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Common age-related eye disorders include glaucoma, cataract, and age-related macular degeneration (AMD); however, little is known about their relationship with age. This study investigated the potential causal relationship between glaucoma and AMD with cataract using genetic data from multi-ethnic populations. Single-nucleotide polymorphisms (SNPs) associated with exposure to cataract were selected as instrumental variables (IVs) from genome-wide association studies using meta-analysis data from BioBank Japan and UK Biobank. A bidirectional two-sample Mendelian randomisation (MR) study was conducted to assess the causal estimates using inverse variance weighted, MR-Egger, and MR pleiotropy residual sum and outlier tests. SNPs with ( p < 5.0 × 10 -8 ) were selected as IVs for cataract, primary open-angle glaucoma, and AMD. We found no causal effects of cataract on glaucoma or AMD (all p > 0.05). Furthermore, there were no causal effects of AMD on cataract (odds ratio [OR] = 1.02, p = 0.400). However, glaucoma had a substantial causal effect on cataract (OR = 1.14, p = 0.020). Our study found no evidence for a causal relationship of cataract on glaucoma or AMD and a casual effect of AMD on cataract. Nonetheless, glaucoma demonstrates a causal link with cataract formation, indicating the need for future investigations of age-related eye diseases.

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population., (© 2024. The Author(s).)

Purpose: This study aims to examine whether perceived levels of job stress, burnout, and mental health are different according to demographic characteristics and working conditions and to investigate the direct and indirect effects of job stress and burnout on the mental health of medical faculty members., Methods: The study sample consists of 855 faculty members in 40 medical schools nationwide in the 2020 Burnout of Faculty Members of Medical Schools in Korea data with a grant from the Korean Association of Medical Colleges. This study employed structural equation modeling to construct causality among latent variables in addition to t-test, analysis of variance, and correlation coefficients for bivariate analyses., Results: Perceived job stress, burnout, and mental health levels of medical faculty members showed significant group differences by demographic characteristics and working conditions. Job stress directly affected mental health (β=0.215, p<0.01) and indirectly affected mental health via burnout (β=0.493, p<0.001). Thus burnout significantly mediated the relationship between job stress and the mental health of medical faculty members., Conclusion: This study found that job stress has direct and indirect effects on the mental health of medical faculty members, and burnout partially mediated this relationship. Further studies need to intervene in job stress and burnout to prevent the adverse mental health of medical faculty members and to introduce proper measures to improve working conditions affecting job stress and burnout.

Background: In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up., Methods: Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized., Results: At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69-78 %) reported being bothered "a little bit" or "not at all" by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline., Conclusion: PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer., Competing Interests: Declaration of Competing Interest SMT reports serving as a consulting or advisory role for Novartis, Pfizer, Merck, Eli Lilly and Company, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant (now Sumitovant Biopharma), Zetagen, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Biopharma, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera; and research funding (to institute) from Genentech/Roche, Merck, Exelixis, Pfizer, Eli Lilly and Company, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Gilead, Seattle Genetics, OncoPep, Daiichi Sankyo, outside of the submitted work. VG reports personal fees for advisory board membership for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly and Company, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, Pierre Fabre; personal fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Exact Sciences, Gilead, GSK Novartis and Zentiva; personal fees for expert testimony for Eli Lilly and Company, outside of the submitted work. JHS reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. JC reports honoraria from Glaxo, AstraZeneca, Roche, Novartis, Pharmamar, Eisai, Eli Lilly and Company, Daichii Sankyo, Gilead, Seagen, MSD, Pierre Fabre, and Pfizer; serves as a consulting or advisory role for AstraZeneca, Roche, Novartis, Pharmamar, Eisai, Eli Lilly and Company, Glaxo, Daichii Sankyo, Gilead, Seagen, Deciphera, and Pfizer; and travel expenses from Novartis, Gilead, Pharmamar, and Daichii-Sankyo, outside of the submitted work. MHA reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. MT reports fees from Eli Lilly and Company for speaker’s bureau, outside of the submitted work. CB reports grants and research support to their institution from Nektar, Pfizer, Polyphor, Amgen, Daiichi Sankyo, Sanofi, Exelixis, Regeneron, Novartis, GSK, Janssen, OBI Pharma, Eli Lilly and Company, Seagen, Roche, Bristol-Myers Squibb, MSD, Merck Serono, AstraZeneca, Novocure, Aveo Oncology, Takeda, TRIO, PharmaMar, Celgene, PPD, Syneos Health, Labcorp, ICON, IQVIA, Parexel, Nuvisan, PSI, Worldwide, Gilead Sciences, Bayer, and Servier; ownership or stocks from Tummi and MEDSIR; and serves on the advisory boards and consulting with Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Eli Lilly and Company, Sanofi, and Daiichi, outside of the submitted work. KM reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. RW, MMunoz, BSA, AML are employees and/or stock shareholders of Eli Lilly and Company. MMartin reports research grants from Roche, PUMA and Novartis; consulting/advisory fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly and Company, PUMA, Taiho Oncology, Daiichi Sankyo, Menarini/Stemline, and Pfizer; speakers’ honoraria from AstraZeneca, Lilly, Amgen, Roche/Genentech, Novartis, and Pfizer, outside of the submitted work. SRDJ reports grants or contracts from Pfizer, Puma Biotechnology, Eli Lilly and Company, AstraZeneca, Novartis, and Roche–Genentech for research funding to institute for laboratory studies and clinical trials; consulting fees from Eli Lilly and Company, AstraZeneca, Puma Biotechnology, Pfizer, Novartis, and Sanofi Genzyme for consulting or an advisory role; and payment or honoraria from Pfizer, Eisai, AstraZeneca, and Roche–Genentech for speaker's bureau, outside of the submitted work. PKL reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. NH reports honoraria for lectures and/or consulting froom Amgen, AstraZeneca, Daiichi-Sankyo, EPG Communication, Gilead, Eli Lilly and Company, MEDSCAPE, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Sandoz, Sanofi, Seagen, Springer, Viatris, and Zuelligpharma; ownership interest in Minority ownership as Co-Director West German Study Group (WSG), outside of the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Applications of base editing are frequently restricted by the requirement for a protospacer adjacent motif (PAM), and selecting the optimal base editor (BE) and single-guide RNA pair (sgRNA) for a given target can be difficult. To select for BEs and sgRNAs without extensive experimental work, we systematically compared the editing windows, outcomes and preferred motifs for seven BEs, including two cytosine BEs, two adenine BEs and three C•G to G•C BEs at thousands of target sequences. We also evaluated nine Cas9 variants that recognize different PAM sequences and developed a deep learning model, DeepCas9variants, for predicting which variants function most efficiently at sites with a given target sequence. We then develop a computational model, DeepBE, that predicts editing efficiencies and outcomes of 63 BEs that were generated by incorporating nine Cas9 variants as nickase domains into the seven BE variants. The predicted median efficiencies of BEs with DeepBE-based design were 2.9- to 20-fold higher than those of rationally designed SpCas9-containing BEs., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Central nervous system diseases, particularly neurodegenerative disorders, pose significant challenges in medicine. These conditions, characterized by progressive neuronal loss, have remained largely incurable, exacting a heavy toll on individuals and society. In recent years, in vivo reprogramming using Yamanaka factors has emerged as a promising approach for central nervous system regeneration. This technique involves introducing transcription factors, such as Oct4, Sox2, Klf4, and c-Myc, into adult cells to induce their conversion into neurons. This review summarizes the current state of in vivo reprogramming research in the central nervous system, focusing on the use of Yamanaka factors. In vivo reprogramming using Yamanaka factors has shown promising results in several animal models of central nervous system diseases. Studies have demonstrated that this approach can promote the generation of new neurons, improve functional outcomes, and reduce scar formation. However, there are still several challenges that need to be addressed before this approach can be translated into clinical practice. These challenges include optimizing the efficiency of reprogramming, understanding the cell of origin for each transcription factor, and developing methods for reprogramming in non-subventricular zone areas. Further research is needed to overcome the remaining challenges, but this approach has the potential to revolutionize the way we treat central nervous system disorders.

Background: Hearing rehabilitation with auditory training (AT) is necessary to improve speech perception ability in patients with hearing loss. However, face-to-face AT has not been widely implemented due to its high cost and personnel requirements. Therefore, there is a need for the development of a patient-friendly, mobile-based AT program., Objective: In this study, we evaluated the effectiveness of hearing rehabilitation with our chat-based mobile AT (CMAT) program for speech perception performance among experienced hearing aid (HA) users., Methods: A total of 42 adult patients with hearing loss who had worn bilateral HAs for more than 3 months were enrolled and randomly allocated to the AT or control group. In the AT group, CMAT was performed for 30 minutes a day for 2 months, while no intervention was provided in the control group. During the study, 2 patients from the AT group and 1 patient from the control group dropped out. At 0-, 1- and 2-month visits, results of hearing tests and speech perception tests, compliance, and questionnaires were prospectively collected and compared in the 2 groups., Results: The AT group (n=19) showed better improvement in word and sentence perception tests compared to the control group (n=20; P=.04 and P=.03, respectively), while no significant difference was observed in phoneme and consonant perception tests (both P>.05). All participants were able to use CMAT without any difficulties, and 85% (17/20) of the AT group completed required training sessions. There were no changes in time or completion rate between the first and the second month of AT. No significant difference was observed between the 2 groups in questionnaire surveys., Conclusions: After using the CMAT program, word and sentence perception performance was significantly improved in experienced HA users. In addition, CMAT showed high compliance and adherence over the 2-month study period. Further investigations are needed to validate long-term efficacy in a larger population., Trial Registration: Clinical Research Information Service (CRiS) KCT0006509; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=22110&search&#95;page=L., (© Jae Sang Han, Ji Hyung Lim, Yeonji Kim, Aynur Aliyeva, Jae-Hyun Seo, Jaehyuk Lee, Shi Nae Park. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org).)

Background: Tinnitus is a bothersome condition associated with various symptoms. However, the mechanisms of tinnitus are still uncertain, and a standardized assessment of the diagnostic criteria for tinnitus is required. We aimed to reach a consensus on diagnosing tinnitus with professional experts by conducting a Delphi study with systematic review of the literature., Methods: Twenty-six experts in managing tinnitus in Korea were recruited, and a two-round modified Delphi study was performed online. The experts evaluated the level of agreement of potential criteria for tinnitus using a scale of 1-9. After the survey, a consensus meeting was held to establish agreement on the results obtained from the Delphi process. Consensus was defined when over 70% of the participants scored 7-9 (agreement) and fewer than 15% scored 1-3 (disagreement). To analyze the responses of the Delphi survey, the content validity ratio and Kendall's coefficient of concordance were evaluated., Results: Consensus was reached for 22 of the 38 statements. For the definition of tinnitus, 10 out of 17 statements reached consensus, with three statements achieving complete agreement including; 1) Tinnitus is a conscious perception of an auditory sensation in the absence of a corresponding external stimulus, 2) Tinnitus can affect one's quality of life, and 3) Tinnitus can be associated with hearing disorders including sensorineural hearing loss, vestibular schwannoma, Meniere's disease, otosclerosis, and others. For the classification of tinnitus, 11 out of 18 statements reached consensus. The participants highly agreed with statements such as; 1) Vascular origin is expected in pulse-synchronous tinnitus, and 2) Tinnitus can be divided into acute or chronic tinnitus. Among three statements on the diagnostic tests for tinnitus only Statement 3, "There are no reliable biomarkers for sensory or emotional factors of tinnitus." reached consensus. All participants agreed to perform pure-tone audiometry and tinnitus questionnaires, including the Tinnitus Handicap Inventory and Tinnitus Questionnaire., Conclusion: We used a modified Delphi method to establish a consensus-based definition, a classification, and diagnostic tests for tinnitus. The expert panel reached agreement for several statements, with a high level of consensus. This may provide practical information for clinicians in managing tinnitus., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: General anesthetic techniques can affect postoperative recovery. We compared the effect of propofol-based total intravenous anesthesia (TIVA) and desflurane anesthesia on postoperative recovery., Methods: In this randomized trial, 150 patients undergoing robot-assisted or laparoscopic nephrectomy for renal cancer were randomly allocated to either the TIVA or desflurane anesthesia (DES) group. Postoperative recovery was evaluated using the Korean version of the Quality of Recovery-15 questionnaire (QoR-15K) at 24 h, 48 h, and 72 h postoperatively. A generalized estimating equation (GEE) was performed to analyze longitudinal QoR-15K data. Fentanyl consumption, pain severity, postoperative nausea and vomiting, and quality of life three weeks after discharge were also compared., Results: Data were analyzed for 70 patients in each group. The TIVA group showed significantly higher QoR-15K scores at 24 and 48 h postoperatively (24 h: DES, 96 [77, 109] vs. TIVA, 104 [82, 117], median difference 8 [95% CI: 1, 15], P = 0.029; 48 h: 110 [95, 128] vs. 125 [109, 130], median difference 8 [95% CI: 1, 15], P = 0.022), however not at 72 h (P = 0.400). The GEE revealed significant effects of group (adjusted mean difference 6.2, 95% CI: 0.39, 12.1, P = 0.037) and time (P < 0.001) on postoperative QoR-15K scores without group-time interaction (P = 0.051). However, there were no significant differences in other outcomes, except for fentanyl consumption, within the first 24 h postoperatively., Conclusions: Propofol-based TIVA showed only a transient improvement in postoperative recovery than desflurane anesthesia, without significant differences in other outcomes.

Introduction: To develop a calcium silicate (CaSi)-based cement containing dimethyl sulfoxide (DMSO) and cement deliver device for new root canal filling technique, and to assess the flow behavior, leakage, and root canal filling quality of CaSi containing DMSO., Methods: CaSi containing DMSO (CSC-DMSO) and CaSi containing PEG (CSC-PEG) were prepared, and the flow characteristics of both cements were compared in gypsum and resin channels using a high-speed camera. Eight root canals were obturated by CSC-DMSO or CSC-PEG using a cement delivery device, and root canal filling quality was assessed in terms of filling length using periapical radiographs. The filling length was evaluated by 'apico-coronal extension,' measuring length in reference to apical constriction. Microleakage was measured for thirty human molars that were randomly filled with CSC-DMSO, CSC-PEG, or gutta-percha and AH plus. Preliminary obturation of CSC-DMSO with cement delivery device in human teeth was analyzed in terms of filling length and void, using periapical radiographs. Statistical analysis was performed with the Kruskal Wallis test for simulated root canal fillings and one-way ANOVA for leakage test., Results: The flow speed of CSC-DMSO reduced in gypsum channels compared to resin channels, but CSC-PEG did not exhibit significant differences in the channels. The median absolute value of apico-coronal extension was significantly lower in CSC-DMSO compared to CSC-PEG (p < 0.05). Microleakage did not statistically differ between the groups (p > 0.05). In the preliminary obturation, the mean apico-coronal extension of CSC-DMSO was -0.297 ± 0.724 mm, while CSC-PEG was not feasible due to excess apical extrusions., Conclusions: CSC-DMSO could be considered as an alternative filling material for root canal obturation., 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., (Copyright © 2023. Published by Elsevier Ltd.)

Objective: To investigate the safety and efficacy of a novel active transcutaneous bone conduction implant (BCI) device for patients with single-sided deafness (SSD)., Study Design: Prospective cohort study., Setting: Tertiary referral hospitals., Methods: This prospective multicenter study was conducted at 15 institutions nationwide. Thirty adult (aged ≥19 years) SSD patients were recruited. They underwent implantation of an active transcutaneous BCI device (Bonebridge BCI602). Objective outcomes included aided pure-tone thresholds, aided speech discrimination scores (SDSs), and the Hearing in Noise Test (HINT) and sound localization test results. The Bern Benefit in Single-Sided Deafness (BBSS) questionnaire, the Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire, and the Tinnitus Handicap Inventory (THI) were used to measure subjective benefits., Results: The mean aided pure-tone threshold was 34.2 (11.3), mean (SD), dB HL at 500 to 4000 Hz. The mean total BBSS score was 27.5 (13.8). All APHAB questionnaire domain scores showed significant improvements: ease of communication, 33.6 (23.2) versus 22.6 (21.3), P = .025; reverberation, 44.8 (16.6) versus 32.8 (15.9), P = .002; background noise, 55.5 (23.6) versus 35.2 (18.1), P < .001; and aversiveness, 36.7 (22.8) versus 25.8 (21.4), P = .028. Moreover, the THI scores were significantly reduced [47.4 (30.1) versus 31.1 (27.0), P = .003]. Congenital SSD was a significant factor of subjective benefit (-11.643; 95% confidence interval: -21.946 to -1.340)., Conclusion: The BCI602 active transcutaneous BCI device can provide functional hearing gain without any adverse effects and is a feasible option for acquired SSD patients with long-term deafness., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

The purpose of this study is to confirm the effect of small, portable low-level laser therapy (light sources in square configuration: 830 nm GaAs diode 3.2 mW at the center, 4 × 650 nm InGaAIP diodes over the corners) treatment in reducing and enhancing hand function in patients with wrist pain. This study was a prospective, randomized, sham-controlled, and home-based self-therapy trial. A total of thirty subjects with wrist pain were enrolled. All participants received low-level laser therapy on painful area at the wrist. The experimental group (n = 15) received laser stimulation, while the control group (n = 15) received sham stimulation using identical equipment that generated only a red light without the laser output. Both groups self-treated for 30 min a day, 5 days per week for 3 weeks, total of 15 sessions. The primary outcome was assessed using a visual analogue scale (VAS) for wrist pain from 0 (painless) to 10 (extreme pain). The secondary outcomes were measured with patient-rated wrist evaluation (PRWE), grip strength, lateral, palmar, and tip pinch strength. Measures were taken before and after treatment. A total of thirty participants provided outcome data. After the intervention, both groups showed a significant decrease in VAS score, from 4.93 to 3.67 in experimental group, from 5.53 to 4.00 in control group (the experiment group: p = 0.020, the control group: p = 0.003). The experimental group showed a significant improvement in function scale score (p = 0.012), the control group did not. Lateral and pinch strength was significantly improved in the experimental group (p = 0.017) and in the control group (p = 0.034) respectively. There were no side effects in the patients. Medical laser irradiation is a portable and easy-to-use laser irradiator without side effects. Clinical Trial Registration number: KCT0006604., (© 2024. The Author(s).)

Bacteriophages (phages) are viruses that infect bacteria with species- and strain-level specificity and are the most abundant biological entities across all known ecosystems. Within bacterial communities, such as those found in the gut microbiota, phages are implicated in regulating microbiota population dynamics and driving bacterial evolution. There has been renewed interest in phage research in the last decade, in part due to the host-specific killing capabilities of lytic phages, which offer a promising tool to counter the increasing threat of antimicrobial resistant bacteria. Furthermore, recent studies demonstrating that phages adhere to intestinal mucus suggest they may have a protective role in preventing bacterial invasion into the underlying epithelium. Importantly, like bacterial microbiomes, disrupted phageomes have been associated with worsened outcomes in diseases such as inflammatory bowel disease. Previous studies have demonstrated that phages can modulate the microbiome of animals and humans through fecal filtrate transplants, benefiting the host's health. With this recent wave of research comes the necessity to establish and standardize protocols for studying phages in the context of the gut microbiome. This protocol provides a set of procedures to study isolated T4 phages and their bacterial host, Escherichia coli, in the context of the murine gastrointestinal tract. The methods described here outline how to start from a phage lysate, administer it to mice and assess effects on bacterial host and phage levels. This protocol can be modified and applied to other phage-bacterial pairs and provides a starting point for studying host-phage dynamics in vivo.

Background: Gastric cancer, one of the leading causes of cancer-related death, is strongly associated with H. pylori infection, although other risk factors have been identified. The sirtuin (Sirt) family is involved in the tumorigenesis of gastric cancer, and sirtuins can have pro- or anti-tumorigenic effects., Methods: After determining the overall survival rate of gastric cancer patients with or without Sirt6 expression, the effect of Sirt6 upregulation was also tested using a xenograft mouse model. The regulation of Sirt6 and Sirt1, leading to the induction of mouse double minute 2 homolog (MDM2) and reactive oxygen species (ROS), was mainly analyzed using Western blotting and immunofluorescence staining, and gastric cancer cell (SNU-638) death associated with these proteins was measured using flow cytometric analysis., Results: Sirt6 overexpression led to Sirt1 suppression in gastric cancer cells, resulting in a higher level of gastric cancer cell death in vitro and a reduced tumor volume. ROS and MDM2 expression levels were upregulated by Sirt6 overexpression and/or Sirt1 suppression according to Western blot analysis. The upregulated ROS ultimately led to gastric cancer cell death as determined via Western blot and flow cytometric analysis., Conclusion: We found that the upregulation of Sirt6 suppressed Sirt1, and Sirt6- and Sirt1-induced gastric cancer cell death was mediated by ROS production. These findings highlight the potential of Sirt6 and Sirt1 as therapeutic targets for treating gastric cancer.

Background/aims: The recent update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease initiative has added normal growth in children as an intermediate target in Crohn's disease and ulcerative colitis. We aimed to investigate factors associated with reaching mid-parental height (MPH) in patients diagnosed with inflammatory bowel disease in childhood and the adolescent period., Methods: This multicenter retrospective observational study included pediatric patients with inflammatory bowel disease that had reached adult height. Factors associated with reaching MPH were investigated by logistic regression analyses., Results: A total of 166 patients were included in this study (128 Crohn's disease and 38 ulcerative colitis). Among them, 54.2% (90/166) had reached their MPH. Multivariable logistic regression analysis revealed that height Z-score at diagnosis and MPH Z-score were independently associated with reaching MPH (odds ratio [OR], 8.45; 95% confidence interval [CI], 4.44 to 17.90; p<0.001 and OR, 0.11; 95% CI, 0.04 to 0.24; p<0.001, respectively). According to the receiver operating characteristic curve analysis, the optimal cutoff level of "height Z-score at diagnosis minus MPH Z-score" that was associated with reaching MPH was -0.01 with an area under the curve of 0.889 (95% CI [0.835 to 0.944], sensitivity 88.9%, specificity 84.2%, positive predictive value 87.0%, negative predictive value 86.5%, p<0.001)., Conclusions: Height Z-score at diagnosis and MPH Z-score were the only factors associated with reaching MPH. Efforts should be made to restore growth in pediatric patients who present with a negative "height Z-score at diagnosis minus MPH Z-score."

Background: Asthma is a heterogeneous disease with different outcomes. For children with asthma at the age of 7 years, 67-75% are symptom-free as adults. Data on the important link between childhood and adult asthma are sparse., Objective: We aimed to investigate factors associated with persistence of childhood asthma over three years of follow-up by linking data between Korea childhood Asthma Study (KAS) and their matched claims data from Health Insurance Review and Assessment Service (HIRA)., Methods: We analyzed data from 450 preadolescent children aged 7 to 10 years and classified them into remission or persistence groups. Baseline clinical characteristics and exposure to air pollution materials including PM2.5 and PM10 during three years of follow-up were compared. The main outcome was asthma persistence which was defined as the presence of asthma episodes with healthcare utilization and prescription of asthma medications within three years after KAS enrollment., Results: At the third year of follow-up, after stepwise regression analysis, lower age at enrollment (adjusted odds ratio (aOR): 0.79; 95% confidence interval (CI): 0.64-0.96), male sex (aOR: 1.66; 95%CI: 1.05-2.63), proximity from an air-polluting facility (aOR: 2.4; 95%CI: 1.34-4.29), higher level outdoor PM2.5 (aOR: 1.1; 95%CI: 1.02-1.20), and higher rate of doctor-diagnosed food allergy (FA) (aOR: 2.33; 95%CI: 1.06-5.12) were significantly associated with persistence., Conclusion: We discovered various independent risk factors for the persistence of childhood asthma. By linking HIRA claims data, we could clarify risk factors for persistence in a well-defined study population.

Background: There are insufficient in-depth studies on whether percutaneous lumbar nucleoplasty (PLN) is effective and safe for the treatment of uncontained lumbar disc herniation (ULDH). This study aimed to investigate the clinical efficacy of PLN on radiating leg pain caused by ULDH., Methods: Patients who underwent PLN for ULDH and met the inclusion criteria between June 2018 and July 2022 were included. Clinical outcomes were evaluated using the numeric rating scale (NRS) for radiating pain preoperatively; at 1 day, 1 week, and 1 month postoperatively; and at the last follow-up. Patient satisfaction was assessed using MacNab criteria., Results: Forty-one patients were enrolled. The mean age was 50.2 years (range 24-73 years). The mean and standard deviation of the preoperative NRS in 39 patients with radiating pain was 9.0 ± 1.2. The NRS scores at 1 day, 1 week, and 1 month postoperatively and at the last follow-up were 4.6 ± 3.2, 3.6 ± 3.3, 2.9 ± 3.2, and 1.4 ± 2.0, respectively, showing significant improvement (all, p < 0.001). The number of patients (percentage) with excellent or good satisfaction according to the MacNab criteria was 29 (70.7%). Major complications were not observed. Three patients underwent additional surgery after PLN because of persistent radiating pain., Conclusions: PLN is a safe and feasible treatment option for ULDH. Treatment outcomes were favorable on average; however, the lack of consistency was a drawback., (© 2023. The Author(s).)

Purpose: This study aimed to investigate the presence of autoantigens in the gastric juices of children., Methods: Gastric juice and serum samples were obtained from 53 children <15 years of age who underwent gastric endoscopy. Among these, 8, 22, and 23 participants were in the age groups 0-5, 6-10, and 11-15 years, respectively. These samples were analyzed using two-dimensional electrophoresis (2-DE), immunoblot analysis, and matrix-assisted laser desorption ionization-time of-flight mass spectrometry. Furthermore, we reviewed the histopathological findings and urease test results and compared them with the results of 2-DE and immunoblot analysis., Results: There were no statistically significant differences in urease test positivity, grades of chronic gastritis, active gastritis, or Helicobacter pylori infiltration of the antrum and body among the three age groups. Three distinct patterns of gastric juice were observed on 2-DE. Pattern I was the most common, and pattern III was not observed below the age of 5 years. Histopathological findings were significantly different among active gastritis ( p =0.037) and H. pylori infiltration ( p =0.060) in the gastric body. The immunoblots showed large spots at an approximate pH of 3-4 and molecular weights of 31-45 kDa. These distinct, large positive spots were identified as gastric lipase and pepsin A and C., Conclusion: Three enzymes, which are normally secreted under acidic conditions were identified as autoantigens. Further investigation of the pathophysiology and function of autoantigens in the stomach is required., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2024 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition.)

Background: There is little evidence regarding the benefits of lung-protective ventilation in patients undergoing one-lung ventilation for thoracic surgery. This study aimed to determine the optimal level of positive end-expiratory pressure (PEEP) during one-lung ventilation for minimizing postoperative atelectasis through lung ultrasonography., Methods: A total of 142 adult patients scheduled for video-assisted thoracoscopic surgery at Seoul National University Hospital between May 2019 and February 2020 were enrolled in this study. Patients were randomly assigned to different groups: 1) PEEP 3 cmH2O group; 2) PEEP 6 cmH2O group; and 3) PEEP 9 cmH2O group during one-lung ventilation. The lung ultrasound score was used to evaluate lung aeration using ultrasonography 1 hour after surgery., Results: The 1-hour post-surgery lung ultrasound scores were 8.1±2.5, 6.8±2.6, and 5.9±2.6 in the PEEP 3, 6, and 9 cmH2O groups, respectively (P<0.001). The PEEP 3 cmH2O group showed significantly higher lung ultrasound scores than the PEEP 6 (adjusted P=0.034) and 9 cmH2O groups (adjusted P<0.001). The PaO2/FiO2 ratio measured at 10 minutes after the end of one-lung ventilation was significantly lower in the PEEP 3 cmH2O group (392 [331 to 469]) than the PEEP 6 cmH2O (458 [384 to 530], adjusted P=0.018) or PEEP 9 cmH2O groups (454 [374 to 522], adjusted P=0.016)., Conclusions: Although the optimal level of PEEP during one-lung ventilation was not determined, the application of higher PEEP can prevent aeration loss in the ventilated lung after video-assisted thoracoscopic surgery under one-lung ventilation.

Purpose: The purpose of this study was to compare the clinical outcomes of A1 pulley release with ulnar superficialis slip resection (group A) and simple A1 pulley release (group B) in trigger finger with flexion contracture of the proximal interphalangeal (PIP) joint., Methods: From January 2016 to December 2019, the 2 surgical procedures were performed alternately every year for trigger fingers with preoperative PIP joint flexion contractures of ≥10°. Twenty-six fingers in group A and 29 fingers in group B that were followed up for >1 year were reviewed in this retrospective study. The visual analog scale (VAS) score; Disabilities of the Arm, Shoulder, and Hand (DASH) score; degree of PIP joint flexion contracture; grip strength; and pinch strength were measured after surgery and compared., Results: The differences in postoperative PIP joint flexion contracture between groups were <4° at 2 and 6 weeks, and there were no clinically relevant differences at 6 weeks and 12 months. At the final follow-up, PIP joint flexion contractures of 5° were observed in 2 fingers in each group. The difference in VAS scores between groups was less than half of a point until 3 months, and there were no clinically relevant differences at 6 weeks and 12 months. The DASH score did not show any difference between groups at the final follow-up. There were clinically relevant differences in the grip and pinch strengths between groups at 6 weeks. However, there were no clinically relevant differences at the final follow-up., Conclusions: Proximal interphalangeal joint flexion contracture measurements and clinical scores did not differ between groups at the final follow-up. Therefore, we recommend use of a simple A1 pulley release, which is simpler than an A1 pulley release with ulnar superficialis slip resection, in cases of trigger finger with PIP joint flexion contracture., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2024. Published by Elsevier Inc.)

Background: The upright head roll test (UHRT) is a recently introduced diagnostic maneuver for lateral semicircular canal benign paroxysmal positional vertigo (LSC-BPPV)., Objective: This study aimed to evaluate the reliability and validity of the UHRT., Methods: Two separate studies were conducted. Study 1 analyzed 827 results of videonystagmography (VNG) to assess UHRT reliability, and Study 2 analyzed 130 LSC-BPPV cases to evaluate UHRT validity., Results: The inter-test reliability between UHRT and the supine head roll test (SHRT) showed substantial agreement (Cohen's kappa = 0.753) in direction-changing positional nystagmus (DCPN) and almost perfect agreement (Cohen's kappa = 0.836) in distinguishing the direction of DCPN. The validity assessment of UHRT showed high accuracy in diagnosing LSC-BPPV (80.0%) and in differentiating the variant types (74.6%). UHRT was highly accurate in diagnosing the canalolithiasis type in LSC-BPPV patients (Cohen's kappa = 0.835); however, it showed only moderate accuracy in diagnosing the cupulolithiasis type (Cohen's kappa = 0.415). The intensity of nystagmus in UHRT was relatively weaker than that in SHRT (P < 0.05)., Conclusion: UHRT is a reliable test for diagnosing LSC-BPPV and distinguishing subtypes. However, UHRT has a limitation in discriminating the affected side owing to a weaker intensity of nystagmus than SHRT.

2'-Fucosyllactose (2'-FL) which is well-known human milk oligosaccharide was biotechnologically synthesized using engineered Corynebacterium glutamicum, a GRAS microbial workhorse. By construction of the complete de novo pathway for GDP-L-fucose supply and heterologous expression of Escherichia coli lactose permease and Helicobacter pylori α-1,2-fucosyltransferase, bioengineered C. glutamicum BCGW&#95;TL successfully biosynthesized 0.25 g L -1 2'-FL from glucose. The additional genetic perturbations including the expression of a putative 2'-FL exporter and disruption of the chromosomal pfkA gene allowed C. glutamicum BCGW&#95;cTTLEΔP to produce 2.5 g L -1 2'-FL batchwise. Finally, optimized fed-batch cultivation of the BCGW&#95;cTTLEΔP using glucose, fructose, and lactose resulted in 21.5 g L -1 2'-FL production with a productivity of 0.12 g L -1 •h, which were more than 3.3 times higher value relative to the batch culture of the BCGW&#95;TL. Conclusively, it would be a groundwork to adopt C. glutamicum for biotechnological production of other food additives including human milk oligosaccharides., (© 2023 Wiley-VCH GmbH.)

Pyloric interventions are surgical procedures employed to increase the gastric emptying rate in gastroparesis patients. In this study, we use an in silico model to investigate the consequences of pyloric intervention on gastric flow and emptying for two phenotypes of gastroparesis: antral hypomotility and decreased gastric tone. The transpyloric pressure gradient predicted by the in silico model, based on viscous fluid flow equations, is compared against in vivo measurements. Both phenotypes exhibit a similar pre-procedural emptying rate reduction, but after pyloric surgery, antral hypomotility case with preserved gastric tone shows significant improvements in emptying rates, up to 131%, accompanied by bile reflux from the duodenum into the stomach. Conversely, severely reduced gastric tone cases exhibited a post-procedural reduction in the net emptying rate due to the relatively larger bile reflux. In cases with a combination of antral hypomotility and reduced gastric tone, post-procedural improvements were observed only when both conditions were mild. Our findings highlight the pivotal role of the relative increase in pyloric orifice diameter in determining post-operative emptying rates. The study suggests a possible explanation for the selective response of patients toward these procedures and underscores the potential of in silico modelling to generate valuable insights to inform gastric surgery.

Background: Ischemia reperfusion (IR) injury may result in rhabdomyolysis and compartment syndrome when blood supply returns after thrombectomy for patients with acute limb ischemia., Objective: We highlight the value of early diagnosis and treatment in post-thrombectomy patients with IR injuries in their lower legs., Case Description: Two patients received thrombectomy due to left superficial femoral artery occlusion. Both patients complained of left calf pain during ambulation at the 1- and 3-day follow up post-thrombectomy, as well as a heating sensation, swelling, weakness, and sensory changes in the affected leg. For early diagnosis musculoskeletal ultrasounds were performed and in both cases revealed swelling and change of echogenicity in the left calf. To further diagnosis, magnetic resonance imaging of the left leg revealed limb IR-induced muscular injury and rhabdomyolysis, respectively. In both cases, an electrodiagnostic study revealed peripheral nerve injury in the left leg. Medications were provided for neuropathic pain control and early rehabilitation was performed to improve function. In both cases, patients reported during their follow-up that their pain and muscle weakness had improved., Conclusion: When post-thrombectomy calf pain occurs early evaluation and treatment should be performed to identify any potential IR injury.

The possible anticancer activity of combination (M + E + F) of metformin (M), efavirenz (E), and fluoxetine (F) was investigated in normal HDF cells and HCT116 human colon cancer cells. Metformin increased cellular FOXO3a, p-FOXO3a, AMPK, p-AMPK, and MnSOD levels in HDFs but not in HCT116 cells. Cellular ATP level was decreased only in HDFs by metformin. Metformin increased ROS level only in HCT116 cells. Transfection of si-FOXO3a into HCT116 reversed the metformin-induced cellular ROS induction, indicating that FOXO3a/MnSOD is the key regulator for cellular ROS level. Viability readout with M, E, and F alone decreased slightly, but the combination of three drugs dramatically decreased cell survival in HCT116, A549, and SK-Hep-1 cancer cells but not in HDF cells. ROS levels in HCT116 cells were massively increased by M + E + F combination, but not in HDF cells. Cell cycle analysis showed that of M + E + F combination caused cell death only in HCT116 cells. The combination of M + E + F reduced synergistically mitochondrial membrane potential and mitochondrial electron transport chain complex I and III activities in HCT116 cells when compared with individual treatments. Western blot analysis indicated that DNA damage, apoptosis, autophagy, and necroptosis-realated factors increased in M + E + F-treated HCT116 cells. Oral administration with M + E + F combination for 3 weeks caused dramatic reductions in tumor volume and weight in HCT116 xenograft model of nude mice when compared with untreated ones. Our results suggest that M + E + F have profound anticancer activity both in vitro and in vivo via a cancer cell-specific ROS amplification (CASRA) through ROS-induced DNA damage, apoptosis, autophagy, and necroptosis.

Cellulose has great potential in the field of piezoelectricity owing to its high crystallinity; however, it exhibits low processability and poor mechanical robustness. In this study, to enhance the applicability of cellulose-based piezoelectric materials, a robust cellulose-based piezoelectric elastomer with excellent piezoelectric properties was developed by cross-linking cellulose with polyrotaxane (PR). The effects of cross-linking on the mechanical properties and crystalline structures of the resulting elastomers were investigated. The ferroelectric and piezoelectric properties were evaluated from their polarization hysteresis loops and voltage generation characteristics. eHPC 25 PR 75 exhibited 2.7 times higher toughness (20.4 MJ m -3 ) than eHPC 100 (7.57 MJ m -3 ). It also shows a power density 4.2 times higher (1.34 μW cm -2 ) than eHPC 100 (0.321 μW cm -2 ). As a result, eHPC 25 PR 75 demonstrated piezosensitivity to mechanical vibrations in a variety of devices that require mechanical robustness. These results can inform the design and development of high-performance piezoelectric devices.

The mass production of polyhydrocarbons (PHCs) is achieved through electrochemical polymerization and its synthetic pathway is investigated using a combination of electrochemical techniques, NMR, and Fourier transform infrared (FTIR) spectroscopy. Here, we present a protocol for the electrochemical polymerization of PHCs from chlorinated methanes and an analysis of its polymerization reaction pathway. We describe steps for large-scale synthesis and characterization of PHCs and studying electrochemical polymerization reactions using cyclic voltammetry and chronoamperometry techniques along with NMR and FTIR spectroscopy using isotope-labeled reactants. For complete details on the use and execution of this protocol, please refer to Seo et al., 1 Lee et al., 2 and Seo et al. 3 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

We introduce Promoter-Enhancer-Guided Interaction Networks (PENGUIN), a method for studying protein-protein interaction (PPI) networks within enhancer-promoter interactions. PENGUIN integrates H3K27ac-HiChIP data with tissue-specific PPIs to define enhancer-promoter PPI networks (EPINs). We validated PENGUIN using cancer (LNCaP) and benign (LHSAR) prostate cell lines. Our analysis detected EPIN clusters enriched with the architectural protein CTCF, a regulator of enhancer-promoter interactions. CTCF presence was coupled with the prevalence of prostate cancer (PrCa) single nucleotide polymorphisms (SNPs) within the same EPIN clusters, suggesting functional implications in PrCa. Within the EPINs displaying enrichments in both CTCF and PrCa SNPs, we also show enrichment in oncogenes. We substantiated our identified SNPs through CRISPR/Cas9 knockout and RNAi screens experiments. Here we show that PENGUIN provides insights into the intricate interplay between enhancer-promoter interactions and PPI networks, which are crucial for identifying key genes and potential intervention targets. A dedicated server is available at https://penguin.life.bsc.es/ ., (© 2023. The Author(s).)

Aims: Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation in obsessive-compulsive disorder (OCD) has been reported, epigenetic changes in HPA axis-related genes have not been well studied in OCD. The present study investigated whether the epigenetic regulation of FK506-binding protein 51 gene (FKBP5) intron 7 is associated with OCD status in each sex. In addition, relationships among the DNA methylation levels of FKBP5 intron 7, OCD status and early-life trauma were explored., Methods: A total of 267 patients with OCD and 201 controls aged between 18 and 40 years were recruited. Demographic and clinical assessment, FKBP5 rs1360780 genotyping, and pyrosequencing of FKBP5 intron 7 were conducted. DNA was extracted from peripheral blood leucocytes. First, multivariate analysis of covariance for differential DNA methylation levels between OCD patients and controls was conducted with adjustment for FKBP5 rs1360780 genotype, early-life trauma, depressive symptoms, and age as covariates in each sex. Next, path analysis was conducted to determine the mediation effects of DNA methylation levels of FKBP5 between early-life trauma and OCD status. In addition, sensitivity analyses for medication and lifetime major depression were also performed., Results: DNA methylation at the FKBP5 intron 7 CpG site was significantly lower in men with OCD, compared to controls (mean difference -1.33%, 95% CI -2.11 to -0.55, p < 0.001). The results remained significant for drug naïve or free subjects (mean difference -1.27%, 95% CI -2.18 to -0.37, p = 0.006, in men) and for subjects without lifetime major depressive disorder (mean difference -1.60%, 95% CI -2.54 to -0.66, p < 0.001, in men). The mediation effect of DNA methylation levels was not significant between early-life trauma and OCD status., Conclusion: These findings suggest that epigenetic factors of HPA axis-related gene FKBP5 may play a role in the pathogenesis of OCD. Further studies are needed to determine how altered DNA methylation of FKBP5 intron 7 and HPA axis function are involved in OCD., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aim: The present study examined the microbiome abundance and composition of drug-naive or drug-free patients with obsessive-compulsive disorder (OCD) compared with healthy controls. In addition, in the OCD group, the microbiome composition was compared between early-onset and late-onset OCD., Methods: Serum samples were collected from 89 patients with OCD and 107 age- and sex-matched healthy controls. Bacterial DNA was isolated from bacteria-derived extracellular vesicles in serum and then amplified and quantified using primers specific to the V3-V4 hypervariable region of the 16S ribosomal RNA gene. The 16S ribosomal DNA gene amplicon sequencing was performed., Results: The pooled estimate showed that α-diversity was significantly reduced in patients with OCD compared with that in healthy controls (P Shannon  = 0.00015). In addition, a statistically significant difference was observed in β-diversity between patients with OCD and healthy controls at the order (P = 0.012), family (P = 0.003), genus (P < 0.001), and species (P = 0.005) levels. In the microbiome composition, Pseudomonas, Caulobacteraceae (f), Streptococcus, Novosphingobium, and Enhydrobacter at the genus level were significantly less prevalent in patients with OCD than in controls. In addition, among patients with OCD, the microbial composition in the early-onset versus late-onset types was significantly different with respect to the genera Corynebacterium and Pelomonas., Conclusion: The present study showed an aberrant microbiome in patients with OCD, suggesting a role of the microbiota-brain interaction in the pathophysiology of OCD. Further longitudinal studies with larger sample sizes adjusting for various confounders are warranted., (© 2023 The Authors. Psychiatry and Clinical Neurosciences © 2023 Japanese Society of Psychiatry and Neurology.)

Intravenous idursulfase is standard treatment for mucopolysaccharidosis II (MPS II) in Japan. In the interim analysis of this open-label, phase 1/2 study (Center for Clinical Trials, Japan Medical Association: JMA-IIA00350), intracerebroventricular (ICV) idursulfase beta was well tolerated, suppressed cerebrospinal fluid (CSF) heparan sulfate (HS) levels, and stabilized developmental decline over 100 weeks in Japanese children with MPS II. Here, we report the final study results, representing 5 years of ICV idursulfase beta treatment. Six male patients with MPS II and developmental delay were enrolled starting in June 2016 and followed until March 2021. Patients received up to 30 mg ICV idursulfase beta every 4 weeks. Outcomes included CSF HS levels, developmental age (DA) (assessed by the Kyoto Scale of Psychological Development), and safety (adverse events). Monitoring by laboratory biochemistry tests, urinary uronic tests, immunogenicity tests, and head computed tomography or magnetic resonance imaging were also conducted regularly. Following ICV idursulfase beta administration, mean CSF HS concentrations decreased from 7.75 μg/mL at baseline to 2.15 μg/mL at final injection (72.3% reduction). Mean DA increased from 23.2 months at screening to 36.0 months at final observation. In five patients with null mutations, mean DA at the final observation was higher than or did not regress compared with that of historical controls receiving intravenous idursulfase only, and the change in DA was greater in patients who started administration aged ≤3 years than in those aged >3 years (+28.7 vs -6.5 months). The difference in DA change versus historical controls in individual patients was +39.5, +40.8, +17.8, +10.5, +7.6 and - 4.5 (mean + 18.6). Common ICV idursulfase beta-related adverse events were vomiting, pyrexia, gastroenteritis, and upper respiratory tract infection (most mild/moderate). These results suggest that long-term ICV idursulfase beta treatment improved neurological symptoms in Japanese children with neuronopathic MPS II., Competing Interests: Declaration of Competing Interest MK has received research grants from JCR Pharmaceuticals and Alexion Pharmaceuticals, and has received honoraria for lectures and presentations from Sanofi. TH has received research grants from Amicus Therapeutics, JCR Pharmaceuticals, and Sanofi. TO has received research grants from AnGes, GC Biopharma Corp., Idorsia Pharmaceuticals Japan, JCR Pharmaceuticals, and Novel Pharma, and is the Principal Investigator for enzyme replacement therapy clinical trials for mucopolysaccharidosis II sponsored by GC Biopharma Corp. and JCR Pharmaceuticals. JHS and HS have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Auditory brainstem response (ABR) is the response of the brain stem through the auditory nerve. The ABR test is a method of testing for loss of hearing through electrical signals. Basically, the test is conducted on patients such as the elderly, the disabled, and infants who have difficulty in communication. This test has the advantage of being able to determine the presence or absence of objective hearing loss by brain stem reactions only, without any communication. This paper proposes the image preprocessing process required to construct an efficient graph image data set for deep learning models using auditory brainstem response data. To improve the performance of the deep learning model, we standardized the ABR image data measured on various devices with different forms. In addition, we applied the VGG16 model, a CNN-based deep learning network model developed by a research team at the University of Oxford, using preprocessed ABR data to classify the presence or absence of hearing loss and analyzed the accuracy of the proposed method. This experimental test was performed using 10,000 preprocessed data, and the model was tested with various weights to verify classification learning. Based on the learning results, we believe it is possible to help set the criteria for preprocessing and the learning process in medical graph data, including ABR graph data.

In this study, the effects of zigzag hydrogen bonding and slidable cross-linking on the design of stretchable elastomers were explored. Poly(ether-thiourea) (TU), capable of generating strong zigzag hydrogen bonds without crystallization, was introduced as the main chain in the non-cross-linked region of the developed elastomer. Consequently, the toughness of the TU-based elastomer was 14 times higher than that of elastomers formed using linear poly(ethylene glycol), despite the relatively low molecular weight of TU (∼3k). When a slidable polyrotaxane cross-linker was introduced into the TU-based elastomer, its flexibility became twice as high as that of the rigid polymer cross-linker. Moreover, the mechanical properties of the elastomer were prevented from deterioration against repeated deformation under the limited strain condition of 150%.

Background: Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3 rd -generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC., Methods: The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA., Results: DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44 high /CD24 low subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function., Conclusions: Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation., (© 2023. The Author(s).)

Archaeoentomological investigations were conducted on soil contents from a grave belonging to the Joseon Dynasty as part of the Urban Environment Maintenance Project (UEMP) in Cheongjin 12-16 dong (districts), Jongno-gu, Seoul, Korea, from December 01, 2008 to February 19, 2011. A total of 28 insect puparia with hard shells of the common green bottle fly Lucilia sericata were identified in the soil. Evidence suggested that the corpse was placed outside for some days instead of being buried immediately after death. This is the first report of fly puparia in soil samples from a tomb of the Joseon Dynasty during 16-17 AD in Korea. Our findings may help determine the timeframe of burial and offer archaeological insights into the funerary customs of the period.

Purpose: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder that leads to secondary ciliary dysfunction. PCD is a rare disease, and data on it are limited in Korea. This study systematically evaluated the clinical symptoms, diagnostic characteristics, and treatment modalities of pediatric PCD in Korea., Methods: This Korean nationwide, multicenter study, conducted between January 2000 and August 2022, reviewed the medical records of pediatric patients diagnosed with PCD. Prospective studies have been added to determine whether additional genetic testing is warranted in some patients., Results: Overall, 41 patients were diagnosed with PCD in 15 medical institutions. The mean age at diagnosis was 11.8 ± 5.4 years (range: 0.5 months-18.9 years). Most patients (40/41) were born full term, 15 (36.6%) had neonatal respiratory symptoms, and 12 (29.3%) had a history of admission to the neonatal intensive care unit. The most common complaint (58.5%) was chronic nasal symptoms. Thirty-three patients were diagnosed with transmission electron microscopy (TEM) and 12 patients by genetic studies. TEM mostly identified outer dynein arm defects (alone or combined with inner dynein arm defects, n = 17). The genes with the highest mutation rates were DNAH5 (3 cases) and DNAAF1 (3 cases). Rare genotypes ( RPGR , HYDIN , NME5 ) were found as well. Chest computed tomography revealed bronchiectasis in 33 out of 41 patients. Among them, 15 patients had a PrImary CiliAry DyskinesiA Rule score of over 5 points., Conclusions: To our knowledge, this is the first multicenter study to report the clinical characteristics, diagnostic methods, and genotypes of PCD in Korea. These results can be used as basic data for further PCD research., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2023 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

In this study, microplastics, including polyethylene (PE), polyethylene terephthalate (PET), polypropylene (PP), and polystyrene (PS), adhering to the feathers of all tracked black-tailed gull individuals were studied. PE was detected in the highest number of feathers (n = 26, 35.6 %), followed by PP (n = 21, 28.8 %), PET and other microplastics (n = 16, 21.9 %), and PS (n = 10, 13.7 %). Furthermore, plastic particles of size 50-100 μm were the most common (n = 33, 45.1 %), followed by ≤50 (n = 21, 28.8 %), 100-150 (n = 11, 15.1 %), ≥200 (n = 7, 9.6 %), and 150-200 μm (n = 1, 1.4 %). Microplastic levels did not differ considerably between the Dokdo and Ulleungdo populations. As black-tailed gulls spend >95 % of their time in coastal areas, coastal pollution caused by oil spills and increasing microplastic levels could lead to physical problems, such as the adherence of oil and microplastics onto feathers., 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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Individualised positive end-expiratory pressure (PEEP) improves respiratory mechanics. However, whether PEEP reduces postoperative pulmonary complications (PPCs) remains unclear. We investigated whether driving pressure-guided PEEP reduces PPCs after laparoscopic/robotic abdominal surgery., Methods: This single-centre, randomised controlled trial enrolled patients at risk for PPCs undergoing laparoscopic or robotic lower abdominal surgery. The individualised group received driving pressure-guided PEEP, whereas the comparator group received 5 cm H 2 O fixed PEEP during surgery. Both groups received a tidal volume of 8 ml kg -1 ideal body weight. The primary outcome analysed per protocol was a composite of pulmonary complications (defined by pre-specified clinical and radiological criteria) within 7 postoperative days after surgery., Results: Some 384 patients (median age: 67 yr [inter-quartile range: 61-73]; 66 [18%] female) were randomised. Mean (standard deviation) PEEP in patients randomised to individualised PEEP (n=178) was 13.6 cm H 2 O (2.1). Individualised PEEP resulted in lower mean driving pressures (14.7 cm H 2 O [2.6]), compared with 185 patients randomised to standard PEEP (18.4 cm H 2 O [3.2]; mean difference: -3.7 cm H 2 O [95% confidence interval (CI): -4.3 to -3.1 cm H 2 O]; P<0.001). There was no difference in the incidence of pulmonary complications between individualised (25/178 [14.0%]) vs standard PEEP (36/185 [19.5%]; risk ratio [95% CI], 0.72 [0.45-1.15]; P=0.215). Pulmonary complications as a result of desaturation were less frequent in patients randomised to individualised PEEP (8/178 [4.5%], compared with standard PEEP (30/185 [16.2%], risk ratio [95% CI], 0.28 [0.13-0.59]; P=0.001)., Conclusions: Driving pressure-guided PEEP did not decrease the incidence of pulmonary complications within 7 days of laparoscopic or robotic lower abdominal surgery, although uncertainty remains given the lower than anticipated event rate for the primary outcome., Clinical Trial Registration: KCT0004888 (http://cris.nih.go.kr, registration date: April 6, 2020)., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Pancreatic duct pressure (PDP) dynamics comprise an intricately modulated system that helps maintain homeostasis of pancreatic function. It is affected by various factors, including the rate of pancreatic fluid secretion, patency of the ductal system, sphincter of Oddi function, and pancreatic fluid characteristics. Disease states such as acute and chronic pancreatitis can alter the normal PDP dynamics. Ductal hypertension or increased PDP is suspected to be involved in the pathogenesis of pancreatic pain, endocrine and exocrine pancreatic insufficiency, and recurrent pancreatitis. This review provides a comprehensive appraisal of the available literature on PDP, including the methods used in the measurement and clinical implications of elevated PDP., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Neuromuscular blocking agents (NMBAs) are one of the most common causes of perioperative anaphylaxis. Although skin test positivity may help identify reactive NMBAs, it is unclear whether skin test negativity can guarantee the safety of systemically administered NMBAs., Objective: This study aimed to evaluate the real-world safety of alternative NMBAs screened using skin tests in patients with suspected NMBA-induced anaphylaxis., Methods: A retrospective cohort of suspected NMBA-induced anaphylaxis were recruited among patients at Seoul National University Hospital from June 2009 to May 2021, and their characteristics and outcomes were assessed., Results: A total of 47 cases (0.017%) of suspected anaphylaxis occurred in 282,707 patients who received NMBAs. Cardiovascular manifestations were observed in 95.7%, whereas cutaneous findings were observed in 59.6%. Whereas 83% had a history of undergoing general anesthesia, 17% had no history of NMBA use. In skin tests, the overall positivity to any NMBA was 94.6% (81.1% to culprit NMBAs) and the cross-reactivity was 75.7%, which is related to the chemical structural similarity among NMBAs; the cross-reactivity and chemical structure similarity of rocuronium were 85.3% and 0.814, respectively, with vecuronium; this is in contrast to 50% and 0.015 with cisatracurium and 12.5% and 0.208 with succinylcholine. There were 15 patients who underwent subsequent surgery with a skin test-negative NMBA; whereas 80.0% (12/15) safely completed surgery, 20.0% (3/15) experienced hypotension., Conclusion: Similarities in chemical structure may contribute to the cross-reactivity of NMBAs in skin tests. Despite the high negative predictability of skin tests for suspected NMBA-induced anaphylaxis, the potential risk of recurrent anaphylaxis has not been eliminated., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Study Objective: To determine whether changes in the pleth variability index (PVi) during preoxygenation with forced ventilation for 1 min could predict anesthesia-induced hypotension., Design: Prospective, observational study., Setting: A tertiary teaching hospital., Patients: Ninety-six patients who underwent general anesthesia using total intravenous anesthesia were enrolled., Interventions: Upon the patient's arrival at the preoperative waiting area, a PVi sensor was affixed to their fourth fingertip. For preoxygenation, forced ventilation of 8 breaths/min in a 1:2 inspiratory-expiratory ratio was conducted using the guidance of an audio file. One minute after preoxygenation, anesthetic administration was initiated. Blood pressure was measured for the next 15 min., Measurements: We calculated the difference (dPVi) and percentage of change (%PVi) between the PVi values immediately before and after forced ventilation. Anesthesia-induced hypotension was defined as a mean arterial pressure of <60 mmHg within 15 min after the infusion of anesthetics., Main Results: Overall, 87 patients were included in the final analysis. Anesthesia-induced hypotension occurred in 31 (35.6%) of the 87 patients. Receiver operating characteristic curve analyses identified a cut-off value of -2 for dPVi, with an area under the curve of 0.691 (95% confidence interval [CI], 0.564-0.818; P < 0.001) and a cut-off value of -7.6% for %PVi, with an area under the curve of 0.711 (95% CI, 0.589-0.832; P < 0.001). Further, multivariate logistic regression analysis showed that a low %PVi with an odds ratio of 9.856 (95% CI, 3.131-31.032; P < 0.001) was a significant determinant of anesthesia-induced hypotension., Conclusions: Hypotension frequently occurs during general anesthesia induction and can impact outcomes. Additionally, the percentage change in the PVi before and after preoxygenation using deep breathing can be used to predict anesthesia-induced hypotension., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Although circulating tumor DNA (ctDNA) assays are increasingly used to inform clinical decisions in cancer care, they have limited ability to identify the transcriptional programs that govern cancer phenotypes and their dynamic changes during the course of disease. To address these limitations, we developed a method for comprehensive epigenomic profiling of cancer from 1 ml of patient plasma. Using an immunoprecipitation-based approach targeting histone modifications and DNA methylation, we measured 1,268 epigenomic profiles in plasma from 433 individuals with one of 15 cancers. Our assay provided a robust proxy for transcriptional activity, allowing us to infer the expression levels of diagnostic markers and drug targets, measure the activity of therapeutically targetable transcription factors and detect epigenetic mechanisms of resistance. This proof-of-concept study in advanced cancers shows how plasma epigenomic profiling has the potential to unlock clinically actionable information that is currently accessible only via direct tissue sampling., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The adoption of laparoscopic surgery in the management of serosa-exposed colorectal cancer has raised concerns. This study aimed to investigate whether laparoscopic surgery is associated with an increased risk of postoperative recurrence in patients undergoing resection for serosa-exposed colon cancer. A retrospective analysis was conducted on a cohort of 315 patients who underwent curative resection for pathologically confirmed T4a colon cancer without distant metastases at the Asan Medical Center between 2006 and 2015. Patients were categorized according to the surgical approach method: laparoscopic surgery (MIS group) versus open surgery (Open group). Multivariate analysis was employed to identify risk factors associated with overall survival (OS) and disease-free survival (DFS). The MIS group included 148 patients and the Open group had 167 patients. Of the total cohort, 106 patients (33.7%) experienced recurrence during the follow-up period. Rates, patterns, and time to recurrence were not different between groups. The MIS group (55.8%) showed more peritoneal metastasis compared to the Open group (44.4%) among recurrence sites, but it was not significant ( p = 0.85). There was no significant difference in the five-year OS (73.5% vs. 78.4% p = 0.374) or DFS (62.0% vs. 64.6%; p = 0.61) between the Open and MIS groups. Age and the pathologic N stage were independently associated with OS, and the pathologic N stage was the only associated risk factor for DFS. The laparoscopic approach for serosa-exposed colon cancer did not compromise the DFS and OS. This study provides evidence that laparoscopic surgery does not compromise oncologic outcomes of patients with T4a colon cancer although peritoneal seeding is the most common type of disease failure of serosa-exposed colon cancer.

Researchers have suggested a potential relationship between gamma-glutamyl transferase (GGT) level and stroke. We investigated a potential causal relationship between GGT level as exposures and stroke and stroke subtypes (cardioembolic, small vessel, and large artery) in a European population. We performed a two-sample Mendelian randomization (MR) study using the genome-wide association study (GWAS) data from the UK Biobank as the exposure set. For the outcome set, we used stroke in the GWAS data from the GIGASTROKE Consortium. We considered alcohol consumption, atrial fibrillation, and body mass index as confounders. We used PhenoScanner searches for removal of SNPs and multivariable MR analysis for assessing confounders. We observed significant causal associations between GGT level and stroke (odds ratio [OR] = 1.23, 95% CI = [1.05-1.44], and p = 0.012 with IVW; OR = 1.19, 95% CI= [1.02-1.39], and p = 0.031 with MR-PRESSO). These results were consistent after removing SNPs related to confounding factors. Similarly, in multivariable MR, GGT was associated with stroke after adjusting for confounding factors (OR = 1.30, 95% CI 1.07-1.60), p = 0.010). Because GGT level has a causal relationship with stroke, researchers should test its significance as a potential risk factor for stroke. Additional research is required to validate these results.

This study aimed to discover the quantitative trait loci (QTL) associated with a high seed protein content in soybean and unravel the potential candidate genes. We developed two recombinant inbred line populations: YS and SI, by crossing Saedanbaek (high protein) with YS2035-B-91-1-B-1 (low protein) and Saedanbaek with Ilmi (low protein), respectively, and evaluated the protein content for three consecutive years. Using single-nucleotide polymorphism (SNP)-marker-based linkage maps, four QTLs were located on chromosomes 15, 18, and 20 with high logarithm of odds values (5.9-55.0), contributing 5.5-66.0% phenotypic variance. In all three experimental years, qPSD20-1 and qPSD20-2 were stable and identified in overlapping positions in the YS and SI populations, respectively. Additionally, novel QTLs were identified on chromosomes 15 and 18. Considering the allelic sequence variation between parental lines, 28 annotated genes related to soybean seed protein-including starch, lipid, and fatty acid biosynthesis-related genes-were identified within the QTL regions. These genes could potentially affect protein accumulation during seed development, as well as sucrose and oil metabolism. Overall, this study offers insights into the genetic mechanisms underlying a high soybean protein content. The identified potential candidate genes can aid marker-assisted selection for developing soybean lines with an increased protein content.