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Objective: To generate a heart failure (HF) readmission prediction model using the Nationwide Readmissions Database to guide management and reduce HF readmissions. Patients and Methods: A retrospective analysis was performed for patients listed for HF admissions in the Nationwide Readmissions Database from January 1, 2010, to December 31, 2014. A Cox proportional hazards model for sample survey data for the prediction of readmission for all patients with HF was implemented using a derivation cohort (2010-2012). We generated receiver operating characteristic (ROC) curves and estimated area under the ROC curve at each time point (30, 60, 90, and 180 days) to assess the accuracy of our predictive model using the derivation cohort (2010-2012) and compared it with the validation cohort (2013-2014). A risk score was computed for the validation cohort. On the basis of the total risk score, we calculated the probability of readmission at 30, 60, 90, and 180 days. Results: Approximately 1,420,564 patients were admitted for HF, contributing to 1,817,735 total HF admissions. Of these, 665,867 patients had at least 1 readmission for HF. The 10 most common comorbidities for readmitted patients included hypertension, diabetes mellitus, renal failure, chronic pulmonary disease, deficiency anemia, fluid and electrolyte disorders, obesity, hypothyroidism, peripheral vascular disorders, and depression. The area under the ROC curve for the prediction model was 0.58 in the derivation cohort and 0.59 in the validation cohort. Conclusion: The prediction model will find clinical utility at point of care in optimizing the management of patients with HF and reducing HF readmissions.

Introduction: The purpose of this study is to investigate the effects of automatic segmentation algorithms on the performance of ultrasound (US) radiomics models in predicting the status of lymph node metastasis (LNM) for patients with early stage cervical cancer preoperatively. Methods: US images of 148 cervical cancer patients were collected and manually contoured by two senior radiologists. The four deep learning-based automatic segmentation models, namely U-net, context encoder network (CE-net), Resnet, and attention U-net were constructed to segment the tumor volumes automatically. Radiomics features were extracted and selected from manual and automatically segmented regions of interest (ROIs) to predict the LNM of these cervical cancer patients preoperatively. The reliability and reproducibility of radiomics features and the performances of prediction models were evaluated. Results: A total of 449 radiomics features were extracted from manual and automatic segmented ROIs with Pyradiomics. Features with an intraclass coefficient (ICC) > 0.9 were all 257 (57.2%) from manual and automatic segmented contours. The area under the curve (AUCs) of validation models with radiomics features extracted from manual, attention U-net, CE-net, Resnet, and U-net were 0.692, 0.755, 0.696, 0.689, and 0.710, respectively. Attention U-net showed best performance in the LNM prediction model with a lowest discrepancy between training and validation. The AUCs of models with automatic segmentation features from attention U-net, CE-net, Resnet, and U-net were 9.11%, 0.58%, –0.44%, and 2.61% higher than AUC of model with manual contoured features, respectively. Conclusion: The reliability and reproducibility of radiomics features, as well as the performance of radiomics models, were affected by manual segmentation and automatic segmentations.

The project was intended to bring all NHGD DXA machines a state of cross-calibration to allow patients to have follow up scans done at different scanners and still have comparable DXA results. DXA machines are measurement instruments which are high internal accuracy but poor external precision when compared against other DXA machines. Cross-calibration between DXA machines are performed to ensure that DXA results obtained from different DXA machines can be compared for comparison study, while allowing flexibility for patients with increased access to wider range of DXA machines without compromising on their DXA results within primary healthcare. The Cross-Calibration exercise was performed according to the guidelines in ISCD Official position 2019 for cross-calibration of DXA scanner of same make and model for 20 days. The NHGD identified "Gold Spine Phantom" was transported in a shockproof case by appointed courier service between the DXA machines during the exercise period. The DXA values obtained during the period were recorded and mean DXA was calculated. Subsequently, Quality Control (QC) plots were reviewed monthly for monitoring after the cross-calibration exercise. The percentage difference of all new DXA scanners to index scanner in NHGD is 0.01%, 0.19% and 0.11% respectively, within 0.5% difference. The QC Plots are stable within limits (0.12%, 0.05%, 0.18% and 0.13% respectively). All 4 unit of NHGD DXA machines were observed to be within cross-calibrated limit, indicating results obtained on the DXA scanners can be used interchangeably, allowing comparing of DXA results within the acceptable limit. This allows flexibility and accessibility of DXA scanners to the community at risk of osteoporosis. This study may provide an insight and could potentially be an initiator for the cross-calibration exercise among multiple DXA facilities within cluster or nationwide. [ABSTRACT FROM AUTHOR]

Osteochondral allograft transplantation is a well-accepted treatment for articular cartilage damage. However, chondrocyte viability declines during graft storage, which may compromise graft performance. We first tested the hypothesis that the composition of commonly used storage media affects the viability of articular chondrocytes over time; we then tested the hypothesis that the addition of insulin growth factor-1 or the apoptosis inhibitor ZVAD-fmk could enhance the storage properties of serum-free media. Bovine osteochondral grafts were stored at 4 degrees C in lactated Ringer's, Dulbecco's modified eagle's media (DMEM), DMEM supplemented with either insulin growth factor-1 or ZVAD-fmk, and a commercial storage media. Chondrocyte viability in lactated Ringer's declined rapidly to 20.4% at 2 weeks. Viability in DMEM declined more slowly to 54.8% at 2 weeks and 31.2% at 3 weeks. Viability in commercial storage media was 83.6% at 3 weeks and 44.8% at 4 weeks. Viability was increased in DMEM + insulin growth factor-1 (56.4%) and DMEM + ZVAD (52.4%) at 3 weeks compared with DMEM alone. These results confirm the hypotheses that media composition greatly influences chondrocyte viability during cold storage and that insulin growth factor-1 and ZVAD improve the storage properties of DMEM. [ABSTRACT FROM AUTHOR]

Osteochondral allograft transplantation is a useful technique to manage larger articular cartilage injuries. One factor that may compromise the effectiveness of this procedure is chondrocyte cell death that occurs during the storage, preparation, and implantation of the osteochondral grafts. Loss of viable chondrocytes may negatively affect osteochondral edge integration and long-term function. A better understanding of the mechanisms responsible for chondrocyte loss could lead to interventions designed to decrease cell death and improve results. Recent studies indicate that apoptosis, or programmed cell death, is responsible for much of the chondrocyte death associated with osteochondral allograft transplantation. Theoretically, some of these cells can be rescued by blocking important apoptotic mediators. We review the role of apoptosis in cartilage degeneration, focusing on apoptosis associated with osteochondral transplantation. We also review the pathways thought to be responsible for regulating chondrocyte apoptosis, as well as experiments testing inhibitors of the apoptotic pathway. These data suggest that key contributors to the apoptotic process can be manipulated to enhance chondrocyte survival. This knowledge may lead to better surgical outcomes for osteochondral transplantation. [ABSTRACT FROM AUTHOR]

Objective: Patients undergoing free flap reconstruction of the oral cavity have traditionally received nothing by mouth for 6-14 days postoperatively to limit the risk of wound complications. Growing evidence suggests that initiation of oral intake may not increase the morbidity. This study further investigates the utility of "early feeding.", Methods: This was a retrospective cohort study conducted at a large, urban tertiary healthcare system. Patients who underwent free flap reconstruction for oral cavity cancer between June 1, 2020, and October 31, 2022, were grouped as early feeding (oral intake on or before Postoperative Day 5) or late feeding (LF) (oral intake after Postoperative Day 5). Outcomes included rate of orocutaneous fistula, development of other local or systemic complications, and hospital length of stay (LOS)., Results: Sixty six patients were studied, with 26 belonging to the LF group and 40 to the early feeding (EF) group. The LF group was significantly older (median age 64.5 vs. 80 years, p = 0.027) and more likely to have a defect extending beyond the oral cavity (25.0% vs. 50.0%, p = 0.037). No significant differences were found in orocutaneous fistula formation between the LF and EF groups (7.7% vs. 0%, p = 0.152), but the rate of total complications was significantly higher in the LF group (38.5% vs. 12.5%, p = 0.014). LOS was significantly longer in the LF group (12.5 vs. 6 days, p < 0.001)., Conclusion: These findings suggest that in the correctly suggested patient population, early postoperative oral intake may facilitate earlier hospital discharge without increasing the risk of postoperative complications., (© 2025 Wiley Periodicals LLC.)

Background : Despite the widespread use of lipid-lowering agents, the risk of atherosclerotic cardiovascular disease (ASCVD) remains; this residual risk has been attributed to remnant cholesterol (RC) levels. However, the causal associations between RC levels and various atherosclerosis-related cardiometabolic and vascular risk factors for ASCVD remain unclear. Methods : Using genetic and biochemical data of 108,876 Taiwan Biobank study participants, follow-up data of 31,790 participants, and follow-up imaging data of 18,614 participants, we conducted a genome-wide association study, a Functional Mapping and Annotation analysis, and bidirectional Mendelian randomization analyses to identify the genetic determinants of RC levels and the causal associations between RC levels and various cardiometabolic and vascular risk factors. Results : We found that higher RC levels were associated with higher prevalence or incidence of the analyzed risk factors. The genome-wide association study unveiled 61 lead genetic variants determining RC levels. The Functional Mapping and Annotation analysis revealed 21 gene sets exhibiting strong enrichment signals associated with lipid metabolism. Standard Mendelian randomization models adjusted for nonlipid variables and low-density lipoprotein cholesterol levels unraveled forward causal associations of RC levels with the prevalence of diabetes mellitus, hypertension, microalbuminuria, and metabolic liver disease. Reverse Mendelian randomization analysis revealed the causal association of diabetes mellitus with RC levels. Conclusions : RC levels, mainly influenced by genes associated with lipid metabolism, exhibit causal associations with various cardiometabolic risk factors, including diabetes mellitus, hypertension, microalbuminuria, and metabolic liver disease. This study provides further insights into the role of RC levels in predicting the residual risk of ASCVD.

Human resistin is a proinflammatory cytokine involving the development and progression of cancer and cardiovascular diseases. However, prediction of long-term outcome using circulating resistin level and its genetic determinants in a population-based study remain to be explored. After genome-wide association study (GWAS), DNA methylation (DNAm) analysis and functional assays of a RETN rs370006313 variant, we tested whether resistin level and its genetic determinants can be used to determine the long-term outcomes of 5678 Taiwan Biobank (TWB) participants. GWAS and DNAm analysis revealed RETN variants, rs3219175, rs370006313, and rs3745368, and DNAm sites, cg21271423 and cg09909011, independently associated with circulating resistin levels. Functional assays showed rs370006313 variant played a key role in affecting RETN promoter activity, whereas genotypes of rs3219175 and rs3745368, but not rs370006313, exhibited genome-wide significant associations with RETN promoter DNAm levels. Using Kaplan-Meier survival and Cox regression analyses, participants with progressively increasing resistin levels had a higher hazard ratio for all-cause mortality and cancer mortality compared to those with lower resistin levels. Participants with all three RETN variants (high mutation burden) also exhibited significantly higher hazard ratios for all-cause mortality and cancer mortality, at 3.99 and 5.55, respectively, compared to those without a high mutation burden. In conclusion, RETN rs370006313 is a functional variant affecting RETN promoter activity. Elevated circulating resistin levels and a high RETN mutation burden predict all-cause and cancer mortality in TWB participants. Both resistin levels and RETN variants may serve as biomarkers of long-term outcomes in the general Taiwanese populations., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

YKL-40 is significantly associated with the prevalence and severity of coronary artery disease (CAD). YKL-40 levels are significantly associated with variations in the CHI3L1 and TRIB1 genes. We investigated candidate genes for YKL-40 levels and evaluated the prognostic value of this biomarker and corresponding variants for long-term outcomes in patients with CAD. We included 4664 and 521 participants from the Taiwan Biobank (TWB) and CAD cohorts, respectively. Candidate variants for circulating YKL-40 levels were investigated using genome-wide association study (GWAS) data from the TWB cohort, and the results were validated in the CAD cohort. The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiac events (MACEs), which included the composite endpoints of all-cause mortality, nonfatal acute coronary syndrome, hospitalization for heart failure, and nonfatal stroke. According to the GWAS data from the TWB cohort, three CHI3L1 variants (rs4950928, rs10399931, and rs872129) and one TRIB1 variant (rs6982502) were independently associated with YKL-40 levels. These findings were validated in the CAD cohort. The combined CHI3L1 and TRIB1 weighted genetic risk scores (WGRSs) were not associated with the long-term outcomes (median follow-up period of 3.7 years) in patients with CAD. Conversely, patients with YKL-40 levels in the upper tertile had the highest rates of all-cause mortality and MACEs (log-rank p = 9.58 × 10 -8 for all-cause mortality and 1.34 × 10 -7 for MACEs). Furthermore, YKL-40 levels predicted poor clinical outcomes only in patients with multivessel CAD (log-rank p = 3.0 × 10 -6 for all-cause mortality and 1.10 × 10 -5 for MACEs) and not in patients with single-vessel CAD. This study revealed that YKL-40 levels but not the combined CHI3L1 and TRIB1 WGRSs were found to be independent predictors of poor clinical outcomes in patients with multivessel CAD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: Our primary objective was to identify and describe trends in head and neck injuries incurred while participating in barbell weightlifting., Study Design: Cross-sectional analysis., Setting: National database., Methods: We used data from the National Electronic Injury Surveillance System (NEISS) from 2014 to 2023. Population characteristics of barbell-related injuries (NEISS Code 3265), including age and sex distributions, were recorded. We further analyzed the distribution of injury anatomic locations, injury types, fracture locations, and patient dispositions. To identify statistical significance, nonparametric tests were performed., Results: Between 2014 and 2023, 3105 cases of barbell-related head and neck injuries were identified, predominantly in males (n = 2227, 71.7%) with a mean age of 27.7 years (SD: 11.9 years). The majority of patients (n = 2193, 74.5%) were treated and released, while 71 patients (2.3%) required hospital admission. The most affected body part was the head (n = 1,368, 44.1%), followed by the neck (n = 993, 32%), the face (n = 614, 19.8%), the mouth (n = 108, 3.5%), and the ear (n = 22, 0.7%). The most common location of injury was a recreational or sports facility (n = 1143; 36.8%), with other significant locations being the home (n = 542; 17.5%), and unspecified locations (n = 1065; 34.3%). Lacerations were the most common injury type (n = 682; 32.4%). Moreover, lacerations were more significantly associated with barbell weightlifting at home ( P  < .001) than in a recreational or sports facility., Conclusion: This study demonstrates that a substantial number of barbell-related injuries occur above the shoulder. This knowledge can inform the development of safety measures, including potential reforms in rules, regulations, and protective equipment., Competing Interests: None., (© 2024 The Author(s). OTO Open published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Objective: To characterize Otolaryngology residency program strategies for recruiting underrepresented minorities in medicine (URiM) residents and their perceived effectiveness, and explore perceived barriers to recruitment., Design: We conducted a survey of Otolaryngology program directors (PDs) at the 122 accredited programs within the United States, utilizing a validated and previously published survey utilized within the OB-GYN literature. We solicited information regarding recruitment of underrepresented minorities in medicine (URiM) applicants, effectiveness of strategies, and perceived barriers in recruitment., Setting: A national survey of U.S. accredited residency programs in Otolaryngology in 2022-2023., Results: A total of 42 (34%) PDs responded. 55% of programs reported an increase in URiM residents, of which 18(43%) described an intentional change. Almost all PDs reported placing at least "some" significance in the recruitment of URiM residents (95%). Statistically significant differences were seen in recruitment methods between programs that saw an increase in URiM resident recruitment an those that did not. Additionally, Program Directors believed that increased face-face interaction with applicants were the most effective forms of recruitment. PDs found the biggest challenge to recruitment was a lack of diverse applicants (6.3/10) and faculty (5.8/10). This perception did not change when adjusted for programs that saw an increase in URiM trainee recruitment., Conclusions: This study demonstrates the URiM resident recruitment practices and perceived effectiveness of these strategies within otolaryngology programs nationally. The results and analysis may provide programs who are looking to diversify their workforce with some effective and meaningful strategies to start the process., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Importance: The most frequent presenting symptom for patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a lateral neck mass. Circulating tumor tissue-modified viral (TTMV)-HPV DNA is a unique biomarker produced by the fragmentation of HPV DNA during the degradation of HPV-associated tumors, and its detection and quantitation are currently being used as an adjunct to imaging in monitoring for disease recurrence and may have utility for diagnosis., Objective: To measure the diagnostic characteristics of TTMV-HPV DNA compared with gold standard tissue biopsy for diagnosing HPV-OPSCC in patients presenting with an indeterminate lateral neck mass., Design, Setting, and Participants: This prospective diagnostic test study enrolled patients 18 years or older who presented with a lateral neck mass to a large urban tertiary health care system from December 2021 to June 2023. Participants underwent standard-of-care testing to obtain a tissue diagnosis and a single TTMV-HPV DNA measurement., Main Outcomes and Measures: The primary outcome of interest was sensitivity, while specificity, positive predictive value, and negative predictive value were secondary end points. A subset analysis was performed comparing test performance metrics between TTMV-HPV DNA testing and fine-needle aspiration., Results: A total of 138 patients were included, of whom 80 (58.0%) were men, with median age of 57.5 years (IQR, 43.3-67.0 years). Of 138 patients, 87 (63.0%) had neck masses in level 2 and 47 (34.1%) had HPV-OPSCC. TTMV-HPV DNA testing exhibited a sensitivity of 95.7% (95% CI, 85.5%-99.5% [45 of 47 patients]), specificity of 97.8% (95% CI, 92.3%-99.7% [89 of 91 patients]), positive predictive value of 95.7% (95% CI, 85.5%-99.5% [45 of 47 patients]), and negative predictive value of 97.8% (95% CI, 92.3%-99.7% [89 of 91 patients])., Conclusions and Relevance: In this diagnostic study of patients presenting with a lateral neck mass, circulating TTMV-HPV DNA demonstrated excellent diagnostic test characteristics for the detection of HPV-OPSCC. Such testing may have particular utility for patients in whom obtaining adequate tissue is problematic, as is often the case with cystic neck masses and unknown primary tumors.

Introduction: Letters of recommendation (LORs) are a highly influential yet subjective and often enigmatic aspect of the residency application process. This study hypothesizes that LORs do contain valuable insights into applicants and can be used to predict outcomes. This pilot study utilizes natural language processing and machine learning (ML) models using LOR text to predict interview invitations for otolaryngology residency applicants., Methods: A total of 1642 LORs from the 2022-2023 application cycle were retrospectively retrieved from a single institution. LORs were preprocessed and vectorized using three different techniques to represent the text in a way that an ML model can understand written prose: CountVectorizer (CV), Term Frequency-Inverse Document Frequency (TF-IDF), and Word2Vec (WV). Then, the LORs were trained and tested on five ML models: Logistic Regression (LR), Naive Bayes (NB), Decision Tree (DT), Random Forest (RF), and Support Vector Machine (SVM)., Results: Of the 337 applicants, 67 were interviewed and 270 were not interviewed. In total, 1642 LORs (26.7% interviewed) were analyzed. The two best-performing ML models in predicting interview invitations were the TF-IDF vectorized DT and CV vectorized DT models., Conclusion: This preliminary study revealed that ML models and vectorization combinations can provide better-than-chance predictions for interview invitations for otolaryngology residency applicants. The high-performing ML models were able to classify meaningful information from the LORs to predict applicant interview invitation. The potential of an automated process to help predict an applicant's likelihood of obtaining an interview invitation could be a valuable tool for training programs in the future., Level of Evidence: N/A Laryngoscope, 134:4016-4022, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter, plays a crucial role in regulating bile acid levels and influencing the risk of HBV infection. Genetic variations in the SLC10A1 gene, which encodes NTCP, affect these functions. However, the impact of SLC10A1 gene variants on the metabolic and biochemical traits remained unclear. We aimed to investigate the association of SLC10A1 gene variants with the clinical and biochemical parameters, and the risk of different HBV infection statuses and gallstone disease in the Taiwanese population. Genotyping data from 117,679 Taiwan Biobank participants were analyzed using the Axiom genome-wide CHB arrays. Regional-plot association analysis demonstrated genome-wide significant association between the SLC10A1 rs2296651 genotypes and lipid profile, gamma glutamyl transferase (γGT) level and anti-HBc-positivity. Genotype-phenotype association analyses revealed significantly lower total cholesterol, low-density lipoprotein (LDL) cholesterol and uric acid levels, a higher γGT level and a higher gallstone incidence in rare rs2296651-A allele carrier. Participants with the rs2296651 AA-genotype exhibited significantly lower rates of anti-HBc-positivity and HBsAg-positivity. Compared to those with the GG-genotype, individuals with non-GG-genotypes had reduced risks for various HBV infection statuses: the AA-genotype showed substantially lower risks, while the GA-genotype demonstrated modestly lower risks. Predictive tools also suggested that the rs2296651 variant potentially induced protein damage and pathogenic effects. In conclusion, our data revealed pleiotropic effects of the SLC10A1 rs2296651 genotypes on the levels of biochemical traits and the risk of HBV infection and gallstone disease. This confirms SLC10A1's versatility and implicates its genotypes in predicting both biochemical traits and disease susceptibility., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To compare human papillomavirus (HPV) testing, prevalence, and association with prognosis between head and neck squamous cell carcinoma (HNSCC) subsites., Materials and Methods: This study utilized the National Cancer Database (NCDB) to identify patients diagnosed with HNSCC between 2010 and 2017. Rates of HPV testing, HPV-positivity, and changes in these rates over time were measured by subsite. The impact of HPV-positivity on overall survival across six head and neck subsites was assessed using multivariable-adjusted Cox proportional hazards analysis., Results: A total of 121,550 patients were included. Of this cohort, 87,575 (72.1%) were tested for HPV, with the oropharynx (55,049/64,158; 85.8%) displaying the highest rates of testing and the sinonasal tract (1519/2853; 53.2%) displaying the lowest testing rates. Of the 86,136 with a definitive result, 46,878 (54.4%) were HPV-positive, with the oropharynx (40,313/54,205; 74.4%) displaying the highest rates of HPV-positivity and the oral cavity (1818/11,505; 15.8%) displaying the lowest. HPV-positive malignancy was associated with significantly improved adjusted overall survival in the oropharynx (HR = 0.42 [95% CI: 0.43-0.47]), oral cavity (HR = 0.86 [95% CI: 0.79-0.95]), sinonasal tract (HR = 0.63 [95% CI: 0.48-0.83]), larynx (HR = 0.78 [95% CI: 0.71-0.87]), and hypopharynx (HR = 0.56 [95% CI: 0.48-0.66]), but not the nasopharynx (HR = 0.93 [95% CI: 0.77-1.14])., Conclusion: HPV testing rates were significantly lower in non-oropharyngeal subsites. This is relevant as HPV-associated disease displayed significantly improved overall survival in both the oropharynx and four of five non-oropharyngeal subsites. While validation with prospective studies is necessary, these findings may warrant HPV testing in all HNSCC subsites., Competing Interests: Declaration of competing interest No conflicts of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Traditionally, patients undergoing free flap reconstruction for oral cavity defects have been given nothing by mouth for 6-14 days post-operatively due to concern for orocutaneous fistula development., Methods: Multiple databases were screened for studies assessing the rate of orocutaneous fistula formation in early (≤5 days) versus late (>5 days) feeding groups following oral cavity free flap reconstruction. Fixed- and random-effects meta-analyses were used., Results: One randomized controlled trial, one prospective cohort, and three retrospective cohort studies were included. The early feeding group displayed no significant increase in orocutaneous fistula formation (RD = -0.02, p = 0.06) or free flap failure (RD = -0.01, p = 0.39), with a significantly shorter hospital length of stay (mean difference [days] = -2.43, p < 0.01)., Conclusions: While further prospective trials are necessary, initiation of oral intake before post-operative day 5 may be appropriate in properly selected patients following oral reconstruction., (© 2024 Wiley Periodicals LLC.)

Importance: There is growing interest in the use of circulating plasma tumor human papillomavirus (HPV) DNA for diagnosis and surveillance of patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Recent advances in the assays, combining the identification of circulating HPV tumor DNA and tumor DNA fragment analysis (tumor tissue-modified viral [TTMV]-HPV DNA), have been shown to be highly accurate. However, use of these newer techniques has been limited to small cohort studies and clinical trials., Objective: To establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary clinical setting., Design, Setting, and Participants: This retrospective observational cohort study included patients with OPSCC who underwent TTMV-HPV DNA testing between April 2020 and September 2022 during the course of routine clinical care. For the diagnosis cohort, patients with at least 1 TTMV-HPV DNA measurement prior to initiation of primary therapy were included. Patients were included in the surveillance cohort if they had at least 1 TTMV-HPV DNA test performed after completion of definitive or salvage therapy., Main Outcomes and Measures: Per-test performance metrics, including sensitivity, specificity, positive predictive value, and negative predictive value, for TTMV-HPV DNA testing., Results: Of 399 patients included in the analysis, 163 were in the diagnostic cohort (median [IQR] age, 63 [56-68.5] years; 142 [87.1%] male), and 290 were in the surveillance cohort (median [IQR] age, 63 [57-70] years; 237 [81.7%] male). Of the 163 patients in the diagnostic cohort, 152 (93.3%) had HPV-associated OPSCC while 11 (6.7%) had HPV-negative OPSCC. The TTMV-HPV DNA sensitivity in pretreatment diagnosis was 91.5% (95% CI, 85.8%-95.4% [139 of 152 tests]), and the specificity was 100% (95% CI, 71.5%-100% [11 of 11 tests]). In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. A total of 23 patients had molecularly confirmed pathologic recurrences. The TTMV-HPV DNA test demonstrated sensitivity of 88.4% (95% CI, 74.9%-96.1% [38 of 43 tests]) and specificity of 100% (95% CI, 99.3%-100% [548 of 548 tests]) in detecting the recurrences. Positive predictive value was 100% (95% CI, 90.7%-100% [38 of 38 tests]), and negative predictive value was 99.1% (95% CI, 97.9%-99.7% [548 of 553 tests]). The median (range) lead time from positive TTMV-HPV DNA test to pathologic confirmation was 47 (0-507) days., Conclusions and Relevance: This cohort study demonstrated that when evaluated in a clinical setting, the TTMV-HPV DNA assay demonstrated 100% specificity in both diagnosis and surveillance. However, the sensitivity was 91.5% for the diagnosis cohort and 88.4% for the surveillance cohort, signifying that nearly 1 in 10 negative tests among patients with HPV-associated OPSCC was a false negative. Additional research is required to validate the assay's performance and, if validated, then further research into the implementation of this assay into standard clinical practice guidelines will be required.

Our study aimed to investigate if genetic variants around 16p13.3's HBA1 locus, associated with erythrocyte indices and HbA1c levels, predict α-thalassemia-related erythrocyte indices, cardiometabolic traits, and diabetes risk in Taiwanese individuals. We analyzed Taiwan Biobank data, including whole-genome sequencing from 1,493 participants and genotyping arrays from 129,542 individuals. First, we performed regional association analysis using whole-genome sequencing data to identify genetic variants significantly associated with erythrocyte indices, confirming their linkage disequilibrium with the α 0 thalassemia -- SEA deletion mutation, a common cause of α-thalassemia in Southeast Asian populations. Deletion mutation sequencing further validated these variants' association with α-thalassemia. Subsequently, we analyzed genotyping array data, revealing associations between specific genetic variants and cardiometabolic traits, including lipid profiles, HbA1c levels, bilirubin levels, and diabetes risk. Using Mendelian randomization, we established causal relationships between α-thalassemia-related erythrocyte indices and cardiometabolic traits, elucidating their role in diabetes susceptibility. Our findings highlight genetic variants around the α-globin genes as surrogate markers for common α-thalassemia mutations in Taiwan, emphasizing the causal links between α-thalassemia-related erythrocyte indices, cardiometabolic traits, and heightened diabetes risk., (© 2023 Hsu et al.)

Objective: In 2016, the encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This reclassification removed the word "carcinoma" and the definition of cancer from the diagnosis. While the nomenclature change was expected to psychologically impact patients, that question has not been systematically explored. Using qualitative methods, we aimed to explore the psychological impact of reclassification on thyroid cancer patients and their preferences for receiving reclassification information., Methods: Semi-structured interviews with nine non-EFVPTC thyroid cancer survivors were conducted. Participants were presented with a hypothetical reclassification scenario, and interview transcripts were analyzed using a thematic content analytic approach., Results: Participants expressed a range of psychological reactions to reclassification information, primarily negative, including anger, mistrust, and uncertainty, but also relief. All participants expressed difficulty understanding the concept of reclassification. Communication preferences favored conversation with an established medical provider over written materials, such as a letter., Discussion and Conclusion: Communication must align with patient preferences. Being mindful of potential negative psychological reactions when providing information on cancer reclassification is vital., Innovation: This study examines reactions to cancer reclassification information and preferences for how this information should be communicated., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Among six extant tiger subspecies, the South China tiger (Panthera tigris amoyensis) once was widely distributed but is now the rarest one and extinct in the wild. All living South China tigers are descendants of only two male and four female wild-caught tigers and they survive solely in zoos after 60 years of effective conservation efforts. Inbreeding depression and hybridization with other tiger subspecies were believed to have occurred within the small, captive South China tiger population. It is therefore urgently needed to examine the genomic landscape of existing genetic variation among the South China tigers., Results: In this study, we assembled a high-quality chromosome-level genome using long-read sequences and re-sequenced 29 high-depth genomes of the South China tigers. By combining and comparing our data with the other 40 genomes of six tiger subspecies, we identified two significantly differentiated genomic lineages among the South China tigers, which harbored some rare genetic variants introgressed from other tiger subspecies and thus maintained a moderate genetic diversity. We noticed that the South China tiger had higher F ROH values for longer runs of homozygosity (ROH > 1 Mb), an indication of recent inbreeding/founder events. We also observed that the South China tiger had the least frequent homozygous genotypes of both high- and moderate-impact deleterious mutations, and lower mutation loads than both Amur and Sumatran tigers. Altogether, our analyses indicated an effective genetic purging of deleterious mutations in homozygous states from the South China tiger, following its population contraction with a controlled increase in inbreeding based on its pedigree records., Conclusions: The identification of two unique founder/genomic lineages coupled with active genetic purging of deleterious mutations in homozygous states and the genomic resources generated in our study pave the way for a genomics-informed conservation, following the real-time monitoring and rational exchange of reproductive South China tigers among zoos., (© 2023. The Author(s).)

ABCG5 and ABCG8 are two key adenosine triphosphate-binding cassette (ABC) proteins that regulate whole-body sterol trafficking. This study aimed to elucidate the association between ABCG5/G8 gene region variants and lipid profile, cardiometabolic traits, and gallstone disease history in Taiwan. A total of 1494 Taiwan Biobank participants with whole-genome sequencing data and 117,679 participants with Axiom Genome-Wide CHB Array data were enrolled for analysis. Using genotype-phenotype and stepwise linear regression analyses, we found independent associations of four Asian-specific ABCG5 variants, rs119480069, rs199984328, rs560839317, and rs748096191, with total, low-density lipoprotein (LDL), and non-high-density lipoprotein (HDL) cholesterol levels (all p ≤ 0.0002). Four other variants, which were in nearly complete linkage disequilibrium, exhibited genome-wide significant associations with gallstone disease history, and the ABCG8 rs11887534 variant showed a trend of superiority for gallstone disease history in a nested logistic regression model ( p = 0.074). Through regional association analysis of various other cardiometabolic traits, two variants of the PLEKHH2 , approximately 50 kb from the ABCG5/G8 region, exhibited significant associations with blood pressure status ( p < 10 -6 ). In conclusion, differential effects of ABCG5/G8 region variants were noted for lipid profile, blood pressure status, and gallstone disease history in Taiwan. These results indicate the crucial role of individualized assessment of ABCG5/G8 variants for different cardiometabolic phenotypes.

Melanotic medullary thyroid carcinoma is morphologically defined by the presence of melanin deposits in the cytoplasm of tumor cells. It is an extremely rare variant with only 15 cases described in the literature to date and only one report of diagnosis by fine needle aspiration (FNA) biopsy. A 51-year-old woman presented with neck swelling. An ultrasound examination revealed a single solid nodule in the right thyroid lobe that measured 5.4 × 4.7 × 4.3 cm. Laboratory examination revealed elevated levels of serum calcitonin (8643.0 pg/ml), carcinoembryonic antigen (CEA) (86.2 ng/ml), and chromogranin A (123.2 ng/ml). An FNA biopsy of the thyroid nodule revealed predominantly single plasmacytoid cells with round to oval eccentric nuclei and dark brown intracytoplasmic granules. Immunohistochemical studies with Melan-A performed on a cell block slide confirmed that the granules contained melanin. The tumor cells were also positive for calcitonin, CEA, synaptophysin, AE1/AE3, CAM5.2, and HMB-45(focal); the tumor cells were negative for chromogranin, thyroglobulin, PAX8 and TTF-1. The diagnosis was reported as melanotic variant of medullary thyroid carcinoma. The patient underwent a total thyroidectomy which revealed tumor cell expression of insulinoma-associated protein 1 and confirmed neuroendocrine differentiation. Shortly after she presented with tumor recurrence in the thyroidectomy bed. The tumor cells were positive for only S100, SOX10, and Melan-A. Molecular analysis with the SEMA4 Solid Tumor Panel revealed mutations in the HRAS, PIK3CA, PIK3R1, MYC, and CCND3 genes. The final diagnosis was reported as melanocytic medullary thyroid carcinoma with high grade transformation and loss of epithelial and neuroendocrine expression., (© 2022 Wiley Periodicals LLC.)

Importance: Involvement of deep margins represents a significant challenge in the treatment of oropharyngeal cancer, and given practical limitations of frozen-section analysis, a need exists for real-time, nondestructive intraoperative margin analysis. Wide-field optical coherence tomography (WF-OCT) has been evaluated as a tool for high-resolution adjunct specimen imaging in breast surgery, but its clinical application in head and neck surgery has not been explored., Objective: To evaluate the utility of WF-OCT for visualizing microstructures at margins of excised oral and oropharyngeal tissue., Design, Setting, and Participants: This nonrandomized, investigator-initiated qualitative study evaluated the feasibility of the Perimeter Medical Imaging AI Otis WF-OCT device at a single academic center. Included participants were adults undergoing primary ablative surgery of the oral cavity or oropharynx for squamous cell carcinoma in 2018 and 2019. Data were analyzed in October 2019., Exposures: Patients were treated according to standard surgical care. Freshly resected specimens were imaged with high-resolution WF-OCT prior to routine pathology. Interdisciplinary interpretation was performed to interpret WF-OCT images and compare them with corresponding digitized pathology slides. No clinical decisions were made based on WF-OCT image data., Main Outcomes and Measures: Visual comparisons were performed between WF-OCT images and hematoxylin and eosin slides., Results: A total of 69 specimens were collected and scanned from 53 patients (mean [SD] age, 59.4 [15.2] years; 35 [72.9%] men among 48 patients with demographic data) undergoing oral cavity or oropharynx surgery for squamous cell carcinoma, including 42 tonsillar tissue, 17 base of the tongue, 4 buccal tissue, 3 mandibular, and 3 other specimens. There were 41 malignant specimens (59.4%) and 28 benign specimens (40.6%). In visual comparisons of WF-OCT images and hematoxylin and eosin slides, visual differentiation among mucosa, submucosa, muscle, dysplastic, and benign tissue was possible in real time using WF-OCT images. Microarchitectural features observed in WF-OCT images could be matched with corresponding features within the permanent histology with fidelity., Conclusions and Relevance: This qualitative study found that WF-OCT imaging was feasible for visualizing tissue microarchitecture at the surface of resected tissues and was not associated with changes in specimen integrity or surgical and pathology workflow. These findings suggest that formal clinical studies investigating use of WF-OCT for intraoperative analysis of deep margins in head and neck surgery may be warranted.

Apolipoprotein B (ApoB) plays a crucial role in lipid and lipoprotein metabolism. The effects of APOB locus variants on lipid profiles, metabolic syndrome, and the risk of diabetes mellitus (DM) in Asian populations are unclear. We included 1478 Taiwan Biobank participants with whole-genome sequence (WGS) data and 115,088 TWB participants with Axiom genome-wide CHB array data and subjected them to genotype-phenotype analyses using APOB locus variants. Five APOB nonsynonymous mutations, including Asian-specific rs144467873 and rs13306194 variants, were selected from participants with the WGS data. Using a combination of regional association studies, a linkage disequilibrium map, and multivariate analysis, we revealed that the APOB locus variants rs144467873, rs13306194, and rs1367117 were independently associated with total, low-density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL) cholesterol levels; rs1318006 was associated with HDL cholesterol levels; rs13306194 and rs35131127 were associated with serum triglyceride levels; rs144467873, rs13306194, rs56213756, and rs679899 were associated with remnant cholesterol levels; and rs144467873 and rs4665709 were associated with metabolic syndrome. Mendelian randomization (MR) analyses conducted using weighted genetic risk scores from three or two LDL-cholesterol-level-associated APOB variants revealed significant association with prevalent DM ( p = 0.0029 and 8.2 × 10 -5 , respectively), which became insignificant after adjustment for LDL-C levels. In conclusion, these results indicate that common and rare APOB variants are independently associated with various lipid levels and metabolic syndrome in Taiwanese individuals. MR analyses supported APOB variants associated with the risk of DM through their associations with LDL cholesterol levels.

While the majority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) display mild or no symptoms, rare individuals develop severe disease presenting with multisystem inflammatory syndrome (MIS-C). The reason for variable clinical manifestations is not understood. Here, we carried out TCR sequencing and conducted comparative analyses of TCR repertoires between children with MIS-C (n = 12) and mild (n = 8) COVID-19. We compared these repertoires with unexposed individuals (samples collected pre-COVID-19 pandemic: n = 8) and with the Adaptive Biotechnologies MIRA dataset, which includes over 135,000 high-confidence SARS-CoV-2-specific TCRs. We show that the repertoires of children with MIS-C are characterised by the expansion of TRBV11-2 chains with high junctional and CDR3 diversity. Moreover, the CDR3 sequences of TRBV11-2 clones shift away from SARS-CoV-2 specific T cell clones, resulting in distorted TCR repertoires. In conclusion, our study reports that CDR3-independent expansion of TRBV11-2+ cells, lacking SARS-CoV-2 specificity, defines MIS-C in children., Competing Interests: E.N.T., M.S.T. and J.H. have a financial interest in Etcembly Ltd. The other authors declare no competing interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Intervertebral disc degeneration (IVDD), for which obesity and genetics are known risk factors, is a chronic process that alters the structure and function of the intervertebral discs (IVD). Circulating leptin is positively correlated with body weight and is often measured to elucidate the pathogenesis of IVD degeneration. In this study, we examined the associations of LEP single nucleotide polymorphisms (SNPs) genetic and environmental effects with IVDD. A total of 303 Taiwanese patients with IVDD (mean age, 58.6 ± 12.7 years) undergoing cervical discectomy for neck pain or lumbar discectomy for back pain were enrolled. Commercially available enzyme-linked immunosorbent assay (ELISA) kits measured the circulating plasma leptin levels. TaqMan SNP genotyping assays genotyped the LEP SNPs rs2167270 and rs7799039. Leptin levels were significantly increased in obese individuals (p < 0.001) and non-obese or obese women (p < 0.001). In the dominant model, recoded minor alleles of rs2167270 and rs7799039 were associated with higher leptin levels in all individuals (p = 0.011, p = 0.012). Further, the association between these LEP SNPs and leptin levels was significant only in obese women (p = 0.025 and p = 0.008, respectively). There was an interaction effect between sex and obesity, particularly among obese women (interaction p = 0.04 and 0.02, respectively). Our findings demonstrate that these SNPs have sex-specific associations with BMI in IVDD patients, and that obesity and sex, particularly among obese women, may modify the LEP transcription effect.

PCSK9 is a candidate locus for low-density lipoprotein cholesterol (LDL-C) levels. The cause-effect relationship between LDL-C levels and diabetes mellitus (DM) has been suggested to be mechanism-specific. To identify the role of PCSK9 and genome-wide association study (GWAS)-significant variants in LDL-C levels and the risk of DM by using Mendelian randomization (MR) analysis, a total of 75,441 Taiwan Biobank (TWB) participants was enrolled for a GWAS to determine common and rare PCSK9 variants and their associations with LDL-C levels. MR studies were also conducted to determine the association of PCSK9 variants and LDL-C GWAS-associated variants with DM. A regional plot association study with conditional analysis of the PCSK9 locus revealed that PCSK9 rs10788994, rs557211, rs565436, and rs505151 exhibited genome-wide significant associations with serum LDL-C levels. Imputation data revealed that three rare nonsynonymous mutations-namely, rs151193009, rs768846693, and rs757143429-exhibited genome-wide significant association with LDL-C levels. A stepwise regression analysis indicated that seven variants exhibited independent associations with LDL-C levels. On the basis of two-stage least squares regression (2SLS), MR analyses conducted using weighted genetic risk scores (WGRSs) of seven PCSK9 variants or WGRSs of 41 LDL-C GWAS-significant variants revealed significant association with prevalent DM ( p = 0.0098 and 5.02 × 10 -7 , respectively), which became nonsignificant after adjustment for LDL-C levels. A sensitivity analysis indicated no violation of the exclusion restriction assumption regarding the influence of LDL-C-level-determining genotypes on the risk of DM. Common and rare PCSK9 variants are independently associated with LDL-C levels in the Taiwanese population. The results of MR analyses executed using genetic instruments based on WGRSs derived from PCSK9 variants or LDL-C GWAS-associated variants demonstrate an inverse association between LDL-C levels and DM.

Background: Human papillomavirus associated oropharyngeal squamous cell carcinoma (HPVOPSCC) usually affects a younger patient population. As such, the risk for long term toxicity associated with therapy is an important consideration. Multiple trials focused on de-escalation of therapy to preserve survival outcomes while minimizing treatment toxicity are currently in progress, however the question of which patients are ideal candidates for de-escalation remains unanswered. Circulating tumor DNA (cfHPVDNA) has emerged as a means of monitoring disease in patients with HPVOPSCC. Undetectable postoperative cfHPVDNA levels portend a better prognosis and by extension, may identify ideal candidates for de-escalation therapy. We propose an overview and rationale for a new institutional clinical trial protocol focusing on the use of cfHPVDNA to risk stratify patients for adjuvant therapy. We hypothesize that many surgical patients currently receiving radiation therapy may be clinically observed without adjuvant therapy., Methods: Patients with measurable cfHPVDNA and clinically resectable HPVOPSCC will undergo TORS resection of tumors and neck dissection. Patients with undetectable cfHPVDNA at 3 weeks post-op will be allocated to low or high-risk treatment protocol groups. The low risk group consists of patients with <4 positive lymph nodes, ≤2 mm extranodal extension (ENE), and perineural invasion (PNI) or lymphovascular invasion (LVI) alone. The high-risk group is made up of patients with ≥4 positive lymph nodes, gross ENE, positive margins, N2c disease and/or the combination of both PNI and LVI. The low-risk group will be allocated to an observation arm, while the high-risk group will receive 46 Gy of adjuvant radiotherapy and weekly cisplatin therapy. The primary outcome of interest is 2-year disease recurrence with secondary outcomes of 2-year disease free survival, locoregional control, overall survival, and quality of life measures. A sample of 126 patients in the low-risk group and 73 patients in the high-risk group will be required to evaluate non-inferiority to the standard of care., Discussion: This study will provide much needed recurrence and survival data for patients that undergo primary TORS followed by observation or de-escalated adjuvant therapy. Additionally, it will help delineate the role of cfHPVDNA in the risk stratification of patients that undergo treatment de-intensification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chai, Ferrandino, Barron, Donboli, Roof, Khan, Teng, Posner, Bakst and Genden.)

Objective: There is concern that current otolaryngology residents may not receive adequate surgical training. We aimed to characterize residents' surgical experiences at 5 academic centers performing the 14 key indicator procedures (KIPs) outlined by the Accreditation Council for Graduate Medical Education., Study Design: Prospective study., Setting: Five otolaryngology training programs., Methods: Data were gathered from December 2019 to December 2020 with a smartphone application from the Society for Improving Medical Professional Learning. After each operation, residents and faculty rated trainee autonomy on a 4-level Zwisch scale and performance on a 5-level modified Dreyfus scale., Results: Residents and attendings (n = 92 and 78, respectively) logged 2984 evaluations. Attending ratings of resident autonomy and performance increased with training level ( P  < .001). Resident self-assessments of autonomy and performance were lower than paired attending assessments ( P  < .001). Among attending evaluations of KIPs performed by senior residents (postgraduate year 4 or 5), 55% of cases were performed with meaningful autonomy (passive help or supervision only). Similarly, attendings rated 55% of these cases as a practice-ready or exceptional performance. Senior residents had meaningful autonomy for ≥50% of cases for most KIPs, with the exception of flaps and grafts (40%), pediatric/adult airway (39%), and stapedectomy/ossiculoplasty (33%). Similarly, senior residents received practice-ready or exceptional performance ratings for ≥50% of cases across all KIPs other than pediatric/adult airway (42%) and stapedectomy/ossiculoplasty (33%)., Conclusion: In this multicenter study, resident surgical autonomy and performance varied across otolaryngology KIPs. The development of nationwide benchmarks will help programs and residents set educational goals., Level of Evidence: 2.

Several apolipoprotein genes are located at the APOE locus on chromosome 19q13.32. This study explored the genetic determinants of cardiometabolic traits and metabolic syndrome at the APOE locus in a Taiwanese population. A total of 81,387 Taiwan Biobank (TWB) participants were enrolled to undergo genotype−phenotype analysis using data from the Axiom Genome-Wide CHB arrays. Regional association analysis with conditional analysis revealed lead single-nucleotide variations (SNVs) at the APOE locus: APOE rs7412 and rs429358 for total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol levels; CLPTM1 rs3786505 and rs11672748 for LDL and HDL cholesterol levels; and APOC1 rs438811 and APOE-APOC1 rs439401 for serum triglyceride levels. Genotype−phenotype association analysis revealed a significant association of rs429358 and rs438811 with metabolic syndrome and of rs7412, rs438811, and rs439401 with serum albumin levels (p < 0.0015). Stepwise regression analysis indicated that CLPTM1 variants were independently associated with LDL and HDL cholesterol levels (p = 3.10 × 10−15 for rs3786505 and p = 1.48 × 10−15 for rs11672748, respectively). APOE rs429358 and APOC1 rs438811 were also independently associated with metabolic syndrome (p = 2.29 × 10−14) and serum albumin levels (p = 3.80 × 10−6), respectively. In conclusion, in addition to APOE variants, CLPTM1 is a novel candidate locus for LDL and HDL cholesterol levels at the APOE gene region in Taiwan. Our data also indicated that APOE and APOC1 variants were independently associated with metabolic syndrome and serum albumin levels, respectively. These results revealed the crucial role of genetic variants at the APOE locus in predicting cardiometabolic traits and metabolic syndrome.

Resistin and soluble suppression of tumorigenicity 2 (sST2) are useful predictors in patients with coronary artery disease (CAD). Their serum levels are significantly attributed to variations in RETN and IL1RL1 loci. We investigated candidate variants in the RETN locus for resistin levels and those in the IL1RL1 locus for sST2 levels and evaluated the prognostication of these two biomarkers and the corresponding variants for long-term outcomes in the patients with CAD. We included 4652, 557, and 512 Chinese participants from the Taiwan Biobank (TWB), cardiovascular health examination (CH), and CAD cohorts, respectively. Candidate variants in RETN and IL1RL1 were investigated using whole-genome sequence (WGS) and genome-wide association study (GWAS) data in the TWB cohort. The weighted genetic risk scores (WGRS) of RETN and IL1RL1 with resistin and sST2 levels were calculated. Kaplan-Meier curves were used to analyze the prognostication of resistin and sST2 levels, WGRS of RETN and IL1RL1 , and their combinations. Three RETN variants (rs3219175, rs370006313, and rs3745368) and two IL1RL1 variants (rs10183388 and rs4142132) were independently associated with resistin and sST2 levels as per the WGS and GWAS data in the TWB cohort and were further validated in the CH and CAD cohorts. In combination, these variants explained 53.7% and 28.0% of the variation in resistin and sST2 levels, respectively. In the CAD cohort, higher resistin and sST2 levels predicted higher rates of all-cause mortality and major adverse cardiac events (MACEs) during long-term follow-up, but WGRS of RETN and IL1RL1 variants had no impact on these outcomes. A synergistic effect of certain combinations of biomarkers with RETN and IL1RL1 variants was found on the prognostication of long-term outcomes: Patients with high resistin levels/low RETN WGRS and those with high sST2 levels/low IL1RL1 WGRS had significantly higher all-cause mortality and MACEs rates, and those with both these combinations had the poorest outcomes. Both higher resistin and sST2 levels, but not RETN and IL1RL1 variants, predict poor long-term outcomes in patients with CAD. Furthermore, combining resistin and sST2 levels with the WGRS of RETN and IL1RL1 genotyping exerts a synergistic effect on the prognostication of CAD outcomes. Future studies including a large sample size of participants with different ethnic populations are needed to verify this finding.

The KLF14 gene is a key metabolic transcriptional transregulator with monoallelic maternal expression. KLF14 variants are only associated with adipose tissue gene expression, and KLF14 promoter methylation is strongly associated with age. This study investigated whether age, sex, and obesity mediate the effects of KLF14 variants and DNA methylation status on body shape indices and metabolic traits. In total, the data of 78,742 and 1636 participants from the Taiwan Biobank were included in the regional plot association analysis for KLF14 variants and KLF14 methylation, respectively. Regional plot association studies revealed that the KLF14 rs4731702 variant and the nearby strong linkage disequilibrium polymorphisms were the lead variants for lipid profiles, blood pressure status, insulin resistance surrogate markers, and metabolic syndrome mainly in female participants and for body shape indices mainly in obese women. Significant age-dependent associations between KLF14 promoter methylation levels and body shape indices, and metabolic traits were also noted predominantly in female participants. KLF14 variants and KLF14 hypermethylation status were associated with metabolically healthy and unhealthy phenotypes, respectively, in obese individuals, and only the KLF14 variants demonstrated a significant association with both higher adiposity and lower cardiometabolic risk in the same allele, revealing uncoupled excessive adiposity from its cardiometabolic comorbidities, especially in obese women. Variations of KLF14 are associated with body shape indices, metabolic traits, insulin resistance, and metabolically healthy status. Differential genetic and epigenetic effects of KLF14 are age-, sex- and obesity-dependent. These results provided a personalized reference for the management of cardiometabolic diseases in precision medicine.

Background: The common non-synonymous mutation of the glucokinase regulator ( GCKR ) gene, namely rs1260326, is widely reported to have pleiotropic effects on cardio-metabolic traits and hematological parameters., Objective: This study aimed to identify whether other GCKR variants may have pleiotropic effects independent of the rs1260326 genotypes., Methods: In total, 81,097 Taiwan Biobank participants were enrolled for the regional plot association studies and candidate variant analysis of the region around the GCKR gene., Results: The initial candidate variant approach showed the significant association of the rs1260326 genotypes with multiple phenotypes. Regional plot association analysis of the GCKR gene region further revealed genome-wide significant associations between GCKR variants and serum total and low-density lipoprotein cholesterol; triglyceride, uric acid, creatinine, aspartate aminotransferase, γ-Glutamyl transferase, albumin, and fasting plasma glucose levels; estimated glomerular filtration rate; leukocyte and platelet counts; microalbuminuria, and metabolic syndrome, with rs1260326 being the most common lead polymorphism. Serial conditional analysis identified genome-wide significant associations of two low-frequency exonic mutations, rs143881585 and rs8179206, with high serum triglyceride and albumin levels. In five rare GCKR exonic non-synonymous or nonsense mutations available for analysis, GCKR rs146175795 showed an independent association with serum triglyceride and albumin levels and rs150673460 showed an independent association with serum triglyceride levels. Weighted genetic risk scores from the combination of GCKR rs143881585 and rs146175795 revealed a significant association with metabolic syndrome., Conclusion: In addition to the rs1260326 variant, low-frequency and rare GCKR exonic mutations exhibit pleiotropic effects on serum triglyceride and albumin levels and the risk of metabolic syndrome. These results provide evidence that both common and rare GCKR variants may play a critical role in predicting the risk of cardiometabolic disorders.

Background: Postparotidectomy sialocele is a frustrating challenge. Published rates of postparotidectomy fluid collections range from 6% to 39%. We report our experience of 398 parotidectomies performed over a 6-year period., Methods: A retrospective chart review of parotidectomies performed over a 6-year period was completed. Drain placement, smoking status, tumor size, and postoperative utilization of scopolamine were analyzed. Binary logistical regression and odds ratio calculations were performed., Results: Postparotidectomy sialocele occurred in 25% of patients. Neither suction drain placement nor usage of immediate postoperative scopolamine (in a 22-patient subset) prevented sialocele formation. Smoking status also did not correlate. Increasing resection size was linearly correlated with the risk of sialocele., Conclusion: Drain placement and smoking status do not correlate with sialocele prevention after parotidectomy. Sialocele formation directly correlates with the resection size. These data may guide preoperative counseling; however, additional work is necessary to identify effective prevention mechanisms for postparotidectomy sialocele., (© 2021 Wiley Periodicals LLC.)

Objectives: Circulating serum amyloid A (SAA) levels are strongly associated with atherosclerotic cardiovascular disease risk and severity. The association between SAA1 genetic variants, SAA levels, inflammatory marker levels, and coronary artery disease (CAD) prognosis has not been fully understood., Materials and Methods: In total, 2199 Taiwan Biobank (TWB) participants were enrolled for a genome-wide association study (GWAS), and the long-term outcomes in 481 patients with CAD were analyzed. The primary endpoint was all-cause mortality, and the secondary endpoint was the combination of all-cause death, myocardial infarction, stroke, and hospitalization for heart failure., Results: Through GWAS, SAA1 rs11024600 and rs7112278 were independently associated with SAA levels ( P = 3.84 × 10 -145 and P = 1.05 × 10 -29 , respectively). SAA levels were positively associated with leukocyte counts and multiple inflammatory marker levels in CAD patients and with body mass index, hemoglobin, high-density lipoprotein cholesterol, and alanine aminotransferase levels in TWB participants. By stepwise linear regression analysis, SAA1 gene variants contributed to 27.53% and 8.07% of the variation of the SAA levels in TWB and CAD populations, respectively, revealing a stronger influence of these two variants in TWB participants compared to CAD patients. Kaplan-Meier survival analysis revealed that SAA levels, but not SAA1 gene variants, were associated with long-term outcomes in patients with CAD. Cox regression analysis also indicated that high circulating SAA levels were an independent predictor of both the primary and secondary endpoints., Conclusion: SAA1 genotypes contributed significantly to SAA levels in the general population and in patients with CAD. Circulating SAA levels but not SAA1 genetic variants could predict long-term outcomes in patients with angiographically confirmed CAD., Competing Interests: Dr. Yu-Lin Ko, an editorial board members at Tzu Chi Medical Journal, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper., (Copyright: © 2022 Tzu Chi Medical Journal.)

Objective: Invasively ventilated patients with acute respiratory failure related to coronavirus disease 2019 (COVID-19) potentially benefit from tracheostomy. The aim of this study was to determine the practice of tracheostomy during the first wave of the pandemic in 2020 in the Netherlands, to ascertain whether timing of tracheostomy had an association with outcome, and to identify factors that had an association with timing., Methods: Secondary analysis of the 'PRactice of VENTilation in COVID-19' (PRoVENT-COVID) study, a multicenter observational study, conducted from March 1, 2020 through June 1, 2020 in 22 Dutch intensive care units (ICU) in the Netherlands. The primary endpoint was the proportion of patients receiving tracheostomy; secondary endpoints were timing of tracheostomy, duration of ventilation, length of stay in ICU and hospital, mortality, and factors associated with timing., Results: Of 1023 patients, 189 patients (18.5%) received a tracheostomy at median 21 [17 to 28] days from start of ventilation. Timing was similar before and after online publication of an amendment to the Dutch national guidelines on tracheostomy focusing on COVID-19 patients (21 [17-28] vs. 21 [17-26] days). Tracheostomy performed ≤ 21 days was independently associated with shorter duration of ventilation (median 26 [21 to 32] vs. 40 [34 to 47] days) and higher mortality in ICU (22.1% vs. 10.2%), hospital (26.1% vs. 11.9%) and at day 90 (27.6% vs. 14.6%). There were no patient demographics or ventilation characteristics that had an association with timing of tracheostomy., Conclusions: Tracheostomy was performed late in COVID-19 patients during the first wave of the pandemic in the Netherlands and timing of tracheostomy possibly had an association with outcome. However, prospective studies are needed to further explore these associations. It remains unknown which factors influenced timing of tracheostomy in COVID-19 patients., Competing Interests: Conflicts of interest The authors have no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier España, S.L.U.)

Background and Aims: Increase soluble E-selectin (sE-selectin) levels are associated with various inflammation and cardiometabolic disorders., Methods: This study aimed to investigate the genetic determinants of circulating sE-selectin levels by genome-wide association study (GWAS) in 4,525 Taiwan Biobank (TWB) participants and genotype-phenotype association analysis for sE-selectin level-determining alleles in over 80,000 TWB participants., Results: By GWAS, ABO, SELE, and FUT6 gene variants were identified as the determinants of sE-selectin levels, which reach genome-wide significance (maximum p = 3.25 × 10 -271 , 4.81 × 10 -14 , and 9.64 × 10 -12 , respectively). After further adjustment for the lead ABO rs2519093 genotypes, three novel gene loci, EVI5, FER and DMAC1, were associated with sE-selectin levels at p < 5 × 10 -7 . Three other previously reported gene loci, CELSR2, ST3GAL6-AS1, and HNF1A-AS1, also showed supportive evidence for the association with sE-selectin levels (maximum p < 0.0073). A multivariate analysis revealed age, body mass index, current smoking, hemoglobin A1C, hematocrit, leukocyte and platelet counts, serum alanine aminotransferase, triglycerides, and uric acid levels were independently associated with sE-selectin levels, in which the above ten gene loci contribute to 27.68% of the variance. For genotype-phenotype association analysis, a pleiotropic effect was demonstrated with genome-wide significant association between ABO gene variants and total and low-density-lipoprotein cholesterol levels, leukocyte counts and hematocrit., Conclusions: Our data provide novel insight into the regulation of sE-selectin levels. These results may open new avenues in understanding the critical role of E-selectin on the pathogenesis of inflammatory and cardiometabolic disorders., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

CDH13 encodes T-cadherin, which is expressed in the vasculature and cardiac myocytes and is the receptor for hexameric and high-molecular-weight adiponectin. The CDH13 region is the most pivotal locus associated with adiponectin level. Mediation analysis is a method to explore the effect of a third variable, it is assumed that the magnitude of the relationship between the independent and dependent variables will be reduced by statistical adjustment for a third variable. In addition, mediation can further occur in the case when the mediator acts as a pathway-suppressor variable that means a suppression effect may be suggested if the statistical removal of a mediation effect could increase the magnitude of the relationship between the independent and dependent variables. Here, we aimed to explore the suppression effect in a genome-wide association study, and investigate possible mechanisms that may link adiponectin to CDH13 variants and high-density lipoprotein cholesterol (HDL-C). Genome-wide association data for adiponectin and HDL-C were accessible for 2349 Taiwan-biobank participants. The mediation analysis was conducted with the CDH13 lead single nucleotide polymorphism (SNP) rs4783244. The cloned constructs of CDH13 haplotypes (GG and TT) identified from the rs4783244 G/T and rs12051272 G/T SNPs were transiently expressed in HEK293T cells and investigated using the luciferase reporter assay. Genome-wide association analysis showed that HDL-C is significantly associated with variants in CDH13 after adjusting for the adiponectin level. The lead SNP rs4783244 was significantly associated with lower adiponectin levels and exhibited a suppression effect on HDL-C when adiponectin was included as a third factor in the mediation analysis. Luciferase reporter assay results further demonstrated that the GG haplotype increased enhancer activity, whereas the haplotype TT significantly reduced the activity of this enhancer. We present the first evidence of the suppressive role of adiponectin in the genome-wide association between CDH13 and HDL-C. CDH13 may increase the HDL-C levels, and its expression is suppressed by adiponectin.

MUC1 is a transmembrane mucin involved in carcinogenesis and cell signaling. Functional MUC1 variants are associated with multiple metabolic and biochemical traits. This study investigated the association of functional MUC1 variants with MUC1 DNA methylation and various metabolic, biochemical, and hematological parameters. In total, 80,728 participants from the Taiwan Biobank were enrolled for association analysis using functional MUC1 variants and a nearby gene regional plot association study. A subgroup of 1686 participants was recruited for MUC1 DNA methylation analysis. After Bonferroni correction, we found that two MUC1 variants, rs4072037 and rs12411216, were significantly associated with waist circumference, systolic blood pressure, hemoglobin A1C, renal functional parameters (blood urea nitrogen, serum creatinine levels, and estimated glomerular filtration rate), albuminuria, hematocrit, hemoglobin, red blood cell count, serum uric acid level, and gout risk, with both favorable and unfavorable effects. Causal inference analysis revealed that the association between the variants and gout was partially dependent on the serum uric acid level. Both gene variants showed genome-wide significant associations with MUC1 gene-body methylation. Regional plot association analysis further revealed lead single-nucleotide polymorphisms situated at the nearby TRIM46 - MUC1 - THBS3 - MTX1 gene region for the studied phenotypes. In conclusion, our data demonstrated the pleiotropic effects of MUC1 variants with novel associations for gout, red blood cell parameters, and MUC1 DNA methylation. These results provide further evidence in understanding the critical role of TRIM46 - MUC1 - THBS3 - MTX1 gene region variants in the pathogenesis of cardiometabolic, renal, and hematological disorders.

Objective: Burnout is defined as work-related emotional exhaustion, depersonalization, and decreased sense of accomplishment. Virtual reality (VR) has emerged as an effective treatment modality for various conditions related to anxiety, however, few studies have assessed its role for stress management in residents. We hypothesize that VR-based mindfulness meditation can reduce resident burnout in real-world settings., Study Design: Prospective randomized crossover trial., Methods: Resident participants completed the validated Maslach Burnout Inventory (MBI). One group used a VR-based meditation app; the second group received no intervention. After a 2-month rotation, all subjects completed an MBI and crossed over to the other arm. Wilcoxon rank-sum tests were used to compare MBI scores before and after intervention, and to compare results by gender and postgraduate year. Mann-Whitney U tests were used to assess qualitative differences between participants., Results: Eighteen residents completed the study. Five participants were female and 13 were male. Weekly use of VR-guided meditation and paced breathing was associated with a significant decrease in emotional exhaustion (P = .009), and on subgroup analysis, male gender specifically was associated with a decrease in emotional exhaustion (P = .027). In the post-intervention survey, 42.9% subjects reported that VR encouraged them to employ paced breathing techniques, 71.4% reported that they would use the technology if regularly available, and 21.4% reported they would use paced breathing in the future., Conclusion: VR-based therapy may serve as a successful tool in stress management and reduce the rate of burnout among otolaryngology residents., Level of Evidence: NA Laryngoscope, 131:1972-1976, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The corrected QT interval (QTc) predicts prognosis for the general population and patients with coronary artery disease (CAD). Growth differentiation factor-15 (GDF-15) is a biomarker of myocardial fibrosis and left ventricular (LV) remodelling. The interaction between these two parameters is unknown., Subjects and Methods: This study included 487 patients with angiographically confirmed CAD. QTc was calculated using the Bazett formula. Multiple biochemistries and GDF-15 levels were measured. The primary endpoint was total mortality, and the secondary endpoints comprised the combination of total mortality, myocardial infarction and hospitalisation for heart failure and stroke., Results: The mean follow-up period was 1029 ± 343 days (5-1692 days), during which 21 patients died and 47 had secondary endpoints. ROC curve analysis for the optimal cut-off value of primary endpoint is 1.12 ng/mL for GDF-15 (AUC = 0.787, P = 9.0 × 10 -6 ) and 438.5 msec for QTc (AUC = 0.698, P = .002). Utilising linear regression, QTc has a positive correlation with Log-GDF-15 (r = .216, P = 1.0 × 10 -6 ). Utilising Kaplan-Meier analysis, both QTc interval and GDF-15 level are significant predictors for primary end point (P = .000194, P = 2.0 × 10 -6 , respectively) and secondary endpoint (P = .00028, P = 6.15 × 10 -8 , respectively). When combined these two parameters together, a significant synergistic predictive power was noted for primary and secondary endpoint (P = 2.31 × 10 -7 , P = 1.26 × 10 -8 , respectively). This combined strategy also showed significant correlation with the severity of CAD (P < .001)., Conclusion: In Chinese patient with angiographically confirmed CAD, a combined strategy utilising an ECG parameter (QTc) and a circulating biomarker (GDF-15) has good correlation with the severity of CAD, and improves the predictive power for total mortality., (© 2021 John Wiley & Sons Ltd.)

Dermal filler injections are common cosmetic procedures and are growing in popularity. While frequently performed, dermal filler injections carry a risk of adverse events including vascular compromise and foreign body granulomas. Here, we discuss an unusual case of a patient with a history of dermal filler injections presenting with a parotid mass and an eyebrow mass requiring surgical resection. This case demonstrates the risk of delayed granuloma formation many years after dermal filler injection and highlights the importance of awareness and management of these potential long-term complications.

Objective: This study aims to analyse the association of chemerin levels with several metabolic, biochemical and haematological parameters in a large Taiwanese population with relative healthy status., Design: Cross-sectional study., Methods: Data of 4101 healthy participants without history of hypertension, diabetes, dyslipidaemia and renal insufficiency from Taiwan Biobank were analysed. The demographic, biochemical and haematologic parameters were retrieved from the database. Chemerin levels were measured using commercially available enzyme-linked immunosorbent assay. Univariate and multivariate analysis was performed to test the independent correlates of chemerin., Results: In the univariate analysis, circulating chemerin levels were positively associated with body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), systolic (SBP) and diastolic blood pressure (DBP), haemoglobin A1C (HbA1C), total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), creatinine, uric acid, alanine aminotransferase (ALT), gamma-glutamyl transferase (γ-GT), leucocyte and platelet counts both in men and women and negatively associated with high-density lipoprotein cholesterol (HDL-C), estimated glomerular filtration rate (eGFR) and total bilirubin. In the multivariate analysis, BMI, HbA1C, triglyceride, uric acid, γ-GT and platelet counts predicted chemerin levels independently both in men and in women with positive correlation, while eGFR, total bilirubin and HDL-C predicted circulating chemerin levels independently with negative correlation., Conclusions: Chemerin level is independently associated with multiple metabolic, biochemical and haematological parameters. This study provides further evidence on the molecular basis linking obesity with several human diseases., (© 2021 John Wiley & Sons Ltd.)

Background: Treatment of human papillomavirus-related oropharyngeal squamous cell carcinoma (HPVOPC) results in unprecedented high survival rates but possibly unnecessary toxicity. We hypothesized that upfront surgery and neck dissection followed by reduced-dose adjuvant therapy for early and intermediate HPVOPC would ultimately result in equivalent progression-free survival (PFS) and overall survival while reducing toxicity., Methods: This study was a nonrandomized phase II trial for early-stage HPVOPC treated with transoral robotic surgery (TORS) followed by reduced-dose radiotherapy. Patients with previously untreated p16-positive HPVOPC and <20 pack years' smoking history were enrolled. After robotic surgery, patients were assigned to group 1 (no poor risk features; surveillance), group 2 (intermediate pathologic risk factors [perineural invasion, lymphovascular invasion]; 50-Gy radiotherapy), or group 3 (poor prognostic pathologic factors [extranodal extension [ENE], more than three positive lymph nodes and positive margin]; concurrent 56-Gy chemoradiotherapy with weekly cisplatin)., Results: Fifty-four patients were evaluable; there were 25 in group 1, 15 in group 2, and 14 in group 3. Median follow-up was 43.9 months (9.6-75.8). Disease-specific survival was 98.1%, and PFS was 90.7%. PFS probability via Kaplan-Meier was 91.3% for group 1, 86.7% for group 2, and 93.3% for group 3. There were five locoregional failures (LRFs), including one distant metastasis and one contralateral second primary. Average time to LRF was 18.9 months (9.6-59.0); four LRFs were successfully salvaged, and the patients remain disease free (11.0-42.7 months); one subject remains alive with disease., Conclusion: The results indicate that upfront surgery with neck dissection with reduced-dose radiation for T1-2, N1 stage (by the eighth edition American Joint Committee on Cancer staging manual) HPVOPC results in favorable survival with excellent function in this population. These results support radiation dose reduction after TORS as a de-escalation strategy in HPVOPC., Implications for Practice: Transoral robotic surgery can provide a safe platform for de-escalation in carefully selected patients with early-stage human papillomavirus-related oropharyngeal cancer. In this clinical trial, disease-specific survival was 100%, over 90% of the cohort had a reduction of therapy from standard of care with excellent functional results, and the five patients with observed locoregional failures were successfully salvaged., (© 2021 AlphaMed Press.)

Background: The optimal extent of surgery and/or radiation to the contralateral lymph node region is unknown in early-stage human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC)., Methods: To investigate the pathologic incidence of and risk factors for contralateral nodal disease (CND) in cT1-T2 HPV-related OPSCC treated with transoral robotic surgery (TORS) and bilateral neck dissection (BND), the records of 120 patients were reviewed., Results: Eleven patients displayed pathologic contralateral nodal disease (pCND), including 7.1% of tonsil and 10.9% of base of tongue (BOT) cases. Medial hemistructure involvement and cN2 disease were significantly associated with pCND. Zero cN0 patients had pCND, and on multivariate analysis only cN classification remained significantly associated with pCND. Four percent of BOT patients and 2% of tonsil patients with a well-lateralized primary and cN0/N1 neck demonstrated pCND., Conclusions: HPV-related OPSCC that are cN0-N1 have exceedingly low rates of pCND. Well-lateralized HPV-related BOT primaries with limited clinical nodal disease may be candidates for ipsilateral only treatment., (© 2021 Wiley Periodicals LLC.)