Efficacy of a RADA-16 peptide hydrogel versus chitosan-based polymer in improving patient comfort during postoperative debridement: A randomized controlled trial.

BACKGROUND: Bioresorbable nasal packing is associated with a decreased incidence of adhesions and bleeding postoperatively after endoscopic sinus surgery (ESS). However, discomfort during postoperative debridement is still a major area of concern for patients. Our objective was to compare the efficacy of a peptide hydrogel to that of a chitosan-based polymer in reducing pain during debridement after ESS. METHODS: A prospective, multicenter, randomized, blinded trial was conducted in adults undergoing bilateral total ethmoidectomy for chronic rhinosinusitis. Participants served as their own controls with each subject receiving the hydrogel in a randomized ethmoid cavity and chitosan-based polymer in the contralateral ethmoid cavity. Participants were evaluated at 1, 4, and 12 weeks postoperatively. Pain during debridement as well as endoscopic evaluation of mucosal healing and hemostasis were measured. RESULTS: Thirty patients who underwent ESS were included in this trial. During the week 1 postoperative debridement, patients reported significantly less pain on the hydrogel-treated side compared to the chitosan-based polymer-treated side. There were no significant differences in bleeding severity, Lund-Kennedy scores, debridement time, or need for further intervention between the two groups. CONCLUSION: This study demonstrated the efficacy of a peptide hydrogel in minimizing pain during postoperative debridement.

Exploring a targeted approach for public health capacity restrictions during COVID-19 using a new computational model.

This work introduces the Queen's University Agent-Based Outbreak Outcome Model (QUABOOM). This tool is an agent-based Monte Carlo simulation for modelling epidemics and informing public health policy. We illustrate the use of the model by examining capacity restrictions during a lockdown. We find that public health measures should focus on the few locations where many people interact, such as grocery stores, rather than the many locations where few people interact, such as small businesses. We also discuss a case where the results of the simulation can be scaled to larger population sizes, thereby improving computational efficiency.

Classification of MLH1 Missense VUS Using Protein Structure-Based Deep Learning-Ramachandran Plot-Molecular Dynamics Simulations Method.

Pathogenic variation in DNA mismatch repair (MMR) gene MLH1 is associated with Lynch syndrome (LS), an autosomal dominant hereditary cancer. Of the 3798 MLH1 germline variants collected in the ClinVar database, 38.7% (1469) were missense variants, of which 81.6% (1199) were classified as Variants of Uncertain Significance (VUS) due to the lack of functional evidence. Further determination of the impact of VUS on MLH1 function is important for the VUS carriers to take preventive action. We recently developed a protein structure-based method named "Deep Learning-Ramachandran Plot-Molecular Dynamics Simulation (DL-RP-MDS)" to evaluate the deleteriousness of MLH1 missense VUS. The method extracts protein structural information by using the Ramachandran plot-molecular dynamics simulation (RP-MDS) method, then combines the variation data with an unsupervised learning model composed of auto-encoder and neural network classifier to identify the variants causing significant change in protein structure. In this report, we applied the method to classify 447 MLH1 missense VUS. We predicted 126/447 (28.2%) MLH1 missense VUS were deleterious. Our study demonstrates that DL-RP-MDS is able to classify the missense VUS based solely on their impact on protein structure.

Radiofrequency Neurolysis of the Posterior Nasal Nerve: A Systematic Review and Meta-Analysis.

OBJECTIVE: Temperature-controlled radiofrequency neurolysis of the posterior nasal nerve (PNN) has been approved for use since 2020. This review synthesized the published data to assess its efficacy for treatment of chronic rhinitis. DATA SOURCES: Pubmed/Medline, Embase, Scopus, Web of Science. REVIEW METHODS: A systematic search was conducted with no restrictions on publication years in April 2023. RCTs and prospective investigations that reported the reflective Total Nasal Symptom Score (rTNSS) outcome of radiofrequency neurolysis as a single procedure in chronic rhinitis patients were included. Pooled estimates for change in rTNSS from baseline at 3 months and responder rates (≥30% reduction in baseline rTNSS) at 3 and 6 months were obtained. Other outcomes, such as postnasal drip and cough scores, quality of life (QoL) measures, and adverse events were included for qualitative review. RESULTS: Five studies were included in the systematic review, of which four were included in the meta-analysis. A total of 284 participants underwent treatment. The pooled change in rTNSS score at 3 months was -4.28 (95% CI, -5.10 to -3.46). The pooled responder rate at 3 months was 77.11% (95% CI, 68.21%-86.01%) and at 6 months 80.80% (95% CI, 70.85%-90.76%). Postnasal drip and cough scores and QoL also improved significantly at follow up. A total of 36 adverse events were reported in 21 (7.4%) patients. CONCLUSIONS: The findings from this review suggest that temperature-controlled radiofrequency neurolysis of the PNN is effective at treating chronic rhinitis symptoms and that it has an overall favorable safety profile. Laryngoscope, 134:507-516, 2024.

Gender-Specific Differences in Preoperative Concerns in Patients Undergoing Endoscopic Sinus Surgery for Chronic Rhinosinusitis.

OBJECTIVES: Among patients with chronic rhinosinusitis (CRS), gender differences in epidemiology as well as quality of life have been reported. However, whether gender differences in endoscopic sinus surgery (ESS) preoperative concerns exist is unclear. METHODS: CRS patients undergoing ESS at 3 tertiary care centers in Los Angeles completed the validated Western Surgical Concern Inventory - ESS assessing ESS preoperative concerns. RESULTS: Of the 75 patients included, female patients expressed greater concern than male patients in regard to nasal packing, undergoing anesthesia, impact of surgery on daily activities, and pain and discomfort following surgery. CONCLUSION: This study suggests there are gender differences in ESS preoperative concerns and otolaryngologists should be aware of these possible concerns during preoperative discussions.

Association of ethnicity and time to surgery among patients with chronic rhinosinusitis.

Objectives: Determine factors associated with delayed endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS). Methods: This is a retrospective cohort study conducted at a tertiary care academic center. Patients were included in the study if they were at least 18 years old and underwent surgery for CRS. Electronic medical records were retrospectively reviewed to collect demographic and clinical data. Patients with CRS secondary to another pathology such as malignancy were excluded. Multiple linear regression was performed to determine factors associated with the number of days between a patient's preoperative consultation and the date of surgery. Results: A total of 103 patients with a mean age of 46.6 ± 16.8 years were included in the analysis; 51.5% of patients were females, 46.6% identified as White, and 29.1% identified as Hispanic. The majority of patients (67.0%) had preferred provider organization health insurance; 43.7% of patients had nasal polyps, 70.9% had a deviated nasal septum, and the mean preoperative Sinonasal Outcomes Test-22 (SNOT-22) score was 41.0 ± 23.8. The mean time to surgery after the final preoperative visit was 71.7 days ± 65.6 days. Hispanic ethnicity was associated with increased time to surgery (p < .05) when controlling for other variables. No other variables were associated with time to surgery on multivariate analysis. Conclusion: Hispanic ethnicity may be an independent predictor of increased time to sinus surgery independent of disease severity and other demographic variables. Level of Evidence: 2b.

An Exploratory Analysis of the Chronic Rhinosinusitis Online Support Community.

Objective: To characterize the users of the largest chronic rhinosinusitis (CRS) online support communities (OSCs), describe the perceived benefits of OSCs for their users, and understand how patient medical decision making is affected by membership in OSCs. Study Design: Cross-sectional online survey. Setting: Online. Methods: A cross-sectional online survey was adapted from the existing literature on patient support groups and modified for CRS patients. The survey was posted on multiple Facebook/Reddit groups aimed at providing support toward patients with CRS. Survey data was collected over 3 months and analyzed thereafter. Results: There were 127 total participants. The majority were female (65.35%), white (76.98%), and the median age was 38 years. Just under half of patients had nasal polyps (48.67%) and 54.54% had undergone surgery. Many participants (69.42%) reported engaging in the OSC at least multiple times per month. The most common reason for joining an OSC was to learn tips on how to manage CRS (89.7%) and the most achieved goal from membership was hearing from others undergoing a similar experience (79.5%). Involvement in an OSC impacted knowledge of CRS in 87.41% of participants. Most users (81.1%) would recommend membership in an OSC and 54.33% reported the OSC influenced their medical decision-making. Conclusion: A majority of patients with CRS who frequently engage in an OSC for CRS have a positive experience. OSCs are a resource that CRS patients utilize to manage their disease.

Head and Neck Cancer Online Support Groups: Disparities in Participation and Impact on Patients.

Objective: To characterize the users of the head and neck cancer (HNC) online support group (OSG) and describe the perceived benefits of membership. Study Design: Cross-sectional. Setting: Online. Methods: An administered survey with questions asking about demographics, cancer history, treatment choices, and feelings about OSGs was posted on the 5 largest HNC OSGs on Facebook. Results: A total of 97 participants completed the survey. Mean age was 57.8 years old (standard deviation = 10.7 years). Most participants were female (50.5%) and Caucasian (92.8%). This cohort was well educated with 65.5% holding at least a college degree. Annual income was high with 41.8% reporting annual income of $100,000 or greater. The most common treatment modality was radiation (88.7%). The most common surgery was neck dissection (46.4%). Most participants preferred OSGs (70.8%) over other support group types. OSGs were heavily utilized with our cohort reporting using the OSG at least several times a week (80.0%). The top reasons for joining the OSG were sharing one's experience of HNC (76.3%) and gaining support from others with HNC (85.6%). OSGs were ranked as the #3 source of medical information for HNC behind otolaryngologists and oncologists. Membership in a HNC OSG had a minimal impact on decision-making. Conclusion: HNC OSGs appear to provide a beneficial community for HNC patients. Otolaryngologists should consider incorporating HNC OSG as a possible supplemental resource for their HNC patients.

Endotype evaluation of Hispanic/Latinx-American patients with chronic rhinosinusitis with nasal polyps.

KEY POINTS: Hispanic-American patients with chronic rhinosinusitis with nasal polyps have a comparable level of tissue eosinophilia compared to their Caucasian counterparts in the United States. Mixed inflammation involving both neutrophils and eosinophils is more common in this population compared to Caucasians. Findings from this study may indicate that Hispanic-American patients have a unique endotype or endotypes that deserves further investigation.

The Differential Experience of COVID-19 on Asian American Subgroups: The Los Angeles Pandemic Surveillance Cohort Study.

Data from Asian Americans (AsA) are commonly aggregated in research studies and reporting, obscuring the significant differences across AsA subgroups. We investigated the differential experience of AsA subgroups in COVID-19 testing, vaccination, engagement in risky and protective behaviors and mental health status against this infectious disease. We surveyed a representative sample of the Los Angeles County population (N = 5500) in April 2021 as part of the Los Angeles Pandemic Surveillance Cohort Study and focused on participants who self-identified as AsA (N = 756). There were significant differences across the AsA subgroups, with Koreans, Asian Indians, and Other Asians living in areas with higher COVID-19 mortality rates, and Asian Indians demonstrating the lowest proportion of COVID-19 vaccination. Vietnamese and Koreans had a higher proportion of becoming unemployed during the pandemic. Although the AsA sample on average demonstrated better outcomes than other racial and ethnic groups, the apparent advantages were heterogenous and due to specific subgroups of AsAs rather than AsAs as a whole. The observed differences in COVID-19 measures across AsA subgroups underscore the need to disaggregate AsA data to identify and reduce existing disparities.

Classification of PTEN missense VUS through exascale simulations.

Phosphatase and tensin homolog (PTEN), a tumor suppressor with dual phosphatase properties, is a key factor in PI3K/AKT signaling pathway. Pathogenic germline variation in PTEN can abrogate its ability to dephosphorylate, causing high cancer risk. Lack of functional evidence lets numerous PTEN variants be classified as variants of uncertain significance (VUS). Utilizing Molecular Dynamics (MD) simulations, we performed a thorough evaluation for 147 PTEN missense VUS, sorting them into 66 deleterious and 81 tolerated variants. Utilizing replica exchange molecular dynamic (REMD) simulations, we further assessed the variants situated in the catalytic core of PTEN's phosphatase domain and uncovered conformational alterations influencing the structural stability of the phosphatase domain. There was a high degree of agreement between our results and the variants classified by Variant Abundance by Massively Parallel Sequencing, saturation mutagenesis, multiplexed functional data and experimental assays. Our extensive analysis of PTEN missense VUS should benefit their clinical applications in PTEN-related cancer. SIGNIFICANCE STATEMENT: Classification of PTEN variants affecting its lipid phosphatase activity is important for understanding the roles of PTEN variation in the pathogenesis of hereditary and sporadic malignancies. Of the 3000 variants identified in PTEN, 1296 (43%) were assigned as VUS. Here, we applied MD and REMD simulations to investigate the effects of PTEN missense VUS on the structural integrity of the PTEN phosphatase domain consisting the WPD, P and TI active sites. We classified a total of 147 missense VUS into 66 deleterious and 81 tolerated variants by referring to the control group comprising 54 pathogenic and 12 benign variants. The classification was largely in concordance with these classified by experimental approaches.

TP53 germline pathogenic variants in modern humans were likely originated during recent human history.

TP53 is crucial for maintaining genome stability and preventing oncogenesis. Germline pathogenic variation in TP53 damages its function, causing genome instability and increased cancer risk. Despite extensive study in TP53, the evolutionary origin of the human TP53 germline pathogenic variants remains largely unclear. In this study, we applied phylogenetic and archaeological approaches to identify the evolutionary origin of TP53 germline pathogenic variants in modern humans. In the phylogenic analysis, we searched 406 human TP53 germline pathogenic variants in 99 vertebrates distributed in eight clades of Primate, Euarchontoglires, Laurasiatheria, Afrotheria, Mammal, Aves, Sarcopterygii and Fish, but we observed no direct evidence for the cross-species conservation as the origin; in the archaeological analysis, we searched the variants in 5031 ancient human genomes dated between 45045 and 100 years before present, and identified 45 pathogenic variants in 62 ancient humans dated mostly within the last 8000 years; we also identified 6 pathogenic variants in 3 Neanderthals dated 44000 to 38515 years before present and 1 Denisovan dated 158 550 years before present. Our study reveals that TP53 germline pathogenic variants in modern humans were likely originated in recent human history and partially inherited from the extinct Neanderthals and Denisovans.

DARVIC: Dihedral angle-reliant variant impact classifier for functional prediction of missense VUS.

BACKGROUND: Of the large number of genetic variants identified, the functional impact for most of them remains unknown. Mutations in DNA damage repair genes such as MUTYH, which is involved in repairing A:8-oxoG mismatches caused by reactive oxygen species, can cause a higher risk of cancer. Mutations happening in other key genes such as TP53 also pose huge health threats and risk of cancer. The interpretation of genetic variants' functional impact is a forefront issue that needs to be addressed. Many different in silico methods based on different principles have been developed and applied in interpreting genetic variants. However, a current challenge is that many existing methods tend to overpredict the pathogenicity of benign variants. A new approach is needed to tackle this issue to improve genetic variant interpretation through the use of in silico methods. METHODS: In this study, we developed another protein structural-based approach called Dihedral angle-reliant variant impact classifier (DARVIC) to predict the deleterious impact of the coding-changing missense variants. DARVIC uses Ramachandran's principle of protein stereochemistry as the theoretical foundation and uses molecular dynamics simulations coupled with a supervised machine learning algorithm XGBoost to determine the functional impact of missense variants on protein structural stability. RESULTS: We characterized the features of dihedral angles in dynamic protein structures. We also tested the performance of DARVIC in MUTYH and TP53 missense variants and achieved satisfactory results in reflecting the functional impacts of the variants on protein structure. The method achieved a balanced accuracy of 84% in a functionally validated MUTYH dataset containing both benign and pathogenic missense variants, higher than other existing in silico methods. Along with that, DARVIC was able to predict 119 (47%) deleterious variants from a dataset of 254 MUTYH VUS. Further application of DARVIC to a functionally validated TP53 dataset had a balanced accuracy of 94%, topping other methods, demonstrating DARVIC's robustness. CONCLUSION: DARVIC provides a valuable tool to predict the functional impacts of missense variants based on their effects on protein structural stability and motion. At its current state, DARVIC performed well in predicting the functional impact of the missense variants both in MUTYH and TP53. We expect its high potential to predict functional impact for the missense variants in other genes.

Integration of deep learning with Ramachandran plot molecular dynamics simulation for genetic variant classification.

Functional classification of genetic variants is a key for their clinical applications in patient care. However, abundant variant data generated by the next-generation DNA sequencing technologies limit the use of experimental methods for their classification. Here, we developed a protein structure and deep learning (DL)-based system for genetic variant classification, DL-RP-MDS, which comprises two principles: 1) Extracting protein structural and thermodynamics information using the Ramachandran plot-molecular dynamics simulation (RP-MDS) method, 2) combining those data with an unsupervised learning model of auto-encoder and a neural network classifier to identify the statistical significance patterns of the structural changes. We observed that DL-RP-MDS provided higher specificity than over 20 widely used in silico methods in classifying the variants of three DNA damage repair genes: TP53, MLH1, and MSH2. DL-RP-MDS offers a powerful platform for high-throughput genetic variant classification. The software and online application are available at https://genemutation.fhs.um.edu.mo/DL-RP-MDS/.

Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans.

MUTYH plays an essential role in preventing oxidation-caused DNA damage. Pathogenic germline variations in MUTYH damage its function, causing intestinal polyposis and colorectal cancer. Determination of the evolutionary origin of the variation is essential to understanding the etiological relationship between MUTYH variation and cancer development. In this study, we analyzed the origins of pathogenic germline variants in human MUTYH. Using a phylogenic approach, we searched MUTYH pathogenic variants in modern humans in the MUTYH of 99 vertebrates across eight clades. We did not find pathogenic variants shared between modern humans and the non-human vertebrates following the evolutionary tree, ruling out the possibility of cross-species conservation as the origin of human pathogenic variants in MUTYH. We then searched the variants in the MUTYH of 5031 ancient humans and extinct Neanderthals and Denisovans. We identified 24 pathogenic variants in 42 ancient humans dated between 30,570 and 480 years before present (BP), and three pathogenic variants in Neanderthals dated between 65,000 and 38,310 years BP. Data from our study revealed that human MUTYH pathogenic variants mostly arose in recent human history and partially originated from Neanderthals.

Nationwide Analysis of Penetrating Thoracic Aortic Injury: Injury Patterns, Management, and Outcomes.

INTRODUCTION: Penetrating thoracic aortic injuries (PTAI) represent a rare form of thoracic trauma. Unlike blunt thoracic aortic injuries (BTAI), only scarce data, included in small case series, are currently available for PTAI. The purpose of this study was to describe injury patterns, surgical management, and outcomes of patients with PTAI and compare to those with BTAI. MATERIALS AND METHODS: A 9-y retrospective cohort study (2007-2015) was conducted using the National Trauma Data Bank. Patient demographics, injury profile, procedures performed, and patient outcomes were compared between the PTAI and BTAI group. RESULTS: A total of 2714 patients with PTAI and 14,037 patients with BTAI were identified. Compared to BTAI, PTAI patients were younger (28 versus 42 y, P < 0.001), more often male (89.1% versus 71.7%, P < 0.001), and more likely to arrive without signs of life (27.6% versus 7.5%, P < 0.001). PTAI patients had less associated injuries, overall, compared to those with BTAI; however, were more likely to have injuries to the esophagus, diaphragm, and heart. Patients with PTAI were less likely to undergo endovascular (5.8% versus 30.5%, P < 0.001) or open surgical repair (3.0% versus 4.2%, P < 0.001) compared to BTAI. While the large majority of PTAI patients expired before their hospital arrival or in the emergency department, the in-hospital mortality rate among those who survivedemergency department stay was 43.1%. CONCLUSIONS: Most patients with PTAI present to the hospital without any signs of life, and their overall mortality rate is extremely high. Only a small portion of PTAI patients who survived the initial resuscitation period underwent surgical interventions for thoracic aortic injuries. Further studies are still warranted to clarify the indications and types of surgical interventions for PTAI.