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Background: Patients' capacities to understand and act upon healthcare information is crucial to decision-making and high-quality care. Cognitive impairment (CI) has been associated with adverse outcomes across a range of diseases and surgeries. Despite the importance of CI, there is little to no information on its prevalence and severity in vascular surgery patients in the United States. We therefore conducted a prospective observational study to better characterize the prevalence and severity of CI in a contemporary vascular surgery practice., Methods: We enrolled 111 outpatients attending a vascular surgery clinic using pragmatic consecutive sampling. Patients were excluded if they had a previous diagnosis of blindness, deafness, or dementia. Subjects completed a demographic survey and the Montreal Cognitive Assessment (MoCA), which was administered by a trained proctor. Chart review was used to assess comorbidities. The MoCA is a validated tool consisting of tasks such as clock drawing for assessing CI. It has a lower educational bias and higher sensitivity for detecting mild impairment compared to other examinations. The MoCA is scored from 0-30 based on an objective grading system. Scores between 0-9, 10-17, 18-25, and 26-30 indicate severe, moderate, mild, and no CI, respectively. Statistical analysis, including multivariable modeling, was performed using SAS (SAS Institute, Cary, NC)., Results: Of 163 patients, our analysis included 111 consecutive vascular patients who completed the MoCA. The average age of the entire cohort was 64.1 years, and 58.6% were male. The majority of the patients in the study were White (80.1%). The mean MoCA score of the entire cohort was 22.6 (mild CI). Of all subjects, 77% had CI: 68% with mild and 9% with moderate CI. Hypertension (P = 0.024), congestive heart failure (CHF) (P = 0.028), fewer years of education (P = 0.032), and Medicaid enrollment (P = 0.046) all had significant univariate associations with CI. There was no statistically significant difference between age (P = 0.11) or the primary vascular diagnosis disease for which the patient sought treatment and CI (P = 0.49). Multivariable models demonstrated that only CHF (odds ratio 3.8, P = 0.046) was statistically significantly associated with risk of CI., Conclusions: In this first-time prospective study of the entire spectrum of vascular patients in the United States, we found that nearly 4 of every 5 vascular surgery patients have undiagnosed CI. Furthermore, we found that having CHF was associated with a higher likelihood of CI. Given the implications on consent, decision-making, and postoperative care, future work should focus on enrollment of a larger cohort along with an examination of the impact of CI on mortality, length of stay, and other outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Compared to adulthood-onset obesity (AO), those with childhood-onset obesity (CO) are at greater risk of metabolic disease. However, the differences between these two obesity phenotypes are not clear. The aim of this study is to investigate how the age of obesity onset (CO vs. AO) affects the use of intramyocellular (IMCL) and extramyocellular (EMCL) lipids in response to exercise., Methods: Males with CO (n = 5) and AO (n = 5) were recruited. At the first study visit, body composition was measured via dual-energy x-ray absorptiometry (DEXA). Energy expenditure and substrate oxidation were measured via indirect calorimetry. Participants were provided with standardized meals for 3 days prior to the exercise study visit. At the exercise study visit, IMCL and EMCL were measured via magnetic resonance spectroscopy (MRS) before and after 90-minutes of moderate intensity cycling with indirect calorimetry., Results: Substrate oxidation at rest and during exercise was not different between groups. Post-exercise, a decrease in IMCL was observed in the AO group that was not demonstrated in the CO group. There were no changes in EMCL post-exercise in either group., Conclusions: This was the first study to compare the effects of exercise on IMCL and EMCL use in males with CO and AO. The decreases in IMCL of the AO group is similar with those observed in the literature in lean individuals. We made the novel observation that with moderate intensity cycling, males with CO do not appear to use IMCL as effectively as those with AO, suggesting perturbations in IMCL metabolism., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study protocol was performed in accordance with the relevant guidelines and regulations as approved by the Comité central d’éthique de la recherche du ministre de la santé et des services sociaux. Prior to participation, written informed consent was obtained from all participants., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: There has been limited research on the influence of race and ethnicity on treatment decision-making for chronic rhinosinusitis (CRS). This prospective study aims to investigate potential factors linked to treatment modality choice among patients with medically refractory CRS, distinguishing between Chinese American and non-Chinese American patients., Methods: CRS patients with persistent symptoms despite prior medical treatment were prospectively enrolled. These patients chose either to continue medical treatment or to undergo endoscopic sinus surgery (ESS) to alleviate CRS symptoms. Demographic and clinical characteristics were compared using bivariate analysis. The association between ethnicity and treatment modality choice was assessed using multivariable logistic regression., Results: Among the 134 patients (29.1% Chinese Americans) included, 79 patients (59.0%) elected to undergo ESS. No significant differences in demographics, nasal polyp status, comorbidities, Sinonasal Outcome Test (SNOT-22), Lund-Mackay, or modified Lund-Kennedy scores were found between the treatment groups. After adjusting for age, income, and SNOT-22 score, non-Chinese American patients were more inclined to select ESS (OR = 7.92; 95% CI: 2.95-21.28; p < 0.001) as opposed to Chinese American patients. Chinese American patients who underwent ESS had a clinically significant improvement in SNOT-22 scores at 1 month (-11.29 points) and 3 months (-16.29 points) postoperatively., Conclusions: Chinese American patients with refractory CRS are less likely to opt for ESS compared to non-Chinese American patients. Surgical treatment is effective in improving quality of life, as measured by the SNOT-22, among Chinese American CRS patients. Further investigations are warranted to identify factors contributing to surgical hesitancy., Level of Evidence: 3 Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

The estimation of foraging parameters is fundamental for understanding predator ecology. Predation and feeding can vary with multiple factors, such as prey availability, presence of kleptoparasites and human disturbance. However, our knowledge is mostly limited to local scales, which prevents studying effects of environmental factors across larger ecological gradients. Here, we compared inter-kill intervals and handling times of Eurasian lynx (Lynx lynx) across a large latitudinal gradient, from subarctic to the Mediterranean ecosystems, using a standardised dataset of predicted adult ungulate kills from 107 GPS-collared lynx from nine distinct populations in Europe. We analysed variations in these two foraging parameters in relation to proxies reflecting prey availability, scavengers' presence and human disturbance, to improve our understanding of lynx predation at a continental scale. We found that inter-kill intervals and handling times varied between populations, social status and in different seasons within the year. We observed marked differences in inter-kill intervals between populations, which do not appear to be driven by variation in handling time. Increases in habitat productivity (expressed by NDVI, used as a proxy for prey availability) resulted in reduced inter-kill intervals (i.e. higher kill rates). We observed less variation in handling (i.e. feeding) times, although presence of dominant scavengers (wild boars and brown bears) and higher human impact led to significantly shorter handling times. This suggests that kleptoparasitism and human disturbance may limit the energetic input that lynx can obtain from their prey. We also observed that the human impact on foraging parameters can be consistent between some populations but context-dependent for others, suggesting local adaptations by lynx. Our study highlights the value of large-scale studies based on standardised datasets, which can aid the implementation of effective management measures, as patterns observed in one area might not be necessarily transferable to other regions. Our results also indicate the high degree of adaptability of these solitary felids, which enables them to meet their energy requirements and persist across a wide range of environmental conditions despite the constraints imposed by humans, dominant scavengers and variable prey availability., (© 2024 The Author(s). Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.)

Key Points: Asian-American (AA) patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have comparable rates of tissue eosinophilia compared to Caucasians when defined as >10 eosinophils/high-powered field (HPF). AA patients with CRSwNP have significantly higher incidence of mixed inflammation defined as >10 eosinophils/HPF and >10 neutrophils/HPF., (© 2024 ARS‐AAOA, LLC.)

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., (© 2024 ARS‐AAOA, LLC.)

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., (© 2023. The Author(s).)

We report a case of small bowel obstruction (SBO) caused by internal hernia from Meckel's diverticulum (MD). Abdominal CT scan showed an abnormal dilated blind-ending structure in continuity with the distal ileum in the right lower quadrant, suggesting Meckel's diverticulum. MPR images revealed a "double beak-sign" at the point of MD and a collapsed closed loop with mesenteric vessels converging to the diverticulum. Since the patient has no prior history of abdominal surgery, the diagnosis of internal hernia caused by Meckel's diverticulum was considered. On laparoscopic exploration, an abnormal orifice for internal hernia created by adhesion from the tip of Meckel's diverticulum to the adjacent mesentery was revealed, confirming the diagnosis. The patient was discharged after 7 days without postoperative complications. MD-associated internal hernia is a rare cause of small bowel obstruction and should be considered to avoid delay in treatment. Multidetector Computed Tomography (MDCT) is the first-line imaging modality of choice and may offer some suggestive imaging features to make an accurate preoperative diagnosis., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Somatic variation is a major type of genetic variation contributing to human diseases including cancer. Of the vast quantities of somatic variants identified, the functional impact of many somatic variants, in particular the missense variants, remains unclear. Lack of the functional information prevents the translation of rich variation data into clinical applications. We previously developed a method named Ramachandran Plot-Molecular Dynamics Simulations (RP-MDS), aiming to predict the function of germline missense variants based on their effects on protein structure stability, and successfully applied to predict the deleteriousness of unclassified germline missense variants in multiple cancer genes. We hypothesized that regardless of their different genetic origins, somatic missense variants and germline missense variants could have similar effects on the stability of their affected protein structure. As such, the RP-MDS method designed for germline missense variants should also be applicable to predict the function of somatic missense variants. In the current study, we tested our hypothesis by using the somatic missense variants in TP53 as a model. Of the 397 somatic missense variants analyzed, RP-MDS predicted that 195 (49.1%) variants were deleterious as they significantly disturbed p53 structure. The results were largely validated by using a p53-p21 promoter-green fluorescent protein (GFP) reporter gene assay. Our study demonstrated that deleterious somatic missense variants can be identified by referring to their effects on protein structural stability., (© The Author(s) 2024. Published by Oxford University Press.)

A novel bioresorbable agent on the market is PuraGel® (3-D Matrix, Tokyo, Japan), a RADA-16 product that acts as a synthetic hemostatic and space-filling gel that promotes wound healing and prevents adhesion formation. Given the reported benefits of accelerated wound healing and scar tissue prevention, there are multiple otolaryngologic applications where RADA-16 might improve outcomes. Our study highlights current utilization and associated post-operative complications with this product., Competing Interests: We have no conflicts of interest to disclose., (© 2024 The Author(s). Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

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., (© 2023 ARS‐AAOA, LLC.)

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (© 2023 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Photovoltaic-coupled electrolysis (PV-E) and photoelectrochemical (PEC) water splitting are two options for storing solar energy as hydrogen. Understanding the requirements for achieving a positive energy balance over the lifetime of facilities using these technologies is important for ensuring sustainability. While neither technology has yet reached full commercialisation, they are also at very different technology readiness levels and scales of development. Here, we model the energy balance of standalone large-scale facilities to evaluate their energy return on energy invested (ERoEI) over time and energy payback time (EPBT). We find that for average input parameters based on present commercialised modules, a PV-E facility shows an EPBT of 6.2 years and ERoEI after 20 years of 2.1, which rises to approximately 3.7 with an EPBT of 2.7 years for favourable parameters using the best metrics amongst large-scale modules. The energy balance of PV-E facilities is influenced most strongly by the upfront embodied energy costs of the photovoltaic component. In contrast, the simulated ERoEI for a PEC facility made with earth abundant materials only peaks at 0.42 after 11 years and about 0.71 after 20 years for facilities with higher-performance active materials. Doubling the conversion efficiency to 10% and halving the degradation rate to 2% for a 10-year device lifetime can allow PEC facilities to achieve an ERoEI after 20 years of 2.1 for optimistic future parameters. We also estimate that recycling the materials used in hydrogen production technologies improves the energy balance by 28% and 14% for favourable-case PV-E and PEC water splitting facilities, respectively., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

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., (© 2024 The Authors.)

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.

Importance: Widespread and frequent testing for COVID-19 was an important strategy to identify infected patients to isolate and control the spread of the disease during the pandemic. The nasopharyngeal swab (NPS) global supply chain and access to trained healthcare professionals for standard NPS collection were often compromised. Patient discomfort and limited access challenged health systems to reach large numbers for testing in adult and pediatric populations. Our study revealed that swish and gargle saliva (SGS) was comparable to NPS in detecting SARS-CoV-2 and more patient-friendly than NPS. Patients were more likely to repeat the test with SGS. SGS was amenable to self-collection instead of relying on skilled professionals. This comprehensive evaluation highlights the challenges of comparing the accuracy of new methods to imperfect gold standards and identifies additional patient-centric factors that should be considered when defining such standards. Thus, SGS is an advantageous alternative specimen collection for outpatient en masse testing., Competing Interests: The authors declare no conflict of interest.

Cancer genome data has been growing in both size and complexity, primarily driven by advances in next-generation sequencing technologies, such as Pan-cancer data from TCGA, ICGC, and single-cell sequencing. Yet, discerning the functional role of individual genomic lesions remains a substantial challenge due to the complexity and scale of the data. Previously, we introduced REVEALER, which identifies groups of genomic alterations that significantly associate with target functional profiles or phenotypes, such as pathway activation, gene dependency, or drug response. In this paper, we present a new mathematical formulation of the algorithm. This version (REVEALER 2.0) is considerably more powerful than the original, allowing for rapid processing and analysis of much larger datasets and facilitating higher-resolution discoveries at the level of individual alleles. REVEALER 2.0 employs the Conditional Information Coefficient (CIC) to pinpoint features that are either complementary or mutually exclusive but still correlate with the target functional profile. The aggregation of these features provides a better explanation for the target functional profile than any single alteration on its own. This is indicative of scenarios where several activating genomic lesions can initiate or stimulate a key pathway or process. We replaced the initial three-dimensional kernel estimation with multiple precomputed one-dimensional kernel estimations, resulting in an approximate 150x increase in speed and efficiency. This improvement, combined with its efficient execution, makes REVEALER 2.0 suitable for much larger datasets and a more extensive range of genomic challenges.

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., Competing Interests: None., (© 2023 The Authors. OTO Open published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

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., Competing Interests: None., (© 2023 The Authors. OTO Open published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

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., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

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., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., Competing Interests: Declaration of Competing Interest The authors declare no competing interests in the study., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.)

Importance: School engagement is the extent to which students commit to and participate in school activities, including internal thoughts, emotions, and observable behaviors. It is critical to children's academic outcomes and mental health. Occupational therapy practitioners support children at school to maintain mental well-being and meet their school outcomes. However, how occupational therapy practitioners should measure school engagement among elementary school students remains unclear., Objective: To identify and characterize how elementary school students' school engagement is currently measured., Data Sources: PsycINFO, Eric, CINAHL, and A+ Education databases. Two reviewers screened titles and abstracts, and one reviewer completed full-text screening and data extraction using Excel., Study Selection: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guided this review. Studies published between 2015 and 2021 were included if full text was available, written in English, and used a measure designed for elementary school-age students. Studies were excluded if they used no school engagement measurement; used only infant, adolescent, or adult scales; were not available for review; and did not meet the inclusion criteria., Findings: The review included 125 studies. A range of self-report, observational, teacher-report, and caregiver-report measures of school engagement were identified. Behavioral school engagement was most commonly measured. Included studies were primarily published in education and psychology fields, with none published in occupational therapy journals., Conclusions and Relevance: A range of school engagement measurements can be found in the literature, but no consensus exists on a validated school engagement measurement for occupational therapy practice. What This Article Adds: This review provides occupational therapy practitioners with a comprehensive understanding of (1) the importance of school engagement to mental health and (2) the range of behavioral, cognitive, and emotional engagement measures currently available for use with elementary school-age children, thereby enhancing the profession's knowledge and scope of practice in school engagement., (Copyright © 2023 by the American Occupational Therapy Association, Inc.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Pathogenic variation in BRCA1 and BRCA2 (BRCA) causes high risk of breast and ovarian cancer, and BRCA variation data are important markers for BRCA-related clinical cancer applications. However, comprehensive BRCA variation data are lacking from the Asian population despite its large population size, heterogenous genetic background and diversified living environment across the Asia continent. We performed a systematic study on BRCA variation in Asian population including extensive data mining, standardization, annotation and characterization. We identified 7587 BRCA variants from 685 592 Asian individuals in 40 Asia countries and regions, including 1762 clinically actionable pathogenic variants and 4915 functionally unknown variants (https://genemutation.fhs.um.edu.mo/Asian-BRCA/). We observed the highly ethnic-specific nature of Asian BRCA variants between Asian and non-Asian populations and within Asian populations, highlighting that the current European descendant population-based BRCA data is inadequate to reflect BRCA variation in the Asian population. We also provided archeological evidence for the evolutionary origin and arising time of Asian BRCA variation. We further provided structural-based evidence for the deleterious variants enriched within the functionally unknown Asian BRCA variants. The data from our study provide a current view of BRCA variation in the Asian population and a rich resource to guide clinical applications of BRCA-related cancer for the Asian population., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The SNO+ Collaboration reports the first evidence of reactor antineutrinos in a Cherenkov detector. The nearest nuclear reactors are located 240 km away in Ontario, Canada. This analysis uses events with energies lower than in any previous analysis with a large water Cherenkov detector. Two analytical methods are used to distinguish reactor antineutrinos from background events in 190 days of data and yield consistent evidence for antineutrinos with a combined significance of 3.5σ.

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.

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/., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Loss of proteostasis can occur due to mutations, the formation of aggregates, or general deficiency in the correct translation and folding of proteins. These phenomena are commonly observed in pathologies, but most significantly, loss of proteostasis characterizes aging. This loss leads to the chronic activation of stress responses and has a generally deleterious impact on the organism. While finding molecules that can alleviate these symptoms is an important step toward solutions for these conditions, some molecules might be mischaracterized on the way. 4-phenylbutyric acid (4PBA) is known for its role as a chemical chaperone that helps alleviate endoplasmic reticulum (ER) stress, yet a scan of the literature reveals that no biochemical or molecular experiments have shown any protein refolding capacity. Here, we show that 4PBA is a conserved weak inhibitor of mRNA translation, both in vitro and in cellular systems, and furthermore-it does not promote protein folding nor prevents aggregation. 4PBA possibly alleviates proteostatic or ER stress by inhibiting protein synthesis, allowing the cells to cope with misfolded proteins by reducing the protein load. Better understanding of 4PBA biochemical mechanisms will improve its usage in basic science and as a drug in different pathologies, also opening new venues for the treatment of different diseases., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Molecular Dynamics (MD) Simulations is increasingly used as a powerful tool to study protein structure-related questions. Starting from the early simulation study on the photoisomerization in rhodopsin in 1976, MD Simulations has been used to study protein function, protein stability, protein-protein interaction, enzymatic reactions and drug-protein interactions, and membrane proteins. In this review, we provide a brief review for the history of MD Simulations application and the current status of MD Simulations applications in protein studies.

Compared to the significant effort dedicated toward developing efficient electrochromic materials for the working electrodes of electrochromic (EC) devices, the attention paid to developing ion storage counter electrode materials for EC devices has been trivial. Herein, we report that a macroporous crystalline V 2 O 5 film as an ion storage layer paired with a WO 3 working electrode results in an EC device with high performance. The macroporous vanadium oxide films are prepared by a simple template-free photodeposition method that allows us to tune the thickness and crystallinity of the film, thus giving access to a full EC device with optimal EC performance: short response time of about 2 s, high electrochromic cycling stability up to 10,000 times, long memory effect over 24 h, and an exceedingly high coloration efficiency of 189 cm 2 /C that are superior to the state-of-the-art performance of solution-processed vanadium oxide based EC devices. The extraordinary EC performance can be attributed to the macroporous structure, high crystallinity, and optimized thickness of the vanadium oxide films that boost the charge-balancing capability of the films. The easy and controllable preparation and the efficient charge-balancing capability of the macroporous vanadium oxide film make it a promising ion storage material for developing high-performance EC devices.

Background: Identifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR) genes including MLH1 , MSH2 , MSH6 and PMS2 play essential roles in maintaining microsatellite stability through DNA mismatch repair, and pathogenic variation in MMR genes causes microsatellite instability and is the genetic predisposition for cancer as represented by the Lynch syndrome. While the prevalence and spectrum of MMR variation has been extensively studied in cancer, it remains largely elusive in the general population. Lack of the knowledge prevents effective prevention for MMR variation-caused cancer. In the current study, we addressed the issue by using the Chinese population as a model., Methods: We performed extensive data mining to collect MMR variant data from 18 844 ethnic Chinese individuals and comprehensive analyses for the collected MMR variants to determine its prevalence, spectrum and features of the MMR data in the Chinese population., Results: We identified 17 687 distinct MMR variants. We observed substantial differences of MMR variation between the general Chinese population and Chinese patients with cancer, identified highly Chinese-specific MMR variation through comparing MMR data between Chinese and non-Chinese populations, predicted the enrichment of deleterious variants in the unclassified Chinese-specific MMR variants, determined MMR pathogenic prevalence of 0.18% in the general Chinese population and determined that MMR variation in the general Chinese population is evolutionarily neutral., Conclusion: Our study provides a comprehensive view of MMR variation in the general Chinese population, a resource for biological study of human MMR variation, and a reference for MMR-related cancer applications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Large quantity of variants of uncertain significance (VUS) has been identified in cancer predisposition genes, but classification of VUS remains a big challenge. We proposed that the impact of VUS on protein structure stability can be used to identify these with deleterious effects by using molecular dynamics simulation (MDS)-based approach and developed a MDS-based method for missense VUS classification. In the current study, we applied the system to classify the missense VUS in BRCA2. BRCA2 plays an important role in maintaining genome stability by repairing double-strand DNA damage through homologous recombination. BRCA2 BRC repeats bring RAD51 from cytoplasm to the break sites in nucleus to initiate the repairing process. Missense variants in BRCA2 BRC repeats can interfere the interaction between BRCA2 and RAD51, impair double-strand break repair, cause genome instability and increase cancer risk. We characterized the missense VUS in BRCA2 BRC4 repeat, the primary site of BRCA2 interacting with RAD51. Based on the well-determined BRC4 structure, we applied MDS to measure the impact of BRC4 missense VUS on the stability of BRC4 structure by testing the equilibrium state, flexibility, compactness, hydrogen bonds and surface accessibility. Of the 46 missense VUS analyzed, we were able to differentiate them into 24 Deleterious and 22 Tolerated variants. Comparison between the MDS-based and other 24 existing computational methods for variant classification showed that the MDS-based approach is highly sensitive and specific for classifying missense VUS in cancer predisposition genes., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Millions of people have acquired and died from SARS-CoV-2 infection during the COVID-19 pandemic. Healthcare workers (HCWs) are required to wear personal protective equipment (PPE), including surgical masks and P2/N95 respirators, to prevent infection while treating patients. However, the comparative effectiveness of respirators and masks in preventing SARS-CoV-2 infection and the likelihood of experiencing adverse events (AEs) with wear are unclear., Methods: Searches were carried out in PubMed, Europe PMC and the Cochrane COVID-19 Study Register to 14 June 2021. A systematic review of comparative epidemiological studies examining SARS-CoV-2 infection or AE incidence in HCWs wearing P2/N95 (or equivalent) respirators and surgical masks was performed. Article screening, risk of bias assessment and data extraction were duplicated. Meta-analysis of extracted data was carried out in RevMan., Results: Twenty-one studies were included, with most having high risk of bias. There was no statistically significant difference in respirator or surgical mask effectiveness in preventing SARS-CoV-2 infection (OR 0.85, [95%CI 0.72, 1.01]). Healthcare workers experienced significantly more headaches (OR 2.62, [95%CI 1.18, 5.81]), respiratory distress (OR 4.21, [95%CI 1.46, 12.13]), facial irritation (OR 1.80, [95%CI 1.03, 3.14]) and pressure-related injuries (OR 4.39, [95%CI 2.37, 8.15]) when wearing respirators compared to surgical masks., Conclusion: The existing epidemiological evidence does not enable definitive assessment of the effectiveness of respirators compared to surgical masks in preventing infection. Healthcare workers wearing respirators may be more likely to experience AEs. Effective mitigation strategies are important to ensure the uptake and correct use of respirators by HCWs., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

In the era of data science, data-driven algorithms have emerged as powerful platforms that can consolidate bioisosteric rules for preferential modifications on small molecules with a common molecular scaffold. Here we present complementary data-driven algorithms to minimize the search in chemical space for phenylthiazole-containing molecules that bind the RNA hairpin within the ribosomal peptidyl transferase center (PTC) of Mycobacterium tuberculosis. Our results indicate visual, geometrical, and chemical features that enhance the binding to the targeted RNA. Functional validation was conducted after synthesizing 10 small molecules pinpointed computationally. Four of the 10 were found to be potent inhibitors that target hairpin 91 in the ribosomal PTC of M. tuberculosis and, as a result, stop translation., (© 2022. The Author(s).)

The COVID-19 pandemic, caused by SARS-CoV-2, has led to catastrophic damage for global human health. The initial step of SARS-CoV-2 infection is the binding of the receptor-binding domain (RBD) in its spike protein to the ACE2 receptor in the host cell membrane. Constant evolution of SARS-CoV-2 generates new mutations across its genome including the coding region for the RBD in the spike protein. In addition to the well-known single mutation in the RBD, the recent new mutation strains with an RBD "double mutation" are causing new outbreaks globally, as represented by the delta strain containing RBD L452R/T478K. Although it is considered that the increased transmissibility of double-mutated strains could be attributed to the altered interaction between the RBD and ACE2 receptor, the molecular details remain to be elucidated. Using the methods of molecular dynamics simulation, superimposed structural comparison, free binding energy estimation, and antibody escaping, we investigated the relationship between the ACE2 receptor and the RBD double mutants of L452R/T478K (delta), L452R/E484Q (kappa), and E484K/N501Y (beta, gamma). The results demonstrated that each of the three RBD double mutants altered the RBD structure and enhanced the binding of the mutated RBD to ACE2 receptor. Together with the mutations in other parts of the virus genome, the double mutations increase the transmissibility of SARS-CoV-2 to host cells.

Rationale: The end of life (EOL) experience in the intensive care unit (ICU) can be psychologically distressing for patients, families, and clinicians. The 3 Wishes Project (3WP) personalizes the EOL experience by carrying out wishes for dying patients and their families. While the 3WP has been integrated in academic, tertiary care ICUs, implementing this project in a community ICU has yet to be described., Objectives: To examine facilitators of, and barriers to, implementing the 3WP in a community ICU from the clinician and implementation team perspective., Methods: This qualitative descriptive study evaluated the implementation of the 3WP in a 20-bed community ICU in Southern Ontario, Canada. Patients were considered for the 3WP if they had a high likelihood of imminent death or planned withdrawal of life-sustaining therapy. Following the qualitative descriptive approach, semi-structured interviews were conducted with purposively sampled clinicians and implementation team. Data from transcribed interviews were analyzed in triplicate through qualitative content analysis., Results: Interviews with 12 participants indicated that the 3WP personalized and enriched the EOL experience. Interviewees indicated higher intensity education strategies were needed to enable spread as the project grew. Clinicians described many physical resources for the project but suggested more non-clinical project support for orientation, continuing education, and data collection. A majority of wishes focused on physical resources including keepsakes, which helped facilitate project spread when clinician capacity was attenuated by competing duties., Conclusions: In this community hospital, ICU clinicians and implementation team members report perceived improved EOL care for patients, families, and clinicians following 3WP initiation and integration. Implementing individualized and meaningful wishes at EOL for dying patients in a community ICU requires adequate planning and time dedicated to optimizing clinician education. Adapting key features of an intervention to local expertise and capacity may facilitate spread during project initiation and integration., (© 2021 John Wiley & Sons, Ltd.)

Background: As the number of households with dogs in the United States has increased, so has the incidence of dog bites. Contemporary analysis of nationwide epidemiological data regarding such injuries is scarce. The purpose of this study is to describe dog bite injury patterns and related surgical interventions with a focus on differences between pediatric and adult age groups., Study Design: This is a retrospective study (2015-2017) using the National Trauma Data Bank. 10 569 patients were included., Results: Of these, 4729 (44.7%) qualified as pediatric (age ≤ 12 years) and 5840 (55.3%) qualified as adults (age ≥ 13 years). Pediatric patients were more frequently admitted with facial injuries (78.1% vs. 29.3%, P < .01) and facial fractures (4.8% vs. 2.5%, P < .01), and had a higher incidence of facial bone surgical procedures (1.3% vs. .5%, P < .01). Adult patients were more frequently admitted with upper extremity injuries (65.8% vs. 21.2%, P < .01) and upper extremity vascular arterial injuries (2.3% vs. .2%, P < .01) with a higher incidence of upper extremity arterial procedures (1.3% vs. .2%, P < .01)., Conclusion: This study demonstrates the contrast in injury patterns from dog bite between adults and children. These findings can dictate injury prevention policies and prepare clinicians to treat dog bite victims.

Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium that caused 1.5 million fatalities globally in 2018. New strains of Mtb resistant to all known classes of antibiotics pose a global healthcare problem. In this work, we have conjugated novel indole-3-acetic acid-based DNA primase/gyrase inhibitor with cell-penetrating peptide via cleavable and non-cleavable bonds. For non-cleavable linkage, inhibitor was conjugated with peptide via an amide bond to the N-terminus, whereas a cleavable linkage was obtained by conjugating the inhibitor through a disulfide bond. We performed the conjugation of the inhibitor either directly on a solid surface or by using solution-phase chemistry. M. smegmatis (non-pathogenic model of Mtb) was used to determine the minimal inhibitory concentration (MIC) of the synthetic conjugates. Conjugates were found more active as compared to free inhibitor molecules. Strikingly, the conjugate also impairs the development of biofilm, showing a therapeutic potential against infections caused by both planktonic and sessile forms of mycobacterium species., (© 2021 John Wiley & Sons Ltd.)

TP53 plays critical roles in maintaining genome stability. Deleterious genetic variants damage the function of TP53, causing genome instability and increased cancer risk. Of the large quantity of genetic variants identified in TP53, however, many remain functionally unclassified as variants of unknown significance (VUS) due to the lack of evidence. This is reflected by the presence of 749 (42%) VUS of the 1785 germline variants collected in the ClinVar database. In this study, we addressed the deleteriousness of TP53 missense VUS. Utilizing the protein structure-based Ramachandran Plot-Molecular Dynamics Simulation (RPMDS) method that we developed, we measured the effects of missense VUS on TP53 structural stability. Of the 340 missense VUS tested, we observed deleterious evidence for 193 VUS, as reflected by the TP53 structural changes caused by the VUS-substituted residues. We compared the results from RPMDS with those from other in silico methods and observed higher specificity of RPMDS in classification of TP53 missense VUS than these methods. Data from our current study address a long-standing challenge in classifying the missense VUS in TP53, one of the most important tumor suppressor genes.

Competing Interests: Competing interests: None declared.