessitate viewing 3 h or more of surgical video and manually splicing together the desired segments. We suggest a novel multi-stage video summarization procedure utilizing deep semantic features, tool detections, and video frame temporal correspondences to create a representative summarization. Summarization by our method resulted in a 98.2% reduction in overall video length while preserving 84% of key medical scenes. Furthermore, resulting summaries contained only 1% of scenes with irrelevant detail such as endoscope lens cleaning, blurry frames, or frames external to the patient. This outperformed leading commercial and open source summarization tools not designed for surgery, which only preserved 57% and 46% of key medical scenes in similar length summaries, and included 36% and 59% of scenes containing irrelevant detail. Experts agreed that on average (Likert Scale = 4) that the overall quality of the video was adequate to share with peers in its current state.

Layperson Perception of Reflux-Related Symptoms.

Objective: To assess for differences of intended meaning in the description of reflux-related symptoms among otolaryngology patients and clinicians. Study Design: Cross-sectional survey-based study. Setting: Five tertiary, academic otolaryngology practices. Methods: Between June 2020 and July 2022, a questionnaire consisting of 20 common descriptors of reflux-related symptoms within four domains (throat-, chest-, stomach-, and sensory-related symptoms) was completed by patients. Attending otolaryngologists at five academic medical centers then completed the same survey. The primary outcome was to assess differences in patient and clinician perceptions of reflux-related symptoms. Differences based on geographic location was a secondary outcome. Results: A total of 324 patients and 27 otolaryngologists participated. Patients selected a median of six terms compared with 10.5 for otolaryngologists (p < .001). Otolaryngologists were more likely to select sensory symptoms (difference: 35.8%; 95% confidence interval [CI]: 19.2%, 52.4%), throat-related symptoms (32.4%; 21.2, 43.6%), and chest-related symptoms (12.4%; 8.8, 15.9). Otolaryngologists and patients were equally likely to consider stomach symptoms as related to reflux (4.0%, -3.7%, 11.7%). No significant differences were identified based on geographic location. Conclusion: There are differences between otolaryngologists and their patients in the interpretation of the symptoms of reflux. Patients tended to have a narrower interpretation of reflux with symptoms primarily limited to classic stomach-related symptoms, while clinicians tended to have a broader definition of reflux that included extra-esophageal manifestations of disease. This has important counseling implications for the clinician, as patients presenting with reflux symptoms may not comprehend the relationship of those symptoms to reflux disease.

Genetic manipulation of candidate phyla radiation bacteria provides functional insights into microbial dark matter.

The study of bacteria has yielded fundamental insights into cellular biology and physiology, biotechnological advances and many therapeutics. Yet due to a lack of suitable tools, the significant portion of bacterial diversity held within the candidate phyla radiation (CPR) remains inaccessible to such pursuits. Here we show that CPR bacteria belonging to the phylum Saccharibacteria exhibit natural competence. We exploit this property to develop methods for their genetic manipulation, including the insertion of heterologous sequences and the construction of targeted gene deletions. Imaging of fluorescent protein-labeled Saccharibacteria provides high spatiotemporal resolution of phenomena accompanying epibiotic growth and a transposon insertion sequencing genome-wide screen reveals the contribution of enigmatic Saccharibacterial genes to growth on their Actinobacteria hosts. Finally, we leverage metagenomic data to provide cutting-edge protein structure-based bioinformatic resources that support the strain Southlakia epibionticum and its corresponding host, Actinomyces israelii , as a model system for unlocking the molecular underpinnings of the epibiotic lifestyle.

Long-term quality of life after treatment in sinonasal malignancy: A prospective, multicenter study.

BACKGROUND: Quality of life (QOL) for individuals with sinonasal malignancy (SNM) is significantly under-studied, yet it is critical for counseling and may impact treatment. In this study we evaluated how patient, treatment, and disease factors impact sinonasal-specific and generalized QOL using validated metrics in a large cohort over a 5-year posttreatment time frame. METHODS: Patients with SNM who underwent definitive treatment with curative intent were enrolled in a prospective, multisite, longitudinal observational study. QOL was assessed using the 22-item Sino-Nasal Outcome Test (SNOT-22) and University of Washington Quality of Life Questionnaire (UWQOL) instruments at pretreatment baseline and multiple follow-ups through 5 years posttreatment. Multivariable modeling was used to determine demographic, disease, and treatment factors associated with disease-specific and generalized physical and social/emotional function QOL. RESULTS: One hundred ninety-four patients with SNM were analyzed. All QOL indices were impaired at pretreatment baseline and improved after treatment. SNOT-22 scores improved 3 months and UWQOL scores improved 6 to 9 months posttreatment. Patients who underwent open compared with endoscopic tumor resection had worse generalized QOL (p < 0.001), adjusted for factors including T stage. Pterygopalatine fossa (PPF) involvement was associated with worse QOL (SNOT-22, p < 0.001; UWQOL Physical dimension, p = 0.02). Adjuvant radiation was associated with worse disease-specific QOL (p = 0.03). Neck dissection was associated with worse generalized physical function QOL (p = 0.01). Positive margins were associated with worse generalized social/emotional function QOL (p = 0.01). CONCLUSION: Disease-specific and generalized QOL is impaired at baseline in patients with SNM and improves after treatment. Endoscopic resection is associated with better QOL. PPF involvement, adjuvant radiation, neck dissection, and positive margins were associated with worse QOL posttreatment.

Recent advances in predicting and modeling protein-protein interactions.

Protein-protein interactions (PPIs) drive biological processes, and disruption of PPIs can cause disease. With recent breakthroughs in structure prediction and a deluge of genomic sequence data, computational methods to predict PPIs and model spatial structures of protein complexes are now approaching the accuracy of experimental approaches for permanent interactions and show promise for elucidating transient interactions. As we describe here, the key to this success is rich evolutionary information deciphered from thousands of homologous sequences that coevolve in interacting partners. This covariation signal, revealed by sophisticated statistical and machine learning (ML) algorithms, predicts physiological interactions. Accurate artificial intelligence (AI)-based modeling of protein structures promises to provide accurate 3D models of PPIs at a proteome-wide scale.

Best practice for wildlife gut microbiome research: A comprehensive review of methodology for 16S rRNA gene investigations.

Extensive research in well-studied animal models underscores the importance of commensal gastrointestinal (gut) microbes to animal physiology. Gut microbes have been shown to impact dietary digestion, mediate infection, and even modify behavior and cognition. Given the large physiological and pathophysiological contribution microbes provide their host, it is reasonable to assume that the vertebrate gut microbiome may also impact the fitness, health and ecology of wildlife. In accordance with this expectation, an increasing number of investigations have considered the role of the gut microbiome in wildlife ecology, health, and conservation. To help promote the development of this nascent field, we need to dissolve the technical barriers prohibitive to performing wildlife microbiome research. The present review discusses the 16S rRNA gene microbiome research landscape, clarifying best practices in microbiome data generation and analysis, with particular emphasis on unique situations that arise during wildlife investigations. Special consideration is given to topics relevant for microbiome wildlife research from sample collection to molecular techniques for data generation, to data analysis strategies. Our hope is that this article not only calls for greater integration of microbiome analyses into wildlife ecology and health studies but provides researchers with the technical framework needed to successfully conduct such investigations.

Layperson Perception of Symptoms Caused by the Sinuses.

OBJECTIVE: To assess the perceived symptoms caused by the sinuses as defined by otolaryngology patients and clinicians. STUDY DESIGN: Multi-institutional cross-sectional study. SETTING: Six academic outpatient otolaryngology practices. METHODS: We performed a multi-institutional, cross-sectional study using a semantics-based questionnaire. Consecutive patients were enrolled at 6 academic otolaryngology centers from June 2020 to May 2021. The primary outcome examined patient and provider definitions for the symptoms caused by the sinuses from a list of 28 proposed terms covering 6 general categories. These data were also collected from otolaryngology faculty at the same institutions. RESULTS: Responses were obtained from 451 patients (54% female, mean age 48.3 years) and 29 otolaryngologists (38% female, mean age 37.4 years). Patients selected a median of 12 terms, compared to 8.5 for otolaryngologists. Among patients, the most frequently selected symptom domains were mucus (419, 92.9%), airflow (412, 91.4%), and pain (389, 86.3%). Compared to clinicians, patients more frequently selected symptoms related to the ear (difference, 48.3%; 95% confidence interval [CI], 34.8%-59.3%), throat (difference, 35.7%, 95% CI, 22.0%-47.5%), systemic (difference, 34.4%, 95% CI, 21.2%-46.0%), mucus (difference, 20.5%, 95% CI, 10.2%-30.6%), and airflow domains (difference, 19.0%, 95% CI, 8.4%-29.3%). Multiple domains were selected by 98% of patients and 79% of providers. CONCLUSION: Semantic differences exist between patients and clinicians regarding the symptoms caused by the sinus with patients having a broader range of perceived symptoms. These differences may provide clues to improve communication between otolaryngologists and their patients.

Orbital resection by intranasal technique (ORBIT): A new classification system for reporting endoscopically resectable primary benign orbital tumors.

BACKGROUND: The Cavernous Hemangioma Exclusively Endonasal Resection (CHEER) staging system has become the gold standard for outcomes reporting in endoscopic orbital surgery for orbital cavernous hemangiomas (OCHs). A recent systematic review demonstrated similar outcomes between OCHs and other primary benign orbital tumors (PBOTs). Therefore, we hypothesized that a simplified and more comprehensive classification system could be developed to predict surgical outcomes of other PBOTs. METHODS: Patient and tumor characteristics as well as surgical outcomes from 11 international centers were recorded. All tumors were retrospectively assigned an Orbital Resection by Intranasal Technique (ORBIT) class and stratified based on surgical approach as either exclusively endoscopic or combined (endoscopic and open). Outcomes based on approach were compared using chi-squared or Fisher's exact tests. The Cochrane-Armitage test for trend was used to analyze outcomes by class. RESULTS: Findings from 110 PBOTs from 110 patients (age 49.0 ± 15.0 years, 51.9% female) were included in the analysis. Higher ORBIT class was associated with a lower likelihood of gross total resection (GTR). GTR was more likely to be achieved when an exclusively endoscopic approach was utilized (p < 0.05). Tumors resected using a combined approach tended to be larger, to present with diplopia, and to have an immediate postoperative cranial nerve palsy (p < 0.05). CONCLUSION: Endoscopic treatment of PBOTs is an effective approach, with favorable short-term and long-term postoperative outcomes as well as low rate of adverse events. The ORBIT classification system is an anatomic-based framework that effectively facilitates high-quality outcomes reporting for all PBOTs.