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OBJECTIVES: MicroRNAs (miRNAs) are endogenous small non-coding RNAs that negatively regular target gene expression by RNA interference. The processing of the pre-miRNA hairpin generates a miRNA duplex, which consists of a miRNA (guide strand) and a miRNA(*) (passenger strand). miR-31 is an oncogenic miRNA and is up-regulated in oral squamous cell carcinoma (OSCC). miR-31(*) shows a high level of conservation across species and, based on this, this study hypothesized that miR-31(*) is a functional miRNA. MATERIALS AND METHODS: The expression of miR-31 and miR-31* in OSCC tissues and oral cells were analyzed. Functional studies were performed on OSCC cells. RESULTS: miR-31(*) is up-regulated in OSCC tissues, but its expression is less abundant than miR-31. miR-31(*) decreases the proliferation and migration of both SAS and Fadu cells. Furthermore, miR-31(*) targets the 3'UTR of RhoA and is able to down-regulate RhoA expression. Knockdown of RhoA expression is known to decrease the proliferation and migration of OSCC cells. However, up-regulation of both miR-31 and miR-31(*) by delivery of pre-mir-31 does still enhance OSCC oncogenicity. CONCLUSION: miR-31(*) is a functional miRNA involving in regulating RhoA, and the activity of miR-31(*)'s activity seems to counteract the functions of miR-31 during OSCC tumorigenesis. [ABSTRACT FROM AUTHOR]

MicroRNAs are short non-coding RNAs that regulate gene expression by RNA interference. Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. miR-146a has been reported to regulate Toll-like receptors and cytokine signaling, which are both crucial for inflammation and oncogenesis. This study identifies that areca nut extract, TNF[alpha] and TGF[beta] up-regulates miR-146a in OSCC cells. The increased expression of miR-146a enhanced the oncogenicity of OSCC cells. In addition, a G to C polymorphism (rs2910164), which is located in the pre-miR-146a and has been associated with functional alterations in miR-146a, was significantly more prevalent among OSCC patients having more advanced nodal involvement. Our analysis also suggested a higher miR-146a expression in OSCC tissues of patients carrying C polymorphism. The present study concluded a higher prevalence of the pre-mir-146a C-variant was associated with OSCC progression in patients with this disease. [ABSTRACT FROM AUTHOR]

This study aims to explore the factors that influence family members in choosing the preferred place of death for hospitalized dying older patients in Taiwan. This study enrolled 100 family members. The relevant factors influencing the families' choice of the preferred place of death for older patients were family members' previous discussions with the patients about their expected place of death; patients' education levels; family members' incomes; whether they were hiring a caregiver to take care of the patients at the hospital; their degree of social support; and their family functioning. The logistic regression analysis showed that family members who had discussed the preferred place of death with the patients, and those with better family functioning, were 1.41 and 2.72 times more likely, respectively, to chose for patients to return home to die than for the patients to die in a hospital., 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.

Background: Low-dose computed tomography (LDCT) has been widely adopted for lung cancer screening due to its proven ability to reduce lung cancer mortality, especially among high-risk populations., Methods: This retrospective study aims to evaluate the impact of LDCT screening on non-small cell lung cancer (NSCLC) staging at Kaohsiung Medical University Hospital (KMUH) from 2011 to 2020, following the introduction of LDCT in 2013. The study examines the correlation between LDCT screening volume and changes in the distribution of NSCLC stages, particularly early-stage (stages 0 and I) and late-stage (stage IV) diagnoses. Additionally, it explores the differences in histopathological subtypes, focusing on adenocarcinoma and squamous cell carcinoma, and assesses the impact of early detection on five-year survival rates., Results: The results show a significant increase in early-stage NSCLC diagnoses, particularly in adenocarcinoma cases, where early-stage diagnoses rose from 10.4% in 2010 to 38.7% in 2019. However, the number of stage IV cases remained stable, indicating that LDCT may not substantially reduce late-stage diagnoses. Pearson's correlation analysis demonstrated a strong positive correlation between LDCT screening and early-stage NSCLC detection, particularly for adenocarcinoma ( p < 0.001), though the early detection of squamous cell carcinoma and small cell carcinoma remained limited., Conclusions: The study concludes that LDCT screening plays a crucial role in improving early NSCLC detection and five-year survival rates. Future research should focus on optimizing screening strategies to capture more at-risk populations and enhance the detection of harder-to-diagnose subtypes like squamous cell carcinoma.

We studied SARS-CoV-2 binding and neutralizing antibody titers among previously infected persons in the United States over time. We assayed SARS-CoV-2 spike protein receptor-binding domain and neutralizing antibody titers for a convenience sample of residual clinical serum specimens that had evidence of prior SARS-CoV-2 infection gathered during January 2021-February 2022. We correlated titers and examined them by age group (<18, 18-49, 50-64, and >65 years) across 4 different SARS-CoV-2 variant epochs. Among selected specimens, 30,967 had binding antibody titers and 744 had neutralizing titers available. Titers in specimens from children and adults correlated. In addition, mean binding antibody titers increased over time for all age groups, and mean neutralization titers increased over time for persons 16-49 and >65 years of age. Incorporating binding and neutralization antibody titers into infectious disease surveillance could provide a clearer picture of overall immunity and help target vaccination campaigns.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma characterized by distinct subtypes and heterogeneous treatment outcomes. Oxidative stress and the dysregulation of related regulatory genes are prevalent in DLBCL, prompting an investigation into the nuclear factor erythroid 2-related factor 2 (Nrf2)-kelch-like ECH-associated protein 1 (Keap1) signaling pathway and associated genes. The present study assessed pathological specimens and clinical data from 43 newly diagnosed patients with DLBCL, comparing the associations and correlations between the expression of Nrf2, Keap1, microtubule-associated protein 1 light chain 3β (LC3B) and nitrotyrosine and the activated B-cell (ABC) and germinal center B-cell (GCB) subtypes of DLBCL using immunohistochemistry and digital image analysis software. Nuclear Nrf2 activation was observed in 33.3% of patients with DLBCL ABC, demonstrating a higher prevalence of hepatitis B surface antigen positivity, calcium ions and significant body weight loss (P<0.05). Total Nrf2 expression was associated with the DLBCL GCB subtype and inversely correlated with Keap1 expression in the DLBCL ABC subtype. Furthermore, a positive correlation was demonstrated between Nrf2 and LC3, indicating that total Nrf2 is inhibited by Keap1 and regulates LC3 expression. The ABC subtype was also associated with lower white blood cell counts and more frequent chemotherapy courses than the GCB subtype. These findings suggest that nuclear Nrf2 could be a biomarker for DLBCL clinical diagnosis., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Hsu et al.)

Introduction: Heatstroke is a critical heat-related condition characterized by coagulopathy and multiple organ dysfunction. One of the most severe complications of heatstroke is disseminated intravascular coagulation. This condition manifests as excessive clot formation and bleeding that are primarily due to platelet depletion and dysfunction. Fibrinogen plays a crucial role in hemostasis because it links integrin αIIbβ3 on adjacent platelets, thereby promoting the platelet activation and aggregation necessary for clot formation. However, reduced fibrinogen levels may impair the formation of the initial platelet plug and increase the risk of bleeding. The current study explored the effect of fibrinogen on platelet dysfunction in a heatstroke model., Materials and Methods: Male Wistar rats were subjected to heat stress, and subsequent changes in hemodynamic, biochemical, and coagulation parameters were analyzed. Platelet viability, aggregation, adhesion, spreading and fibrin clot retraction were assessed., Results: The rats with heatstroke exhibited a variety of clinical symptoms, including hypotension, tachycardia, multiple organ dysfunction, and coagulopathy. Platelet viability in the heatstroke group was comparable to that in the healthy control group. However, the heatstroke group exhibited significant reductions in plasma fibrinogen levels and platelet aggregation, adhesion, spreading, and fibrin clot retraction. Notably, fibrinogen supplementation markedly augmented the aggregation responses of platelets in the heatstroke group. The impairment of platelet adhesion, spreading, and fibrin clot retraction in the rats with heatstroke was partially ameliorated by fibrinogen supplementation., Conclusions: An early use of fibrinogen replacement may serve as a therapeutic intervention to alleviate platelet hyporeactivity and prevent the complications in patients with heatstroke., Competing Interests: Declaration of competing interest All authors declared that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Dysregulated host response to infection causes life-threatening organ dysfunction. Excessive inflammation and abnormal blood coagulation can lead to disseminated intravascular coagulation (DIC) and multiple-organ failure in the late sepsis stages. Platelet function impairment in sepsis contributes to bleeding, secondary infection, and tissue injury. Platelet transfusion is considered in patients with sepsis with DIC and bleeding; however, its benefits are limited and of low quality. Fibrinogen plays a crucial role in platelet function, and establishing a fibrin network binds to activated integrin αIIbβ3 and promotes outside-in signaling that amplifies platelet functions. However, the role of fibrinogen in sepsis-induced platelet dysfunction remains unclear., Materials and Methods: We evaluated the effects of fibrinogen on platelet hyporeactivity during septic shock in adult male Wistar rats using lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP) surgery. Changes in the hemodynamic, biochemical, and coagulation parameters were examined. Platelet activation and aggregation were measured using whole-blood assay, 96-well plate-based aggregometry, and light-transmission aggregometry. Additionally, platelet adhesion, spreading, and fibrin clot retraction were evaluated., Results: Rats with LPS- and CLP-induced sepsis displayed considerable decreases in plasma fibrinogen levels and platelet aggregation, adhesion, spreading, and clot retraction. The aggregation of platelets obtained from rats with sepsis was markedly augmented by fibrinogen supplementation. Additionally, fibrinogen administration improved platelet adhesion, spreading, and clot retraction in rats with sepsis., Conclusions: Fibrinogen supplementation could serve as a potential therapeutic intervention for alleviating platelet hyporeactivity in patients with sepsis and bleeding., Competing Interests: Declaration of competing interest All authors declared that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Acute body mass loss before competitions in combat sports usually leads to loss in fat-free mass. Beta-hydroxy-beta-methylbutyrate (HMB) has been shown to increase skeletal muscle mass and muscle strength in various muscle wasting conditions. This study investigated the effect of HMB supplementation on body composition and sport-specific performance in well-trained boxers consuming a hypocaloric diet. Twelve male college boxers were divided into the HMB and placebo (PLA) groups using a body weight-matched single-blind parallel design. The study comprised a 6-day weight loss period (days 1-6), followed by a 3-day competition period (days 7-9). The participants in both the groups consumed 16 kcal/kg/day, including 1.6-1.7 g/kg of carbohydrates, 1.2-1.3 g/kg of protein, and 0.45-0.5 g/kg of fat during the 9-day period. The HMB group consumed 3 g/day HMB. Body composition measurement, isometric mid-thigh pull (IMTP), and a simulated boxing match were performed at baseline and on days 7, 8, and 9. Fasting blood samples were collected on the day before day 1 and on days 7, 8, and 9. Body mass was significantly decreased after the 6-day weight loss period (HMB group: baseline: 69.4 ± 11.2 kg, day 7: 67.1 ± 11.2 kg; PLA group: baseline: 68.6 ± 12.1 kg, day 7: 65.7 ± 11.5 kg, P < 0.05) while it was unchanged on the 3-day competition period in both the groups. Fat-free mass in the HMB group was maintained throughout the 9-day period (baseline: 56.7 ± 9.3 kg, day 7: 56.3 ± 8.7 kg, day 9: 55.8 ± 9.5 kg) whereas it significantly decreased on days 7 and 9 compared to the baseline in the PLA group (baseline: 55.2 ± 6.4 kg, day 7: 54.1 ± 6.6 kg, day 9: 54.0 ± 6.6 kg, P < 0.05). In the PLA group, the average and maximal heart rates in round 1 and the average heart rate in round 2 on days 8 and 9 were significantly lower than those at baseline, while these parameters were unchanged in the HMB group. The maximal force and the rate of force development in the IMTP remained unchanged among the different timepoints in both the groups. The blood biochemical parameters were similar at any timepoint between the PLA and HMB groups. HMB supplementation during acute weight loss may preserve fat-free mass and maintain heart rate response in subsequent simulated matches in well-trained boxers. In addition, HMB supplementation had a nonsignificant effect on glucose, fat, and protein metabolism during energy restriction., Competing Interests: None

Introduction: Vestibular schwannoma (VS) is an intracranial tumor that arises on the vestibular branch of cranial nerve VIII and typically presents with sensorineural hearing loss (SNHL). The mechanisms of this SNHL are postulated to involve alterations in the inner ear's microenvironment mediated by the genetic cargo of VS-secreted extracellular vesicles (EVs). We aimed to identify the EV cargo associated with poor hearing and determine whether its delivery caused hearing loss and cochlear damage in a mouse model in vivo., Methods: VS tissue was collected from routinely resected tumors of patients with good (VS-GH) or poor (VS-PH) pre-surgical hearing measured via pure-tone average and word recognition scores. Next-generation sequencing was performed on RNA isolated from cultured primary human VS cells and EVs from VS-conditioned media, stratified by patients' hearing ability. microRNA expression levels were compared between VS-PH and VS-GH samples to identify differentially expressed candidates for packaging into a synthetic adeno-associated viral vector (Anc80L65). Viral vectors containing candidate microRNA were infused to the semicircular canals of mice to evaluate the effects on hearing, including after noise exposure., Results: Differentially expressed microRNAs included hsa-miR-431-5p (enriched in VS-PH) and hsa-miR-192-5p (enriched in VS-GH). Newborn mice receiving intracochlear injection of viral vectors over-expressing hsa-miR-431-GFP, hsa-miR-192-GFP, or GFP only (control) had similar hearing 6 weeks post-injection. However, after acoustic trauma, the miR-431 group displayed significantly worse hearing, and greater loss of synaptic ribbons per inner hair cell in the acoustically traumatized cochlear region than the control group., Conclusion: Our results suggest that miR-431 contributes to VS-associated hearing loss following cochlear stress. Further investigation is needed to determine whether miR-431 is a potential therapeutic target for SNHL., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Fujita, Seist, Kao, Soares, Panano, Khetani, Landegger, Batts and Stankovic.)

Objectives: A major strategy to reduce the impact of breast cancer (BC) among African Americans (AA) is patient navigation, defined here as individualized assistance for reducing barriers to healthcare use. The primary focus of this study was to estimate the added value of incorporating breast health promotion by navigated participants and the subsequent BC screenings that network members may obtain., Methods: In this study, we compared the cost-effectiveness of navigation across 2 scenarios. First, we examine the effect of navigation on AA participants (scenario 1). Second, we examine the effect of navigation on AA participants and their networks (scenario 2). We leverage data from multiple studies in South Chicago. Our primary outcome (BC screening) is intermediate, given limited available quantitative data on the long-term benefits of BC screening for AA populations., Results: When considering participant effects alone (scenario 1), the incremental cost-effectiveness ratio was $3845 per additional screening mammogram. When including participant and network effects (scenario 2), the incremental cost-effectiveness ratio was $1098 per additional screening mammogram., Conclusion: Our findings suggest that inclusion of network effects can contribute to a more precise, comprehensive assessment of interventions for underserved communities., (Copyright © 2023. Published by Elsevier Inc.)

Background: Diffuse large B-cell lymphoma (DLBCL) is a malignant lymphoid tumor disease that is characterized by heterogeneity, but current treatment does not benefit all patients, which highlights the need to identify oncogenic genes and appropriate drugs. G9a is a histone methyltransferase that catalyzes histone H3 lysine 9 (H3K9) methylation to regulate gene function and expression in various cancers., Methods: TCGA and GTEx data were analyzed using the GEPIA2 platform. Cell viability under drug treatment was assessed using Alamar Blue reagent; the interaction between G9a and niclosamide was assessed using molecular docking analysis; mRNA and protein expression were quantified in DLBCL cell lines. Finally, G9a expression was quantified in 39 DLBCL patient samples., Results: The TCGA database analysis revealed higher G9a mRNA expression in DLBCL compared to normal tissues. Niclosamide inhibited DLBCL cell line proliferation in a time- and dose-dependent manner, reducing G9a expression and increasing p62, BECN1, and LC3 gene expression by autophagy pathway regulation. There was a correlation between G9a expression in DLBCL samples and clinical data, showing that advanced cancer stages exhibited a higher proportion of G9a-expressing cells., Conclusion: G9a overexpression is associated with tumor progression in DLBCL. Niclosamide effectively inhibits DLBCL growth by reducing G9a expression via the cellular autophagy pathway; therefore, G9a is a potential molecular target for the development of therapeutic strategies for DLBCL.

Motivation: Alternative splicing (AS) of introns from pre-mRNA produces diverse sets of transcripts across cell types and tissues, but is also dysregulated in many diseases. Alignment-free computational methods have greatly accelerated the quantification of mRNA transcripts from short RNA-seq reads, but they inherently rely on a catalog of known transcripts and might miss novel, disease-specific splicing events. By contrast, alignment of reads to the genome can effectively identify novel exonic segments and introns. Event-based methods then count how many reads align to predefined features. However, an alignment is more expensive to compute and constitutes a bottleneck in many AS analysis methods., Results: Here, we propose fortuna, a method that guesses novel combinations of annotated splice sites to create transcript fragments. It then pseudoaligns reads to fragments using kallisto and efficiently derives counts of the most elementary splicing units from kallisto's equivalence classes. These counts can be directly used for AS analysis or summarized to larger units as used by other widely applied methods. In experiments on synthetic and real data, fortuna was around 7× faster than traditional align and count approaches, and was able to analyze almost 300 million reads in just 15 min when using four threads. It mapped reads containing mismatches more accurately across novel junctions and found more reads supporting aberrant splicing events in patients with autism spectrum disorder than existing methods. We further used fortuna to identify novel, tissue-specific splicing events in Drosophila., Availability and Implementation: fortuna source code is available at https://github.com/canzarlab/fortuna., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: Whether oral lichen planus (OLP) was potentially malignant remains controversial. Here, we examined associations of ZNF582 methylation (ZNF582 m ) with OLP lesions, dysplastic features and squamous cell carcinoma (OSCC)., Materials and Methods: This is a case-control study. ZNF582 m was evaluated in both lesion and adjacent normal sites of 42 dysplasia, 90 OSCC and 43 OLP patients, whereas ZNF582 m was evaluated only in one mucosal site of 45 normal controls. High-risk habits affecting ZNF582 m such as betel nut chewing and cigarette smoking were also compared in those groups., Results: OLP lesions showed significantly lower ZNF582 m than those of dysplasia and OSCC. At adjacent normal mucosa, ZNF582 m increased from patients of OLP, dysplasia, to OSCC. In addition, ZNF582 m at adjacent normal sites in OLP patients was comparable to normal mucosa in control group. Dysplasia/OSCC patients with high-risk habits exhibited significantly higher ZNF582 m than those without high-risk habits. However, ZNF582 m in OLP patients was not affected by those high-risk habits., Conclusions: OLP is unlikely to be potentially malignant based on ZNF582 m levels. ZNF582 m may also be a potential biomarker for distinguishing OLP from true dysplastic features and OSCC, and for monitoring the malignant transformation of OLP, potentially malignant disorders with dysplastic features and OSCC., (© 2021 Wiley Periodicals LLC.)

Recreational boats are important vectors of spread of aquatic invasive species (AIS) among waterbodies of the United States. To limit AIS spread, state and county agencies fund watercraft inspection and decontamination stations at lake access points. We present a bi-level model for determining how a state planner can efficiently allocate inspection resources to county managers, who independently decide where to locate inspection stations. In our formulation, each county manager determines a set of optimal plans for the locations of inspection stations under various resource constraints. Each plan maximizes inspections of risky boats that may carry AIS from infested to uninfested lakes within the county. Then, the state planner selects the set of county plans (i.e., one plan for each county) that maximizes the number of risky boats inspected throughout the state subject to a statewide resource constraint. We apply the model using information from Minnesota, USA, including the infestation status of 9182 lakes and estimates of annual numbers of boat movements from infested to uninfested lakes. Comparison of solutions of the bi-level model with solutions of a state-level model where a state planner selects lakes for inspection stations statewide shows that when state and county objectives are not aligned, the loss in efficiency at the state-level can be substantial., Competing Interests: Declaration of competing interest 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., (Published by Elsevier Ltd.)

The Omicron variant BA.2 is the dominant form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in many countries, including those that have already implemented the strictest quarantine mandates that effectively contained the spread of the previous variants. Although many individuals were partially or fully vaccinated, confirmed Omicron infections have far surpassed all other variants combined in just a couple of months since the Omicron variant emerged. The ChAdOx1-S (AstraZeneca), BNT162b2 (Pfizer-BioNTech), and mRNA-1273 (Moderna) vaccines offer protection against the severe illness of SARS-CoV-2 infection; however, these currently available vaccines are less effective in terms of preventing Omicron infections. As a result, a booster dose of BNT162b2 or mRNA-1273 is recommended for individuals >12 years old who had received their second dose of the approved vaccines for >5 months. Herein, we review the studies that assessed the clinical benefits of the booster dose of vaccines against Omicron infections. We also analyzed public data to address whether early booster vaccination effectively prevented the surge of the Omicron infections. Finally, we discuss the consideration of a fourth dose of vaccine as a way to prevent possible upcoming infections., Competing Interests: Conflicts of interest: Dr. Shou-Yen Kao, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Background: Airway fibrosis is one of the pathological characteristics of severe asthma. Transforming growth factor (TGF)-β has been known to promote epithelial-mesenchymal transition formation and to play a role in the progression of tissue fibrosis. Cellular communication network factor 2 (CCN2) and fibronectin (FN) are well-known markers of EMT and fibrosis. However, whether AREG is involved in TGF-β-induced CCN2 and FN expression in human lung epithelial cells is unknown., Methods: AREG and FN were analyzed by immunofluorescence staining on ovalbumin-challenged mice. CCN2 and FN expression were evaluated in human lung epithelial (A459) cells following TGF or AREG treatment for the indicated times. Secreted AREG from A549 cells was detected by ELISA. Cell migration was observed by a wound healing assay. Chromatin immunoprecipitation was used to detect the c-Jun binding to the CCN2 promoter., Results: AREG and FN expression colocalized in lung tissues from mice with ovalbumin-induced asthma by immunofluorescence staining. Moreover, TGF-β caused the release of AREG from A549 cells into the medium. Smad3 siRNA down-regulated AREG expression. AREG also stimulated CCN2 and FN expression, JNK and c-Jun phosphorylation, and cell migration in A549 cells. AREG small interfering (si) RNA inhibited TGF-β-induced expression of CCN2, FN, and cell migration. Furthermore, AREG-induced CCN2 and FN expression were inhibited by EGFR siRNA, a JNK inhibitor (SP600125), and an activator protein-1 (AP-1) inhibitor (curcumin). EGFR siRNA attenuated AREG-induced JNK and c-Jun phosphorylation. Moreover, SP600125 downregulated AREG-induced c-Jun phosphorylation., Conclusion: These results suggested that AREG mediates the TGF-β-induced EMT in human lung epithelial cells through EGFR/JNK/AP-1 activation. Understanding the role of AREG in the EMT could foster the development of therapeutic strategies for airway remodeling in severe asthma., (© 2022. The Author(s).)

Context: Mask mandates are one form of nonpharmaceutical intervention that has been utilized to combat the spread of SARS-CoV2, the virus that causes COVID-19., Objective: This study examines the association between state-issued mask mandates and changes in county-level and hospital referral region (HRR)-level COVID-19 hospitalizations across the United States., Design: Difference-in-difference and event study models were estimated to examine the association between state-issued mask mandates and COVID-19 hospitalization outcomes., Participants: All analyses were conducted with US county-level data., Interventions: State-issued mask mandates. County-level data on the mandates were collected from executive orders identified on state government Web sites from April 1, 2020, to December 31, 2020., Main Outcome Measures: Daily county-level (and HRR-level) estimates of inpatient beds occupied by patients with confirmed or suspected COVID-19 were collected by the US Department of Health and Human Services., Results: The state issuing of mask mandates was associated with an average of 3.6 fewer daily COVID-19 hospitalizations per 100 000 people (P < .05) and a 1.2-percentage-point decrease in the percentage of county beds occupied with COVID-19 patients (P < .05) within 70 days of taking effect. Event study results suggest that this association increased the longer mask mandates were in effect. In addition, the results were robust to analyses conducted at the HRR level., Conclusions: This study demonstrated that state-issued mask mandates were associated with reduction in COVID-19 hospitalizations across the United States during the earlier portion of the pandemic. As new variants of the virus cause spikes in COVID-19 cases, reimposing mask mandates in indoor and congested public areas, as part of a layered approach to community mitigation, may reduce the spread of COVID-19 and lessen the burden on our health care system., Competing Interests: The authors have no relevant conflicts of interest to disclose.

Background: Visual oral examination (VOE) is a conventional oral cancer screening method. This study aimed to evaluate the value of methylation marker to assist VOE in identifying oral epithelial dysplasia and oral squamous cell carcinoma (OED/OSCC) from non-cancerous lesions in a real-world situation., Methods: 201 patients with high-risk personal habits who self-perceived oral anomaly were VOE examined, ZNF582 methylation ( ZNF582 m ) tested, and histologically diagnosed., Results: Among them, 132 patients (65.7%) were histologically diagnosed OED/OSCC. Using VOE, 56.1% OED/OSCC patients had possible oral cancer, whereas 37.7% non-OED/OSCC patients had leukoplakia. ZNF582 m -positive was detected in 90.2% OED/OSCC patients and 44.9% non-OED/OSCC patients. Various logistic regression models were postulated to evaluate the diagnostic performance of conventional VOE and new strategies using ZNF582 m . ROC analysis and its corresponding C-index demonstrated that either triage or co-testing models of VOE and ZNF582 m could improve diagnostic performance and discriminative abilities compared with the VOE only approach., Conclusions: In conclusion, methylation marker test shows equivalent performance to an experienced judgment by oral maxillofacial surgeons and plays a significantly supplementary role in increasing the efficacy in identifying oral malignant lesions. ZNF582 m may be an especially important tool for family physicians or general dentists to properly diagnose suspicious oral lesions.

Background: To help achieve Ending the HIV Epidemic (EHE) goals of reducing new HIV incidence, pre-exposure prophylaxis (PrEP) use and engagement must increase despite multidimensional barriers to scale-up and limitations in funding. We investigated the cost-effectiveness of interventions spanning the PrEP continuum of care., Setting: Men who have sex with men in Atlanta, GA, a focal jurisdiction for the EHE plan., Methods: Using a network-based HIV transmission model, we simulated lifetime costs, quality-adjusted life years (QALYs), and infections averted for 8 intervention strategies using a health sector perspective. Strategies included a status quo (no interventions), 3 distinct interventions (targeting PrEP initiation, adherence, or persistence), and all possible intervention combinations. Cost-effectiveness was evaluated incrementally using a $100,000/QALY gained threshold. We performed sensitivity analyses on PrEP costs, intervention costs, and intervention coverage., Results: Strategies averted 0.2%-4.2% new infections and gained 0.0045%-0.24% QALYs compared with the status quo. Initiation strategies achieved 20%-23% PrEP coverage (up from 15% with no interventions) and moderate clinical benefits at a high cost, while adherence strategies were relatively low cost and low benefit. Under our assumptions, the adherence and initiation combination strategy was cost-effective ($86,927/QALY gained). Sensitivity analyses showed no strategies were cost-effective when intervention costs increased by 60% and the strategy combining all 3 interventions was cost-effective when PrEP costs decreased to $1000/month., Conclusion: PrEP initiation interventions achieved moderate public health gains and could be cost-effective. However, substantial financial resources would be needed to improve the PrEP care continuum toward meeting EHE goals., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Oral squamous cell carcinoma (OSCC) is a type of malignancy characterized by high relapse and recurrence rates in the late stage despite optimal surgical intervention and postoperative chemoradiotherapy. Because the management of relapse following definitive treatment is challenging, accurate risk stratification is of clinical significance to improve treatment outcomes. Circular RNAs (circRNAs) are noncoding RNAs featured with cell-type specificity and high stability, owing to their circular structure, making these molecules excellent biomarkers for a variety of diseases., Methods: The levels of hsa&#95;circ&#95;0000190 and 0001649 in plasma samples from 30 healthy controls and 66 OSCC patients were determined by droplet digital polymerase chain reaction. The same primer sets were used with PCR to examine the expression of these two circRNAs in cancerous and adjacent normal tissues. A receiver operating characteristics curve was generated to evaluate the diagnostic value. The Kaplan-Meier method with a log-rank test was used for survival analysis., Results: We identified two circRNAs as potential biomarkers for OSCC, showing that the plasma level of hsa&#95;circ&#95;0000190 was significantly decreased in the late stage and marginally correlated with the development of second primary OSCC. We also found that the decreased plasma hsa&#95;circ&#95;0001649 was correlated with the recurrence and poor prognosis of patients. Additionally, we found that high plasma hsa&#95;circ&#95;0000190, but not hsa&#95;circ&#95;0001649, possibly predicted a better response of patients to induction chemotherapy., Conclusion: Our study demonstrated the potential of biomarkers in plasma to inform not just the tumor but the entire oral cavity, thereby offering a prediction for early recurrence and second primary OSCC. The plasma circRNAs remain valuable for OSCC, albeit the easy accessibility to the oral cavity., Competing Interests: Conflicts of interest: Dr. Shou-Yen Kao, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Background: Virtual reality (VR)-based simulation in hospital settings facilitates the acquisition of skills without compromising patient safety. Despite regular text-based training, a baseline survey of randomly selected healthcare providers revealed deficiencies in their knowledge, confidence, comfort, and care skills regarding tracheostomy. This prospective pre-post study compared the effectiveness of regular text- and VR-based intervention modules in training healthcare providers' self-efficacy in tracheostomy care skills., Methods: Between January 2018 and January 2020, 60 healthcare providers, including physicians, nurses, and respiratory therapists, were enrolled. For the intervention, a newly developed head-mounted display (HMD) and web VR materials were implemented in training and clinical services. Subsequently, in-hospital healthcare providers were trained using either text or head-mounted display virtual reality (HMD-VR) materials in the regular and intervention modules, respectively. For tracheostomy care skills, preceptors directly audited the performance of trainees and provided feedback., Results: At baseline, the degree of trainees' agreement with the self-efficacy-related statements, including the aspects of familiarity, confidence, and anxiety about tracheostomy-related knowledge and care skills, were not different between the control and intervention groups. At follow-up stage, compared with the regular group, a higher percentage of intervention group' trainees reported that they are "strongly agree" or "somewhat agree" that the HMD-VR simulation increases their self-efficacy, including the aspects of familiarity and confidence, and reduced their anxiety about tracheostomy-related knowledge and care skills. After implementation, a higher degree of trainees' average satisfaction with VR-based training and VR materials was observed in the intervention group than in the regular group. Most reported that VR materials enabled accurate messaging and decreased anxiety. The increasing trend of the average written test and hands-on tracheostomy care skills scores among the intervention group trainees was significant compared to those in the regular group. The benefits of HMD-VR simulations and web-VR material-based clinical services for in-hospital healthcare providers and patient families persisted until 3 to 4 weeks later., Conclusion: The current study suggests that VR materials significantly enhance trainees' self-efficacy (increased familiarity, increased confidence, and reduced anxiety) and their satisfaction with the training, while motivating them to use acquired knowledge and skills in clinical practice., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective/design/setting: This study aims to develop preprocedural communication-specific framework that emphasises the use of audiovisual materials and compares its acceptability by trainees with a regular module., Trainees: Between October 2018 and July 2021, 96 medical clerks were enrolled and randomly divided into regular and intervention groups. Another 48 trainees whose did not join the framework-based training but complete self-assessments were enrolled as the control group., Interventions: In the intervention training module, the key steps of preprocedural communication-specific skills were structuralised into a framework using the acronym of OSCAR., Primary and Secondary Outcome Measures: This study compared the acceptability of trainees for two modules by measuring the degree of increase in the end-of-rotation and follow up (4 weeks later) competency from baseline by trainees' self-assessments and physician assessments after serial trainings., Results: In comparison with regular group trainees, greater degree of improvements (framework-1 statement: 111%±13% vs 27%±5%, p<0.001; framework-2 statement: 77%±9% vs 48%±2%, p<0.05; skill-1 statement: 105%±9% vs 48%±3%, p<0.001); skill-2 statement: 71%±11% vs 50%±9%, p<0.05) were noted in the framework-related and skill-related statement 1-2 (the familiarity and confidence to use the framework and skills) than those of intervention group. At the end-of-rotation stage, the trainees ability to use the ' A -step: using audiovisual materials' of the OSCAR was significantly improved (229%±13%, p<0.001), compared with other steps. In the intervention group, the degree of improvement of the end-of-rotation data of trainees' self-assessment from baseline was significantly correlated with the degree of the improvement in physicians' assessment data in the aspects of skills, framework and steps in framework (R=0.872, p<0.01; R=0.813, p<0.001; R=0.914, p<0.001)., Conclusions: The OSCAR framework-based intervention module is well accepted by medical clerks and motivates them to integrate the acquired skills in clinical practice, which leads to trainees' primary care patients being satisfied with their preprocedural communication., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Undertaking a standard-setting exercise is a common method for setting pass/fail cut scores for high-stakes examinations. The recently introduced equal Z standard-setting method (EZ method) has been found to be a valid and effective alternative for the commonly used Angoff and Hofstee methods and their variants. The current study aims to estimate the minimum number of panelists required for obtaining acceptable and reliable cut scores using the EZ method., Methods: The primary data were extracted from 31 panelists who used the EZ method for setting cut scores for a 12-station of medical school’s final objective structured clinical examination (OSCE) in Taiwan. For this study, a new data set composed of 1,000 random samples of different panel sizes, ranging from 5 to 25 panelists, was established and analyzed. Analysis of variance was performed to measure the differences in the cut scores set by the sampled groups, across all sizes within each station., Results: On average, a panel of 10 experts or more yielded cut scores with confidence more than or equal to 90% and 15 experts yielded cut scores with confidence more than or equal to 95%. No significant differences in cut scores associated with panel size were identified for panels of 5 or more experts., Conclusion: The EZ method was found to be valid and feasible. Less than an hour was required for 12 panelists to assess 12 OSCE stations. Calculating the cut scores required only basic statistical skills.

Oral cancers are the seventh most common cancer globally. While progresses in oral cancer treatment have been made, not all patients respond to these therapies in the same way. To overcome this difficulty, numerous studies have been devoted to identifying biomarkers, which enable early identification of patients who may benefit from a particular treatment modality or at risk for poor prognosis. Biomarkers are protein molecules, gene expression, DNA variants, or metabolites that are derived from tumors, adjacent normal tissue or bodily fluids, which can be acquired before treatment and during follow-up, thus extending their use to the evaluation of cancer progression and prediction of treatment outcome. In this review, we employed a basic significance level (<0.05) as the minimal requirement for candidate biomarkers. Effect sizes of the biomarkers in terms of odds ratio, hazard ratio, and area under the receiver operating characteristic curves were subsequently used to evaluate the potential of their clinical use. We identified the CCND1 from the tumor, human papillomavirus, HSP70, and IL-17 from the peripheral blood, and high density of CD45RO+ tumor-infiltrating lymphocytes as the clinically relevant biomarkers for oral cancers., Competing Interests: Conflicts of interest: Dr. Shou-Yen Kao, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Objective: Acute pancreatitis can usually recover after conservative treatment. Five to 10 percent of acute pancreatitis may proceed into peripancreatic fluid collection and necrosis development, called necrotizing pancreatitis (NP), which has a high mortality rate. If it is accompanied by the occurrence of abdominal compartment syndrome (ACS) and does not respond to medical therapy, surgical intervention is indicated., Methods: We analyzed our experience of surgical intervention strategies for NP patients with medically irreversible ACS from January 1, 2004, to December 31, 2018., Results: Of the 47 NP patients with ACS, mean Ranson score was 6.5, mean Acute Physiology and Chronic Health Evaluation II score was 22.2, and Modified computed tomography severity index score was all 8 or greater. The mean total postoperative hospital length of stay was 80.2 days, of which the mean intensive care unit length of stay was 16.6 days. The overall complication rate was 31.9%. The mortality rate was 8.5%. Among the 47 patients, only fungemia was significantly associated with mortality incidence., Conclusions: The combination of multiple drainage tube placement, feeding jejunostomy, and ileostomy at the same time were effective surgical intervention strategies for NP patients with ACS, which brought a lower mortality rate., Competing Interests: The authors declare no conflict of interest. This study was sponsored by grants from Ten-Chan General Hospital Zhongli, Taipei Veterans General Hospital (V108C-044, V109C-130, V108B-002, V109C-131), the Ministry of Science and Technology (MOST 107-2314-B-010-056-MY3, MOST 108-2314-B-010-053), and Taiwan Association of Cardiovascular Surgery Research. We declare that the sponsors of the study and the authors have no conflicts of interest to report. The funding sources had no role in the study design, data collection, data interpretation, data analysis, or writing of the report., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Peritoneal dialysis (PD) is a kind of renal replacement therapy for end-stage renal disease (ESRD). While PD has many advantages, various complications may arise. Methods: This retrospective study analyzed the complications of ESRD patients who received PD catheter implantation in a single medical center within 15 years. Results: This study collected 707 patients. In the first 14 days after PD implantation, 54 patients experienced bleeding complications, while 47 patients experienced wound infection. Among all complications, catheter-related infections were the most common complication 14 days after PD implantation (incidence: 38.8%). A total of 323 patients experienced PD catheter removal, of which 162 patients were due to infection, while 96 were intentional due to kidney transplantation. Excluding those whose catheters were removed due to transplantation, the median survival of the PD catheter was 4.1 years; among them, patients without diabetes mellitus (DM) were 7.4 years and patients with DM were 2.5 years ( p < 0.001). Further, 50% probability of surviving was beyond 3.5 years in DM patients with HbA1CC < 7 and 1.6 years in DM patients with HbA1C <7 ( p ≥ 0.001). Conclusions: Catheter-related infections were the most common complications following PD catheter implantation. DM, especially with HbA1C ≥7, significantly impacted on the catheter-related infection and the survival probability of the PD catheter., 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 © 2021 Chang, Chang, Hsiao, Kao, Chen, Chen and Tsai.)

The proper regulation of RNA processing is critical for muscle development and the fine-tuning of contractile ability among muscle fiber-types. RNA binding proteins (RBPs) regulate the diverse steps in RNA processing, including alternative splicing, which generates fiber-type specific isoforms of structural proteins that confer contractile sarcomeres with distinct biomechanical properties. Alternative splicing is disrupted in muscle diseases such as myotonic dystrophy and dilated cardiomyopathy and is altered after intense exercise as well as with aging. It is therefore important to understand splicing and RBP function, but currently, only a small fraction of the hundreds of annotated RBPs expressed in muscle have been characterized. Here, we demonstrate the utility of Drosophila as a genetic model system to investigate basic developmental mechanisms of RBP function in myogenesis. We find that RBPs exhibit dynamic temporal and fiber-type specific expression patterns in mRNA-Seq data and display muscle-specific phenotypes. We performed knockdown with 105 RNAi hairpins targeting 35 RBPs and report associated lethality, flight, myofiber and sarcomere defects, including flight muscle phenotypes for Doa , Rm62 , mub , mbl , sbr , and clu . Knockdown phenotypes of spliceosome components, as highlighted by phenotypes for A-complex components SF1 and Hrb87F (hnRNPA1), revealed level- and temporal-dependent myofibril defects. We further show that splicing mediated by SF1 and Hrb87F is necessary for Z-disc stability and proper myofibril development, and strong knockdown of either gene results in impaired localization of kettin to the Z-disc. Our results expand the number of RBPs with a described phenotype in muscle and underscore the diversity in myofibril and transcriptomic phenotypes associated with splicing defects. Drosophila is thus a powerful model to gain disease-relevant insight into cellular and molecular phenotypes observed when expression levels of splicing factors, spliceosome components and splicing dynamics are altered.

Background: Nonradiographic axial spondyloarthropathies (nr-axSpA) are diagnosed by the absence of radiographic sacroiliitis and the presence of bone marrow edema (BME) on magnetic resonance imaging (MRI). According to the classification criteria of the international Assessment of Spondyloarthritis Society (ASAS), structural changes to sacroiliac joints (SIJs) on MRI cannot be used as criteria in the absence of BME. However, less than half the Asian patients with clinically active axSpA show BME. The incidence of human leukocyte antigen (HLA)-B27 is low in Asian populations, which makes it more difficult to identify nr-axSpA. We used MRI to evaluate the structural damage to SIJs in patients with nr-axSpA with and without BME with the aim of identifying the best methodology for accurate diagnosis, especially in populations with less common BME and HLA-B27., Methods: One hundred three patients with inflammatory back pain were included in this prospective study. No patient's radiograph met the definition of positive modified New York criteria. BME and structural damage to SIJ including sclerosis and erosion were assessed independently on coronal and axial short-tau inversion recovery and T1-weighted spin echo MRI scans by two well-trained musculoskeletal radiologists using the Spondyloarthritis Research Consortium of Canada (SPARCC) score. Demographics of patients were collected. Disease characteristics and structural damage were analyzed in patients with and without BME on SIJ MRI. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of structural damage., Results: All individuals in the cohort had at least one abnormal finding on SIJ MRI, including BME or structural damage; 36 of 103 patients had BME. We identified a significant positive correlation between SPARCC scores and severe erosion assessed by focal joint space widening (fJSW) (p = 0.001) in these 36 patients. Fifty-eight of the 103 enrolled patients fulfilled the ASAS criteria for nr-axSpA in the either absence or presence of BME. Of these 58 patients, 57 and 19 had erosions or fJSW, respectively, and the presence of BME was significantly correlated with fJSW (phi score of 0.319 and p = 0.015). We demonstrated a significant positive correlation between fJSW and either the presence or the severity of BME in patients with nr-axSpA who met the ASAS definition. There was a positive correlation between BME and fJSW across the whole study cohort (phi score of 0.389; p < 0.001). The area under the ROC curve (AUC) for fJSW on SIJ MRI was 0.736, p < 0.001. In both HLA-B27-positive and -negative groups, BME was more common in the presence of fJSW (phi scores of 0.370 and 0.377, p = 0.018 and 0.003, respectively) and SPARCC scores were higher in patients with fJSW (p < 0.001 and p = 0.005). We also identified a positive correlation between fJSW and BME in patients with nr-axSpA and normal serum levels of C-reactive protein (phi score of 0.362 and p = 0.001)., Conclusion: Structural damage detected on SIJ MRI, sclerosis, erosions and fJSW may be present in patients without detectable inflammation on SIJ MRI. However, fJSW is significantly correlated with the severity of inflammation seen on SIJ MRI, which contributes to the accurate diagnosis of nr-axSpA, and it could be used as an alternative diagnostic test for nr-axSpA in the general population, especially for those who do not carry the HLA-B27 gene, Asian patients without BME, or patients with normal serum inflammatory biomarkers., (© 2021. The Author(s).)

Background: A recent study suggested to develop and implement more interacted material for preprocedural education to decrease patients' anxiety about the atrial fibrillation (AF) ablation. This study compared the effectiveness of using either newly developed virtual reality (VR) materials (VR group) or paper-based materials (paper group) on giving AF preprocedural education., Methods: This study consequentially enrolled 33 AF patients preparing for ablation from November 2019 to October 2020. After enrollment, patients were randomized as either paper (n = 22) or VR (n = 11) groups., Results: In comparison with the baseline stage, at the posteducation stage, the degree of improvement in patients' self-assessed self-efficacy on AF ablation knowledge was higher among VR group patients than those in the paper group. At the posteducation stage, the patients' satisfaction to preprocedural education and used materials were higher among the VR group than that among the paper group. In addition to meet their needs and give accurate medical information, VR group patients reported that VR materials increased the effectiveness of education, increased their preparedness for AF catheter ablation, achieved paperless purposes, and willing to recommend VR materials to others. Operators subjectively reported that the periprocedure cooperation was increased both among paper and VR group patients after preprocedural education for the details of procedure. Better preparedness of VR group patients was supported by less periprocedure pain, anxiety, and impatience than those among paper group patients., Conclusion: Interactive VR-based materials are superior to the paper-based materials to provide patients immerse and imagine the journey and detail knowledge of AF catheter ablation before the procedure and better prepared patients for the procedure., Competing Interests: Conflicts of interest: Dr. Shih-Ann Chen, Dr. Shou-Yen Kao and Dr. Fa-Yauh Lee, editorial board members at Journal of the Chinese Medical Association, have no roles in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Dry eye disease (DED), also called the keratoconjunctivitis sicca, is one of the most common diseases in the ophthalmology clinics. While DED is not a life-threatening disease, life quality may be substantially affected by the discomfort and the complications of poor vision. As such, a large number of studies have made contributions to the investigation of the DED pathogenesis and novel treatments. DED is a multifactorial disease featured with various phenotypic consequences; therefore, animal models are valuable tools suitable for the related studies. Accordingly, selection of the animal model to recapitulate the clinical presentation of interest is important for appropriately addressing the research objective. To this end, we systemically reviewed different murine and rabbit models of DED, which are categorized into the quantitative (aqueous-deficient) type and the qualitative (evaporative) type, based on the schemes to establish. The clinical manifestations of dry eye on animal models can be induced by mechanical or surgical approaches, iatrogenic immune response, topical eye drops, blockage of neural pathway, or others. Although these models have shown promising results, each has its own limitation and cannot fully reproduce the pathophysiological mechanisms that occur in patients. Nonetheless, the animal models remain the best approximation of human DED and represent the valuable tool for the DED studies., Competing Interests: Conflicts of interest: Dr. Shou-Yen Kao, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest relating to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

The bone encasing the inner ear, known as the otic capsule, is unique because it remodels little postnatally compared to other bones in the body. Previous studies established that osteoprotegerin (OPG) in the inner ear inhibits otic capsule remodeling. OPG acts as a decoy receptor of receptor activator of nuclear factor κB ligand (RANKL) to disrupt the interaction between RANKL and RANK, the primary regulators of bone metabolism. Here we studied the expression and function of RANK and RANKL in the murine cochlea. Using a combination of in situ hybridization, real-time quantitative RT-PCR, and western blot, we demonstrate that Rankl and Rank genes and their protein products are expressed in the intracochlear soft tissues and the otic capsule in a developmentally regulated manner. Using a culture of neonatal murine cochlear neurons, we show that the interaction between RANK and RANKL inhibits neurite outgrowth in these neurons, and is associated with upregulation of NOGO-A expression. Taken together, our results suggest that, in addition to regulating otic capsule bone remodeling, RANK and RANKL expressed by intracochlear soft tissues may also regulate spiral ganglion neuron function by affecting neurite outgrowth., (Copyright © 2020. Published by Elsevier Inc.)

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and increasing numbers of patients receive AF ablation nowadays. Therefore, in the cardiology division, residents need to be familiar with the AF ablation procedure-related knowledge for primary care. This study evaluated the baseline residents and patients' self-efficacy to the AF ablation procedure-related knowledge, developed the specific virtual reality (VR) informative aids, and evaluated the effects of VR training and resident-led VR aids-based patient education on their self-efficacy, in the aspects of familiarity, confidence and anxiety, and satisfaction., Methods: From 2019, April to 2020, April, this 1-year prospective prestudy and poststudy was undergone in the cardiology division. Between 2019, April and 2019, December, the experienced physicians were invited to develop VR informative aids for AF ablation procedure-related knowledge. Between January 2020 and April 2020, newly developed VR informative aids were implemented in the educational program of training rotated residents for giving patient education., Result: A total of 20 residents and 32 patients were enrolled. The baseline self-reported self-efficacy and knowledge scores were relatively low among rotated residents and their patients. In addition to the high level of satisfaction, self-efficacy and knowledge scores of residents and their patients were increased after VR aids-based training and resident-led patient education. Higher degree of improvement in self-efficacy was noted among patients with depression/anxiety history than those without history. The follow-up assessments among residents showed that the positive effects of VR aids were sustained until 2 weeks later., Conclusion: Overall, residents and patients reported that the VR aids increase the effectiveness of patient education, achieve the purpose of a paperless environment, and motivate them to recommend it to others. The implementation of resident-to-patient education has a positive impact on trainees and patients understanding about AF ablation procedures-related knowledge., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2020, the Chinese Medical Association.)

The present study aimed to evaluate the effects of virtual reality (VR) simulations combined with bedside assignments on nurses’ self-efficacy in providing pre-treatment educational services. Between March 2019 and November 2020, we conducted a study of VR educational materials that were developed to cover information about the treatment of oral cancers. The effects of the VR simulation, the thinking-path tracking map method, and bedside assignments on the nurses’ treatment decision-related knowledge were evaluated in a ward for oral cancer patients at Taipei Veterans General Hospital, Taipei, Taiwan. The blended training model significantly increased nurses’ familiarity (P<0.01) and confidence (P<0.03) regarding their knowledge of treatments and treatment decision-related knowledge. This model also significantly increased their confidence in their skills in bedside pre-treatment education for admitted oral cancer patients (P<0.002). Oral cancer-specific VR materials enhanced the effectiveness of skills training among nurses in the oral cancer ward.

Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated deaths worldwide. Family members in miR-371/372/373 miRNA cluster, which is localized at human chromosome 19q13.4, are co-expressed in both human stem cells and malignancies. The individual miRNA in this cluster are also involved in modulating the pathogenesis of malignancies as either oncogenes or suppressors. The 19q13 region is frequently gained in head and neck cancers. High expression of miR-372 and miR-373 are survival predictors for OSCC. However, the role of the miR-371/372/373 cluster in oral carcinogenesis remains to be fully investigated. We use the clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 system to establish OSCC cell subclones that had the miR-371/372/373 cluster deleted. In addition, further subclones were established that had the promoter of this cluster deleted. Concordant silencing in SAS cells of miR-371/372/373 decreased oncogenic potential, increased cisplatin sensitivity, activated p53, and upregulated the expression of Bad and DKK1. We also employed the CRISPR/dCas9 synergistic activation mediator system, which allowed robust transcriptional activation of the whole miR-371/372/373 cistron. Upregulation of endogenous miR-371/372/372 expression increased both oncogenicity and drug resistance. These were accompanied by a slight activation of AKT, β-catenin, and Src. This study identifies the oncogenic role of the miR-371/372/373 cluster in OSCC. Using CRISPR based strategy can be a powerful paradigm that will provide mechanistic insights into miRNA cluster functionality, which will also likely help the development of targeting options for malignancies.

Objective: This study aimed to investigate the risk of dementia among subgroups of patients receiving concurrent antidepressant and hypnotic treatment, antidepressants alone, and hypnotics alone., Methods: Multivariate Cox proportional hazards regression models were used to determine the effects of antidepressants and hypnotics on dementia risk after adjusting for potential confounders., Results: Compared with the reference group, patients receiving concurrent antidepressant and hypnotic treatment had the highest adjusted hazard ratio (aHR: 2.390, 95% CI: 2.224-2.536; P < 0.001) for all-cause dementia, followed by those receiving antidepressants alone (aHR: 1.919, 95% CI: 1.811-2.012; P < 0.001) and hypnotics alone (aHR: 1.458, 95% CI: 1.397-1.527; P < 0.001). With regard to dementia subtypes, trends similar to those for all-cause dementia were observed for Alzheimer's dementia, vascular dementia and other types of dementia. The sensitivity analysis conducted also found the robustness of findings. Notably, inconsistent findings were observed in subgroup with depression, revealing a null association between concurrent antidepressant and hypnotic treatment (aHR: 0.496; 95% CI: 0.183-1.343; P = 0.175) or hypnotics alone (aHR: 2.750; 95% CI: 0.797-9.482; P = 0.102) and the risk of dementia, and a negative association between antidepressants alone (aHR: 0.351; 95% CI: 0.130-0.942; P = 0.032) and the risk of dementia., Conclusion: A null or negative association was observed between concurrent antidepressant and hypnotic treatment, antidepressants alone, hypnotics alone, and the dementia risk in the subgroup of patients with depression, suggesting the absence of an association between dementia risk and antidepressants alone or hypnotics alone., (Copyright © 2020. Published by Elsevier B.V.)

As of April 15, 2020, the US Food and Drug Administration has granted emergency use authorization to a first saliva test for diagnosis of severe acute respiratory syndrome coronavirus 2 infection, the device developed by RUCDR Infinite Biologics laboratory, Rutgers University. A key feature that distinguishes the saliva-based test from nasopharyngeal or oropharyngeal (throat) swabs is that this kit allows self-collection and can spare healthcare professionals to be at risk during collecting nasopharyngeal or oropharyngeal samples, thereby preserving personal protective equipment for use in patient care rather than sampling and testing. Consequently, broader testing than the current methods of nasal or throat swabs will significantly increase the number of people screening, leading to more effective control of the spread of COVID-19. Nonetheless, a comparison of saliva-based assay with current swab test is needed to understand what and how we can benefit from this newly developed assay. Therefore, in this mini-review article, we aimed to summarize the current and emerging tools, focusing on diagnostic power of different clinical sampling and specimens.

Animals possess a wide variety of muscle types that support different kinds of movements. Different muscles have distinct locations, morphologies and contractile properties, raising the question of how muscle diversity is generated during development. Normal aging processes and muscle disorders differentially affect particular muscle types, thus understanding how muscles normally develop and are maintained provides insight into alterations in disease and senescence. As muscle structure and basic developmental mechanisms are highly conserved, many important insights into disease mechanisms in humans as well as into basic principles of muscle development have come from model organisms such as Drosophila, zebrafish and mouse. While transcriptional regulation has been characterized to play an important role in myogenesis, there is a growing recognition of the contributions of alternative splicing to myogenesis and the refinement of muscle function. Here we review our current understanding of muscle type specific alternative splicing, using examples of isoforms with distinct functions from both vertebrates and Drosophila. Future exploration of the vast potential of alternative splicing to fine-tune muscle development and function will likely uncover novel mechanisms of isoform-specific regulation and a more holistic understanding of muscle development, disease and aging., Competing Interests: Declaration of Competing Interest The authors declare they have no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients undergoing pancreaticoduodenectomy (PD) for periampullary lesions are usually elderly with a high risk of postoperative morbidity and mortality. This retrospective cohort study investigated whether postoperative preemptive light sedation aids in recovery of elderly patients following PD., Methods: Ninety-nine geriatric patients undergoing PD at one hospital were enrolled from 2009 to 2018. Patients in the sedation group received mechanical ventilation support and preemptively light sedation with fentanyl and propofol or dexmedetomidine in the first 5 days postoperatively in the intensive care unit (ICU). Patients in the control group underwent early extubation and received morphine for pain control but no postoperative sedatives in the ordinary ward. Patients in the two groups were matched 1:1 using propensity scoring. The postoperative complication rate, surgical mortality, and postoperative hospital length of stay (LOS) were recorded. We also tested inflammation in an immortal human bronchial epithelial cell line., Results: After 1:1 matching, 40 patients in the sedation group were compared with 40 patients in the control group. The sedation group had a significantly lower pulmonary complication rate and fewer patients with postoperative gastroparesis. Both groups had similar postoperative hospital LOS and identical surgical mortality rates. Patients in the sedation group had significantly better postoperative quality of life, including less pain and less heartbeat variation. In vitro cell experiments supported the above clinical observations, showing that adequate use of sedatives could significantly elevate the cell viability rate, protect cells from damage, decrease interleukin-6 production, and reduce inflammation., Conclusion: Postoperative preemptive light sedation in the ICU in geriatric patients following PD may not only reduce the rates of postoperative pulmonary complications and gastroparesis but also improve postoperative quality of life without prolonging the postoperative hospital LOS.

Background: This study aims to assess the feasibility, reliability and validity of the panel-based Equal Z-score (EZ) method applied to objective structural clinical examination (OSCE) of Chinese medical students and undertaking a comparison with the statistical techniques-based Borderline Regression Method (BRM)., Methods: Data received from two cohorts of 6th and 7th year medical students in Taiwan who set the mock OSCE as a formative assessment. Traditionally this medical school uses BRM to set the pass/fail cut-score. For the current study, 31 OSCE panellists volunteered to participate in the EZ method in parallel to the BRM., Results: In the conduct of this study, each panel completed this task for an OSCE exam comprising 12 stations within less than 60 min. Moreover, none of the 31 panellists, whose are busy clinicians, had indicated that the task was too difficult or too time-consuming. Although EZ method yielded higher cut-scores than the BRM it was found reliable. Intraclass correlation (ICC) measuring absolute agreement, across the three groups of panellists was .893 and .937 for the first and second rounds respectively, demonstrating high level of agreement across groups with the EZ method and the alignment between the BRM and the EZ method was visually observed. The paired t-test results identified smaller differences between the cut-scores within methods than across methods., Conclusions: Overall this study suggests that the EZ method is a feasible, reliable and valid standard setting method. The EZ method requires relatively little resources (takes about an hour to assess a 12 station OSCE); the calculation of the cut-score is simple and requires basic statistical skills; it is highly reliable even when only 10 panellists participate in the process; and its validity is supported by comparison to BRM. This study suggests that the EZ method is a feasible, reliable and valid standard setting method.

Although they receive regular training, the survey we administered to our junior physicians and lab technicians revealed that they lack familiarity and confidence regarding the proper segregation/disposal of clinical wastes. In this pilot prospective study, carried out between September 2017 and September 2019, we developed a virtual reality (VR) simulation and integrated it into the steps of Gangen's training flow. Next, we analysed objective performance, recorded by the App in the VR system as well as the subjective self-assessments of 96 junior physicians and lab technicians after two practices of VR games. Before receiving training, lab technicians ' self-assessed familiarity and confidence regarding proper clinical wastes segregation/disposal were higher than among physicians. Compared with the first VR game, we noted greater improvement in accuracy as well as a higher percentage of shortened time to complete 10 actions of segregation/disposal of VR clinical wastes, among junior physicians/male trainees, that of junior lab technicians/female trainees in the second VR game. Most of the trainees (81%-88%) reported that they found the VR game-based training to be useful, in contrast to poster-mass media-based training. Our initial positive results indicated the possibility of applying this VR game-based simulation system to regular institution-wide staff education in future., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The Accreditation Council for Graduate Medical Education (ACGME) core competencies (CC) in general medicine-based primary care are essential for junior medical trainees. In this country, a regular faculty development (FD) program aimed at training faculty in instructing (teaching and assessing) these CC had operated. However, leadership was not emphasized. In a new intervention module, the roles and associated responsibilities of clinical instructors to conduct, design, and lead CC-based education were emphasis., Aims: This follow-up explanatory case study compares the effectiveness of intervention module with that of the previous regular module., Methods: The regular group (n = 28) comprised clinical instructors who participated in the FD module during the 2013-2014 year while the intervention group (n = 28) was composed of 2015-2016 participants. Prior to the formal (hands-on) training, participants in the intervention group were asked to study the online materials of the regular module. These participants then received a 30-h hands-on training in conducting, designing, and leading skills. Finally, they prepared a 10-h reflective end-of-module presentation of their real-world practices., Results: Following the training, a higher degree improvement in participants self-reported familiarity with CC education, self-confidence in their ability to deliver CC education and sustained involve CC education were noted among the intervention FD group, compared with the regular FD group. In the intervention group, senior academicians (associate and full professor) are more substantially involved in designing and leading CC-based courses than junior academicians (lecturers and assistant professors). Among non-teaching award winners of in the intervention FD group, the follow-up degree of sustained involvement in delivering, designing and leading CC-based courses was significantly higher than that of the regular group., Conclusions: Our study demonstrated that leadership training in the intervention FD modules substantially motivated clinical instructors to become leaders in CC education.

Background: Oral squamous cell carcinoma (OSCC) leads to thousands of deaths every year in Taiwan. Nearly 40% of OSCC patients are diagnosed with stage IV disease, which has a poor prognosis. Multimodality treatments including surgery and adjuvant therapy have been utilized, but their treatment outcomes are generally poor. In this study, we sought to identify possible clinical impact factors that may contribute to the survival of stage IV OSCC., Methods: Data for patients with malignant neoplasms of the oral cavity registered in the Cancer Registry Database of Taipei Veterans General Hospital between 2002 and 2011 were retrieved. The study patients consisted of OSCC patients with clinical stage IV disease who had undergone a surgery and adjuvant therapy. The primary endpoints were the 5-year disease-free survival (DFS) and overall survival (OS) rates. The clinicopathological characteristics of the patients were also stratified and compared., Results: A total of 191 OSCC patients were included for retrospective analysis. The different subgroups of stage IV disease presented different treatment outcomes. The 5-year OS versus DFS rates of each subgroup were as follows: T4N0: 70.9% versus 52.6%; T1-3N23: 66.1% versus 49.8%; T4N1: 49.6% versus 31.6%; and T4N23: 40.9% versus 31.0% (p < 0.01). Patients with diabetes, moderate or poor cell differentiation, perineural invasion, and extracapsular spread presented lower 5-year OS rates (hazard ratio [HR] = 1.87, 1.65, 2.42, and 2.14, respectively), and patients with perineural invasion, positive cut margin, and extracapsular spread presented lower 5-year DFS rates (HR = 1.57, 1.62, and 1.71, respectively)., Conclusion: In this study, we elucidated the different survival rates of different subgroups of stage IV OSCC following the same treatment scheme. The results of the study provide clinical physicians with references by which to evaluate prognosis and determine post-operative disease monitoring timetables based upon different characteristics.

miR-372 has been shown a potent oncogenic miRNA in the pathogenesis of oral squamous cell carcinoma (OSCC). The zinc finger and BTB domain containing 7A protein (ZBTB7A) is a transcriptional regulator that is involved in a great diversity of physiological and oncogenic regulation. However, the modulation of ZBTB7A in OSCC remains unclear. Tissue analysis identifies a reverse correlation in expression between miR-372 and ZBTB7A in OSCC tumors. When OSCC cells have stable knockdown of ZBTB7A, their oncogenic potential and drug resistance is increased. By way of contrast, such an increase is attenuated by expression of ZBTB7A. Screening and validation confirms that ZBTB7A is able to modulate expression of the death receptors TRAIL-R1, TRAIL-R2, Fas and p53 phosphorylated at serine-15. In addition, ZBTB7A transactivates TRAIL-R2, which sensitizes cells to cisplatin-induced apoptosis. The ZBTB7A-TRAIL-R2 cascade is involved in both the extrinsic and intrinsic cisplatin-induced pathways of apoptosis. Database analysis indicates that the expression level of and the copy status of ZBTB7A and TRAIL-R2 are important survival predictors for head and neck cancers. Collectively, this study indicates the importance of the miR-372 -ZBTB7A-TRAIL-R2 axis in mediating OSCC pathogenesis and in controlling OSCC drug resistance. Therefore, silencing miR-372 and/or upregulating ZBTB7A would seem to be promising strategies for enhancing the sensitivity of OSCC to cisplatin therapy., (Copyright © 2020 Yeh, Yang, Wu, Kao, Liu, Chen, Lin and Chang.)

Cancer stem cells (CSC) are a subpopulation of tumor cells that have superior capacities of self-renewal, metastatic dissemination, and chemoresistance. These characteristics resemble, to some extent, the outcome of certain biological processes, including epithelial-mesenchymal transition (EMT), autophagy, and cellular stress response. Indeed, it has been shown that the stimuli that induce these processes and CSC are overlapping, and CSC and tumor cells that underwent EMT or autophagy are much alike. However, as the cross talk between CSC, EMT, autophagy, and cellular stress is further explored, these processes are also found to have an opposing role in CSC, depending on the condition and status of cells. This contextual effect is likely due to overwhelming reliance on CSC markers for their identification, and/or discrepancies in recognition of CSC as a particular cell population or cellular state. In this review, we summarize how EMT, autophagy, and cellular stress response are tied or unwound with CSC. We also discuss the current view of CSC theory evolved from the emphasis of heterogenicity and plasticity of CSC.