Aldehyde dehydrogenase 2 preserves kidney function by countering acrolein-induced metabolic and mitochondrial dysfunction.

The prevalence of chronic kidney diseases (CKD) varies by race due to genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asians, alters the enzyme's function in detoxifying alcohol-derived aldehydes, impacting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicates that diminished ALDH2 levels are linked to worse CKD outcomes, with correlations between ALDH2 expression, estimated glomerular filtration rate, urinary levels of acrolein, an aldehyde metabolized by ALDH2, and fibrosis severity. In mouse models of unilateral ureteral obstruction and folic acid nephropathy, reduced ALDH2 levels and elevated acrolein were observed in kidneys, especially in ALDH2 Glu504Lys knock-in mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and co-activation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduces acrolein and mitigates fibrosis in both wild-type and Glu504Lys knock-in mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.

Association Between Gastroesophageal Reflux Disease and Laryngeal Disorders: Real-World Evidence.

OBJECTIVE: The association between gastroesophageal reflux disease (GERD) and laryngeal disorders remains debatable, although it has been the focus of extensive clinical and laboratory research. We conducted this study to obtain evidence on the association. STUDY DESIGN: Population-based cohort study. SETTING: Taiwan National Health Insurance Research Database (NHIRD). METHODS: Using data from Taiwan's NHIRD (January 2000 to December 2018), we performed a population-based analysis to estimate the risk of laryngeal disorders in patients with GERD and those without GERD. RESULTS: The GERD and non-GERD cohorts comprised 176,319 and 705,276 patients, respectively. The cohorts were matched at a ratio of 1:4 based on sex, age, urbanization level, and income level. The risk of laryngeal disorders was higher in the GERD cohort than in the non-GERD cohort (adjusted hazard ratio: 1.64; 95% confidence interval: 1.61-1.67). CONCLUSION: This study is the first to use population data for identifying the association between GERD and laryngeal disorders for real-world findings. Our population-based analysis indicates that patients with GERD have an elevated risk of laryngeal disorders.

The updated Asia-Pacific consensus statement on the role of endoscopic management in malignant hilar biliary obstruction.

The first Asia-Pacific consensus recommendations for endoscopic and interventional management of hilar cholangiocarcinoma were published in 2013. Since then, new evidence on the role of endoscopy for management of malignant hilar biliary obstruction (MHBO) has emerged. To update the recommendation, we reviewed the literature using a PICO (population/intervention/comparison/outcomes) framework and created consensus statements. The expert panel voted anonymously using the modified Delphi method and all final statements were evaluated for the quality of evidence and strength of recommendation. The important points with inadequate supporting evidence were classified as key concepts. There were seven statements and five key concepts that reached consensus. The statements and key concepts dealt with multiple aspects of endoscopy-based management in MHBO starting from diagnosis, strategies and options for biliary drainage, management of recurrent biliary obstruction, management of cholecystitis after biliary stenting, and adjunctive treatment before stenting. Although the recommendations may assist physicians in planning the treatment for MHBO patients, they should not replace the decision of a multidisciplinary team in the management of individual patients.

A de novo int22h-1/int22h-2-flanked Xq28 deletion-associated preferential X-inactivation in a female with severe hemophilia B.

A 5-year-old female diagnosed with severe hemophilia B began experiencing frequent muscular and joint bleeds at 19 months old. Molecular studies, including Sanger sequencing, Giemsa banding, human androgen receptor (HUMARA) assay, array-based comparative genomic hybridization (aCGH), whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA), revealed a heterozygous factor IX (F9) intron 3 substitution (c.277+1G>T) inherited from her mother and a de novo heterozygous 441 kb deletion in the Xq28 region, which flanked intron 22 homologous regions 1 (int22h1) and 2 (int22h2). This rare genetic profile explains her severe phenotype and guides hereditary consultation for family planning.

Advanced Glycation End-Products Acting as Immunomodulators for Chronic Inflammation, Inflammaging and Carcinogenesis in Patients with Diabetes and Immune-Related Diseases.

Increased production of advanced glycation end products (AGEs) among reducing sugars (glucose, fructose, galactose, or ribose) and amino acids/proteins via non-enzymatic Maillard reaction can be found in lifestyle-related disease (LSRD), metabolic syndrome (MetS), and obesity and immune-related diseases. Increased serum levels of AGEs may induce aging, diabetic complications, cardiovascular diseases (CVD), neurodegenerative diseases (NDD), cancer, and inflamm-aging (inflammation with immunosenescence). The Maillard reaction can also occur among reducing sugars and lipoproteins or DNAs to alter their structure and induce immunogenicity/genotoxicity for carcinogenesis. AGEs, as danger-associated molecular pattern molecules (DAMPs), operate via binding to receptor for AGE (RAGE) or other scavenger receptors on cell surface to activate PI3K-Akt-, P38-MAPK-, ERK1/2-JNK-, and MyD88-induced NF-κB signaling pathways to mediate various pathological effects. Recently, the concept of "inflamm-aging" became more defined, and we have unveiled some interesting findings in relation to it. The purpose of the present review is to dissect the potential molecular basis of inflamm-aging in patients with diabetes and immune-mediated diseases caused by different AGEs.

Astragalus Polysaccharides and Metformin May Have Synergistic Effects on the Apoptosis and Ferroptosis of Lung Adenocarcinoma A549 Cells.

Astragalus polysaccharides (APSs), the compounds extracted from the common herb Astragalus membranaceus, have been extensively studied for their antitumor properties. In this study, we investigated the effect of APS on lung adenocarcinoma A549 cells. The effects of APS and the anti-diabetic drug metformin on apoptosis and ferroptosis were compared. Furthermore, the combination treatment of APS and metformin was also investigated. We found that APS not only reduced the growth of lung cancer cells but also had a synergistic effect with metformin on A549 cells. The study results showed that it may be promising to use APS and metformin as a combination therapy for the treatment of lung adenocarcinoma.

Erratum: Therapeutic potential of EGFR/mTOR/Nf-kb targeting small molecule for the treatment of non-small cell lung cancer.

[This corrects the article on p. 2598 in vol. 13, PMID: 37424807.].

Free Fibular Osteocutaneous Flap Combined With Simultaneous Tendon Reconstruction for Midfoot Restoration After Myoepithelial Carcinoma Resection.

ABSTRACT: Myoepithelial carcinomas of soft tissue are rare, and most are malignant. The optimal treatment is surgical excision. The arches of the foot are a composite structure responsible for weight bearing and pressure distribution, so it is a vast challenge in reconstruction. We report a case of reconstruction of the midfoot with a free fibular bone flap and tendon graft. We review the literature to compare various options in foot reconstructions and sort out the outcomes of different bone flaps. The free fibula osteocutaneous flap is the superior choice for midfoot reconstruction owing to its sufficient length, strength, flexible skin paddles, easy-to-withstand osteotomy, and simultaneous tendon graft harvesting.

Imbalance in Unc80 RNA Editing Disrupts Dynamic Neuronal Activity and Olfactory Perception.

A-to-I RNA editing, catalyzed by the ADAR protein family, significantly contributes to the diversity and adaptability of mammalian RNA signatures, aligning with developmental and physiological needs. Yet, the functions of many editing sites are still to be defined. The Unc80 gene stands out in this context due to its brain-specific expression and the evolutionary conservation of its codon-altering editing event. The precise biological functions of Unc80 and its editing, however, are still largely undefined. In this study, we first demonstrated that Unc80 editing occurs in an ADAR2-dependent manner and is exclusive to the brain. By employing the CRISPR/Cas9 system to generate Unc80 knock-in mouse models that replicate the natural editing variations, our findings revealed that mice with the "gain-of-editing" variant (Unc80G/G) exhibit heightened basal neuronal activity in critical olfactory regions, compared to the "loss-of-editing" (Unc80S/S) counterparts. Moreover, an increase in glutamate levels was observed in the olfactory bulbs of Unc80G/G mice, indicating altered neurotransmitter dynamics. Behavioral analysis of odor detection revealed distinctive responses to novel odors-both Unc80 deficient (Unc80+/-) and Unc80S/S mice demonstrated prolonged exploration times and heightened dishabituation responses. Further elucidating the olfactory connection of Unc80 editing, transcriptomic analysis of the olfactory bulb identified significant alterations in gene expression that corroborate the behavioral and physiological findings. Collectively, our research advances the understanding of Unc80's neurophysiological functions and the impact of its editing on the olfactory sensory system, shedding light on the intricate molecular underpinnings of olfactory perception and neuronal activity.

Evaluating the Margins of Breast Cancer Tumors by Using Digital Breast Tomosynthesis with Deep Learning: A Preliminary Assessment.

BACKGROUND: The assessment information of tumor margins is extremely important for the success of the breast cancer surgery and whether the patient undergoes a second operation. However, conducting surgical margin assessments is a time-consuming task that requires pathology-related skills and equipment, and often cannot be provided in a timely manner. To address this challenge, digital breast tomosynthesis technology was utilized to generate detailed cross-sectional images of the breast tissue and integrate deep learning algorithms for image segmentation, achieving an assessment of tumor margins during surgery. METHODS: this study utilized post-operative tissue samples from 46 patients who underwent breast-conserving treatment, and generated image sets using digital breast tomosynthesis for the training and evaluation of deep learning models. RESULTS: Deep learning algorithms effectively identifying the tumor area. They achieved a Mean Intersection over Union (MIoU) of 0.91, global accuracy of 99%, weighted IoU of 44%, precision of 98%, recall of 83%, F1 score of 89%, and dice coefficient of 93% on the training dataset; for the testing dataset, MIoU was at 83%, global accuracy at 97%, weighted IoU at 38%, precision at 87%, recall rate at 69%, F1 score at 76%, dice coefficient at 86%. CONCLUSIONS: The initial evaluation suggests that the deep learning-based image segmentation method is highly accurate in measuring breast tumor margins. This helps provide information related to tumor margins during surgery, and by using different datasets, this research method can also be applied to the surgical margin assessment of various types of tumors.

OTUB1 contributes to the stability and function of Influenza A virus NS2.

The influenza A virus (IAV) consists of 8 single-stranded, negative-sense viral RNA (vRNA) segments. After infection, vRNA is transcribed, replicated, and wrapped by viral nucleoprotein (NP) to form viral ribonucleoprotein (vRNP). The transcription, replication, and nuclear export of the viral genome are regulated by the IAV protein, NS2, which is translated from spliced mRNA transcribed from viral NS vRNA. This splicing is inefficient, explaining why NS2 is present in low abundance after IAV infection. The levels of NS2 and its subsequent accumulation are thought to influence viral RNA replication and vRNP nuclear export. Here we show that NS2 is ubiquitinated at the K64 and K88 residues by K48-linked and K63-linked polyubiquitin (polyUb) chains, leading to the degradation of NS2 by the proteasome. Additionally, we show that a host deubiquitinase, OTUB1, can remove polyUb chains conjugated to NS2, thereby stabilizing NS2. Accordingly, knock down of OTUB1 by siRNA reduces the nuclear export of vRNP, and reduces the overall production of IAV. These results collectively demonstrate that the levels of NS2 in IAV-infected cells are regulated by a ubiquitination-deubiquitination system involving OTUB1 that is necessary for optimal IAV replication.

Discrepancies Among Hospitals and Regions in the Provision of Low-Value Care.

BACKGROUND: Low-value care (LVC) is a critical issue in terms of patient safety and fiscal policy; however, little has been known in Asia. For the purpose of better understanding the extent of LVC on a national level, the utilization, costs, and associated characteristics of selected international recommendations were assessed in this study. METHODS: This retrospective cohort study used the National Health Insurance (NHI) claims data during 2013-2017 to evaluate the LVC utilization. Adult beneficiaries who enrolled in the NHI program and received at least one of the low-value services in hospitals were included. We measured seven procedures derived from the international recommendations at the hospital level, and a composite measure was created by summing the total utilization of selected services to determine the overall prevalence and corresponding cost. The generalized estimating equation (GEE) model was adopted to estimate the association. RESULTS: A total of 1 970 496 episodes of LVC was identified among 1 218 146 beneficiary-year observations and 2054 hospital-year observations. Overall, the utilization rate of the composite measure increased from 150.70 to 186.23 episodes per 10 000 beneficiaries with the growth in cost from US$ 5.40 to US$ 6.90 million. LVC utilization was proportional to the volume of outpatient visits and length of stay. Also, hospitals with a large volume of outpatient visits (adjusted odds ratio [aOR]: 95% CI, 2.10: 1.26 to 3.49 for Q2-Q3, 2.88: 1.45 to 5.75 for ≥Q3) and a higher proportion of older patients (aOR: 95% CI, 1.06: 1.02 to 1.11) were more likely to have high costs. CONCLUSION: The utilization and corresponding cost of LVC appeared to increase annually despite the relatively lower prevalence compared to other countries. Multicomponent interventions such as recommendations, de-implementation policies and payment reforms are considered effective ways to reduce LVC. Repeated measurements would be needed to evaluate the effectiveness of interventions.

Temporal changes in biomarkers of neutrophil extracellular traps and NET-promoting autoantibodies following adenovirus-vectored, mRNA, and recombinant protein COVID-19 vaccination.

Neutrophil extracellular traps (NETs) play a role in innate pathogen defense and also trigger B-cell response by providing antigens. NETs have been linked to vaccine-induced thrombotic thrombocytopenia. We postulated a potential link between NET biomarkers, NET-promoting autoantibodies, and adverse events (AEs) after COVID-19 vaccine boosters. Healthy donors (HDs) who received ChAdOx1-S (A), mRNA-1273 (M), or recombinant protein (MVC-COV1901) vaccines at the National Taiwan University Hospital between 2021 and 2022 were recruited. We measured serial NET-associated biomarkers, citrullinated-histone3 (citH3), and myeloperoxidase (MPO)-DNA. Serum citH3 and MPO-DNA were significantly or numerically higher in HDs who reported AEs (n = 100, booster Day 0/Day 30, p = 0.01/p = 0.03 and p = 0.30/p = 0.35, respectively). We also observed a positive correlation between rash occurrence in online diaries and elevated citH3. A linear mixed model also revealed significantly higher citH3 levels in mRNA-1273/ChAdOx1-S recipients than MVC-COV1901 recipients. Significant positive correlations were observed between the ratios of anti-heparin platelet factor 4 and citH3 levels on Booster Day 0 and naïve and between the ratios of anti-NET IgM and citH3 on Booster Day 30/Day 0 in the AA-M and MM-M group, respectively. The increased levels of citH3/MPO-DNA accompanied by NET-promoting autoantibodies suggest a potential connection between mRNA-1273/ChAdOx1-S vaccines and cardiovascular complications. These findings provide insights for risk assessments of future vaccines.

Algorithm-Driven Tele-otoscope for Remote Care for Patients With Otitis Media.

OBJECTIVE: The COVID-19 pandemic has spurred a growing demand for telemedicine. Artificial intelligence and image processing systems with wireless transmission functionalities can facilitate remote care for otitis media (OM). Accordingly, this study developed and validated an algorithm-driven tele-otoscope system equipped with Wi-Fi transmission and a cloud-based automatic OM diagnostic algorithm. STUDY DESIGN: Prospective, cross-sectional, diagnostic study. SETTING: Tertiary Academic Medical Center. METHODS: We designed a tele-otoscope (Otiscan, SyncVision Technology Corp) equipped with digital imaging and processing modules, Wi-Fi transmission capabilities, and an automatic OM diagnostic algorithm. A total of 1137 otoscopic images, comprising 987 images of normal cases and 150 images of cases of acute OM and OM with effusion, were used as the dataset for image classification. Two convolutional neural network models, trained using our dataset, were used for raw image segmentation and OM classification. RESULTS: The tele-otoscope delivered images with a resolution of 1280 × 720 pixels. Our tele-otoscope effectively differentiated OM from normal images, achieving a classification accuracy rate of up to 94% (sensitivity, 80%; specificity, 96%). CONCLUSION: Our study demonstrated that the developed tele-otoscope has acceptable accuracy in diagnosing OM. This system can assist health care professionals in early detection and continuous remote monitoring, thus mitigating the consequences of OM.

Gender Self-Identification: Opinions About Transgender Women from a National Online Survey in Taiwan.

Gender self-identification (transgender) is not permitted in most Asian countries. In Taiwan, individuals recognized as transgender must meet requirements mandated by the Gender Recognition Act. Currently, lifting the requirement for proof of sex-reassignment surgery is pending. The aim of this study was to survey a large sample of Taiwanese to gain a better understanding of the general population's attitudes toward gender self-identification. A self-report survey, entitled "Opinions of Gender Self-Identification," collected demographic information and responses (agree = 1, disagree = 0) to 14 statements about transgender women and women's safety, personal rights, and the law; one statement discussed rights of transgender men to give birth; total scores ranged from 0 to 14. The online survey was distributed to non-government organizations across Taiwan and the Taiwanese islands and was available between April 16 and 30, 2022. Most of the 10,158 respondents were female (77.4%); ages of respondents ranged from 15 to > 65 years. The mean total score was 0.95 ± 2.27, indicating respondents strongly disagreed with support for transgender females; 91.56% disagreed with all statements. Although there were significant differences in scores between parents and non-parents, and those ≤ 35 years versus ≥ 36 years (p < .01), all strongly disagreed with gender self-identification. Given the majority of respondents were females, survey findings should be regarded with caution. Public acceptance of gender self-identification requires support from its residents. Our findings suggest that gender self-identification has not begun to approach even a moderate level of public support among survey respondents.

Consensus statements on endoscopic ultrasound-guided tissue acquisition. Guidelines from the Asian Endoscopic Ultrasound Group.

OBJECTIVES: This consensus was developed by the Asian EUS Group (AEG), who aimed to formulate a set of practice guidelines addressing various aspects of endoscopic ultrasound-guided tissue acquisition (EUS-TA). METHODS: The AEG initiated the development of consensus statements and formed an expert panel comprising surgeons, gastroenterologists, and pathologists. Three online consensus meetings were conducted to consolidate the statements and votes. The statements were presented and discussed in the first two consensus meetings and revised according to comments. Final voting was conducted at a third consensus meeting. The Grading of Recommendations, Assessment, Development, and Evaluation system was adopted to define the strength of the recommendations and quality of evidence. RESULTS: A total of 20 clinical questions and statements regarding EUS-TA were formulated. The committee recommended that fine-needle biopsy (FNB) needles be preferred over conventional fine-needle aspiration (FNA) needles for EUS-TA of subepithelial lesions. For solid pancreatic masses, rapid on-site evaluation is not routinely recommended when FNB needles are used. For dedicated FNB needles, fork-tip and Franseen-tip needles have essentially equivalent performance. CONCLUSION: This consensus provides guidance for EUS-TA, thereby enhancing the quality of EUS-TA.

Optimizing nonintubated laryngeal microsurgery: The effectiveness and safety of superior laryngeal nerve block with high-flow nasal oxygen-A prospective cohort study.

BACKGROUND: Laryngeal microsurgery (LMS) typically requires intubated general anesthesia (ITGA). Although nonintubated general anesthesia (NIGA) with high-flow nasal oxygen (HFNO) can be applied with LMS, a muscle relaxant is required, which can cause apnea and hypercapnia. This study evaluated the effectiveness of a superior laryngeal nerve block (SLNB) in improving safety during LMS. METHODS: This prospective cohort study enrolled a cumulative total of 61 adult patients received LMS under intravenous general anesthesia and allocated to three groups: ITGA group (n = 18), which patients performed intubation; neuromuscular blocking (NMB) group (n = 21), which patients administrated muscle relaxant without intubation and superior laryngeal nerve block (NB) group (n = 22), which patients performed SLNB without intubation or muscle relaxant. RESULTS: The average (SD) values of PaCO 2 after surgery in ITGA, NMB, and NB group were 50.8 (7.5), 97.5 (24.9), and 54.8 (8.8) mmHg, respectively. The mean postoperative pH values were 7.33 (0.04), 7.14 (0.07), and 7.33 (0.04), respectively. The results were all p < 0.001, and the average pH value of the NMB group was lower than that of the ITGA and NB groups. During the LMS, the mean heart rate (HR) (93.9 [18.1] bpm) and noninvasive blood pressure systolic (NBPs) (143.5 [28.2] mmHg) in the NMB group were higher than those in the ITGA group (HR = 77.4 [13.5] bpm and NBPs = 132.7 [20.8] mmHg) and NB group (HR = 82.3 [17.4] bpm and NBPs = 120.9 [25.0] mmHg). The results of p value by HR and NBPs are p < 0.001. The PaCO 2 and pH values are similar between ITGA group and NB group. CONCLUSION: Our approach of using HFNO with SLNB was successful for performing nonintubated LMS, enabling the patients to maintain spontaneous breathing and effectively eliminate CO 2 . This approach reduces the risks of hypercapnia and acidosis even when the duration of LMS exceeds 30 minutes.

Efficacy of Adjuvant Sublingual Immunotherapy After Septomeatoplasty.

BACKGROUND: The efficacy of adjuvant sublingual immunotherapy (SLIT) in correcting structural problems in patients with allergic rhinitis (AR) caused by mite who have undergone septomeatoplasty (SMP) has not been studied. METHODS: This non-randomized controlled study recruited patients with AR (caused by mite) and concurrent septal deviation and inferior turbinate hypertrophy, at a tertiary hospital in Taiwan. SMP was performed on all patients as a surgical intervention. The patients were then divided into two groups: the control group, which underwent surgery only, and the experimental group, which received SLIT as an adjuvant treatment. Demographic data and rhinitis control assessment test (RCAT) results were analyzed. RESULTS: A total of 96 patients were enrolled in the study (SMP + SLIT group, n = 52; SMP only group, n = 44). No significant differences were observed in any of the variables between the two groups before and one month after surgery. However, during evaluations at the third and sixth month, the SMP + SLIT group showed significant improvement in the total RCAT scores compared to the SMP only group (28.6 ± 1.56 vs. 24.5 ± 3.66, p < 0.001; 27.1 ± 2.87 vs. 19.9 ± 5.56, p < 0.001). In addition, significantly better control of all RCAT sub-categories was observed in the SMP + SLIT group at the third and sixth month evaluations. CONCLUSIONS: SLIT may serve as an ideal adjuvant therapy after SMP in patients with AR. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3073-3079, 2024.

Eugenol Suppresses Platelet Activation and Mitigates Pulmonary Thromboembolism in Humans and Murine Models.

Platelets assume a pivotal role in the pathogenesis of cardiovascular diseases (CVDs), emphasizing their significance in disease progression. Consequently, addressing CVDs necessitates a targeted approach focused on mitigating platelet activation. Eugenol, predominantly derived from clove oil, is recognized for its antibacterial, anticancer, and anti-inflammatory properties, rendering it a valuable medicinal agent. This investigation delves into the intricate mechanisms through which eugenol influences human platelets. At a low concentration of 2 µM, eugenol demonstrates inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Notably, thrombin and U46619 remain unaffected by eugenol. Its modulatory effects extend to ATP release, P-selectin expression, and intracellular calcium levels ([Ca2+]i). Eugenol significantly inhibits various signaling cascades, including phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3ß, mitogen-activated protein kinases, and cytosolic phospholipase A2 (cPLA2)/thromboxane A2 (TxA2) formation induced by collagen. Eugenol selectively inhibited cPLA2/TxA2 phosphorylation induced by AA, not affecting p38 MAPK. In ADP-treated mice, eugenol reduced occluded lung vessels by platelet thrombi without extending bleeding time. In conclusion, eugenol exerts a potent inhibitory effect on platelet activation, achieved through the inhibition of the PLCγ2-PKC and cPLA2-TxA2 cascade, consequently suppressing platelet aggregation. These findings underscore the potential therapeutic applications of eugenol in CVDs.