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Chieh-Hsin Lin,1– 3 Hui-Ting Yang,4 Ping-Kun Chen,5,6 Shi-Heng Wang,7 Hsien-Yuan Lane2,8,9 1Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; 3School of Medicine, Chang Gung University, Taoyuan, Taiwan; 4School of Food Safety, Taipei Medical University, Taipei, Taiwan; 5School of Medicine, China Medical University, Taichung, Taiwan; 6Department of Neurology, China Medical University Hospital, Taichung, Taiwan; 7Department of Occupational Safety and Health, China Medical University, Taichung, Taiwan; 8Department of Psychiatry & Brain Disease Research Center, China Medical University Hospital, Taichung, Taiwan; 9Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung, TaiwanCorrespondence: Hsien-Yuan LaneDepartment of Psychiatry, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung 404, TaiwanEmail hylane@gmail.comObjective: Behavioral and psychological symptoms of dementia (BPSD) are associated with poorer prognosis of dementia. A 24-week study demonstrated that sodium benzoate, a D-amino acid oxidase (DAAO) inhibitor, surpassed placebo in improving cognitive function in early-phase Alzheimer’s disease; however, benzoate did not excel placebo in another 6-week study on BPSD. The current study examined whether the precision medicine approach was able to identify specific individuals with BPSD who could benefit from benzoate treatment.Methods: In the randomized, double-blind, placebo-controlled, 6-week trial, 97 patients with BPSD were allocated to receive 250– 1500 mg/day of sodium benzoate or placebo. Cognitive function was measured by the Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) and behavioral and psychological symptoms were mainly measured by Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD). DAAO level, amino acids (L-serine, D-serine, L-alanine, and D-alanine, glycine), and two antioxidants (catalase, superoxide dismutase) were assayed in peripheral blood.Results: After benzoate treatment, DAAO inhibition was correlated with ADAS-cog decrease (p = 0.034), while baseline DAAO level was correlated with baseline BEHAVE-AD score. Multiple linear regression analyses showed that cognitive improvement after benzoate treatment was correlated with DAAO decrease, female gender, younger age, BMI, baseline BPSD severity, and antipsychotic use.Conclusion: The finding suggests that sodium benzoate may have potential to benefit cognitive function in a fraction of BPSD patients after 6 weeks of treatment. Of note, the precision medicine approach may be helpful for identifying individuals who could respond to benzoate. More studies are warranted to confirm the preliminary findings.Trial Registration: The trial was registered online (https://clinicaltrials.gov/ct2/show/NCT02103673).Keywords: behavioral and psychological symptoms of dementia, BPSD, N-methyl-D-aspartate, D-amino acids oxidase, DAAO, inhibitor, sodium benzoate, precision medicine

The efficacious placement of dental implants in diabetic patients remains controversial. Definitive guidelines with objective criteria, including the type of diabetes, age of onset, and level of long-term control, have not been determined. In addition, few relevant literature citations assess the survival rate of implants in diabetic patients. Therefore, it is the purpose of this study to assess the success and survival rates of dental implants in diabetic patients. In this retrospective analysis, 215 implants placed in 40 patients at 2 clinical centers were evaluated. Chart reviews and interviews provided medical and implant data. From the analysis, 31 failures occurred, for an overall success rate of 85.6%. Of these failures, 24 occurred within the first year of functional loading. The mean time of functional load was 4.05 +/- 2.6 years. When the success rate was analyzed by implant location, success rates for the maxilla and mandible were 85.5% and 85.7%, respectively. For the anterior and posterior regions, success rates were 83.5% and 85.6%, respectively. The lifetable analysis revealed a cumulative success rate of 85.7% after 6.5 years of function. Based on the data, the survival rate of dental implants in controlled diabetic patients is lower than that documented for the general population, but there is still a reasonable success rate. The increase in failure rate occurs during the first year following prosthetic loading. [ABSTRACT FROM AUTHOR]

Abstract Objective: To develop the Stress Scale for Parents With Cleft Lip and/or Palate Children in Taiwan and to evaluate the psychometric properties of the scale with a group of parents who have children with cleft lip and/or palate. Design: In phase 1, qualitative procedures were conducted in constructing the item pool for the Stress Scale for Parents With Cleft Lip and/or Palate Children. Psychometric properties of the scale were assessed in phase 2. Setting: Outpatient department of a children's hospital in northern Taiwan. Participants: Phase 1 included 21 parents of children with cleft lip and/or palate. Phase 2 included 184 parents of children with cleft lip and/or palate. Interventions: The item pool was developed by interview, content analysis, and literature review. Problematic items were identified by item analysis. Main Outcome Measures: Exploratory factor analysis was used to examine the construct validity. Reliabilities were evaluated by Cronbach alpha and intraclass correlation coefficients. Results: Thirty-three items with a content validity index greater than .80 were recognized. They were grouped into four categories by exploratory factor analysis and accounted for 42.34% of the total variance. Internal consistency reliability was high for the total scale (Cronbach alpha = .90) and ranged from .71 to .84 on the subscales. Test-retest reliability with intraclass correlation coefficient was .94 on the total scale (p < .0001, 95% confidence interval) and from .90 to .96 for the subscales. Conclusions: The Stress Scale for Parents With Cleft Lip and/or Palate Children appears to be a reliable tool with strong evidence of content and construct validity that may be useful in assessing parental stress in the caretakers of children with cleft lip and/or palate. [ABSTRACT FROM AUTHOR]

Introduction: Accumulative evidence indicates that both innate and adaptive immunity are involved in pathogenesis of Still's disease, an autoinflammatory disease. With Increasing insights into the pathogenesis of Still's disease coupled with the availability of emerging targeted therapeutics, it may be the unmet need for personalizing therapy and achieving a treat-to-target goal. We aim to summarize the available evidence regarding immunopathogenesis of Still's disease and therapeutic strategies based on immunologic endotypes., Areas Covered: We searched MEDLINE database using the PubMed interface and reviewed relevant English-language literature from 1971 to 2024. This review focuses on the existing evidence on pathophysiology and immunological endotypes of Still's disease and their implications for personalized strategies for patients with this disease., Expert Opinion: Targeting the complex immunopathogenesis of Still's disease, emerging new agents are available for treatment, including biologic disease-modifying anti-rheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) such as Janus kinase inhibitors (JAKi). According to the updated evidence, meta-analyses, and recommendations, we propose a flow chart emphasizing personalized therapeutic strategies based on immunological endotypes. Hopefully, the therapeutic strategy might help guide the optimal selection of b/tsDMARDs to achieve a 'treat-to-target' goal in Still's disease. This proposed flow chart will be updated as newer evidence emerges.

Objectives: Individuals infected with extensively-drug-resistant (XDR) Acinetobacter baumannii are difficult to cure and have a high mortality rate. This study compared the genomic and phenotypic differences between XDR and non-multi-drug-resistant (MDR) A. baumannii, and further characterized hypervirulent XDR A. baumannii., Methods: In total, 1403 acinetobacter isolates were collected from patients with bacteraemia between 1997 and 2015. Antimicrobial susceptibility tests were performed to categorize isolates into non-MDR, MDR and XDR groups. The presence of selected virulence-associated genes was determined by polymerase chain reaction. Bacterial phenotypes, including iron acquisition, biofilm formation, capsule production, and virulence to larvae and mice, were determined., Results: Multi-locus sequence typing revealed a high prevalence of sequence type (ST) 2 (81.6%) and ST129 (18.4%) among 49 XDR isolates, and the STs of 18 non-MDR isolates were more diverse. Virulence-associated phenotypic assays showed that XDR isolates had higher iron acquisition ability, greater capsule production, and virulence to Galleria mellonella larvae. However, their ability to form biofilm was lower compared with that of non-MDR isolates. XDR isolates were more likely to have virulence genes (tonB, hemO, abaI and ptk), while non-MDR isolates were more likely to have pld and ompA genes. Twenty-one XDR isolates that had a <20% larvae survival rate after 7 days post-infection were defined as hypervirulent XDR isolates. Among them, isolates 1677 (ST129) and 929-1 (ST2) caused the death of all infected mice within 2 days., Conclusion: Some subpopulations of highly-drug-resistant ST2 isolates exhibit high virulence. As such, it is of utmost importance to continue monitoring the spread of hypervirulent XDR A. baumannii isolates., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To maximize the cost-effectiveness of tofacitinib, one of Janus kinase inhibitors, there is an unmet need to identify predictors of therapeutic response. Utilizing phage immunoprecipitation sequencing (PhIP-Seq), we aim to identify peptide biomarkers for predicting good response to tofacitinib in rheumatoid arthritis (RA) patients., Methods: We enrolled 106 patients who had received 24-week tofacitinib therapy, including twelve patients undergoing PhIP-Seq analysis in the discovery stage and ninety-four patients validated with enzyme-linked immunosorbent assay (ELISA) in the replication stage. Disease activity was assessed using the 28-joint disease activity score-erythrocyte sedimentation rate, and therapeutic response was evaluated using EULAR response criteria. Plasma levels of caspase-1 and IL-18 were determined using ELISA., Results: PhIP-Seq analysis identified antibodies to sucrose non-fermenting-related kinase (SNRK) and HUWE1 (ubiquitin E3 ligase) as peptide biomarkers for discriminating good responders from the non-good responders. Using ELISA for validation on another cohort, an optimal cut-off value of anti-SNRK antibody for predicting good response was 0.381, with AUC 0.823, specificity 80.6%, and sensitivity 78.1% (p = 3.01E-07), and anti-HUWE1 antibody at 0.362, with AUC 0.740, specificity 74.2%, and sensitivity 62.5% (p < 0.001). Plasma levels of anti-SNRK and anti-HUWE1 antibodies were positively correlated with levels of caspase-1 and IL-18 (both p < 0.05). Multivariate logistic regression analysis revealed anti-SNRK antibody as a significant predictor of good therapeutic response. After tofacitinib therapy, anti-SNRK antibody levels significantly declined in good responders, but not in non-good responders., Conclusion: We identify two peptide antibodies, anti-SNRK and anti-HUWE1 antibodies, as pretreatment predictors of good therapeutic response to tofacitinib in RA patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) remains inadequately defined. Consequently, this study aims to evaluate the predictive value of remnant cholesterol (RC) for assessing CVD risk in RA patients., Methods: Plasma RC levels were measured in 114 RA patients and 41 healthy controls, calculated as total cholesterol minus HDL-C and LDL-C. These levels were further analyzed using 1 H-NMR lipid/metabolomics. Meanwhile, the 28-joint Disease Activity Score (DAS28) assessed RA activity., Results: RC levels were significantly elevated in RA patients (19.0 mg/dl, p  < 0.001) compared to healthy controls (14.5 mg/dl). Furthermore, RC levels were significantly elevated at 37.4 mg/dl in patients who experienced cardiovascular event (CVE) compared to 17.4 mg/dl in those without CVE ( p  < 0.001). To enhance the precision and reliability of RC measurements, RC concentrations were further validated using 1 H-NMR spectroscopy. Additionally, a positive correlation was observed between RC levels and DAS28. Multivariate analysis identified RC as a significant predictor of CVE (odds ratio = 1.82, p  = 0.013). ROC curve analysis revealed superior predictive capability of RC for CVE (AUC = 0.919, p  < 0.001) compared to LDL-C (AUC = 0.669, p  = 0.018), with a high sensitivity of 94.7% and a specificity of 82.1%., Conclusion: Elevated RC levels demonstrate greater accuracy in predicting CVE occurrence in RA patients compared to traditional measures such as LDL-C. These findings suggest that elevated RC levels may serve as a novel predictor for occurrence of CVE in RA patients, facilitating early intervention strategies based on the risk stratification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor C-HC declared a past co-authorship with the authors., (© 2024 Chang, Li, Chen, Chang and Chen.)

Herpes zoster (HZ) risk is increased in rheumatoid arthritis (RA) patients receiving Janus kinase inhibitors (JAKi) therapy. Identifying and evaluating the risk factors of HZ development in patients receiving JAKi therapy would be clinically helpful. We investigated HZ's incidence rates (IR), identified the risk factors, and further assessed their influence on HZ development in RA patients undergoing JAKi therapy. We retrospectively evaluated 249 RA patients who received JAKi therapy between 2015 and 2023. Data regarding clinical characteristics, HZ reactivation, HZ vaccination status, and concomitant medication use were collected. Among 249 JAKi-treated patients, 44 developed new-onset HZ (tofacitinib, 28/142; baricitinib, 6/35; upadacitinib,10/72), with an IR of 5.11/100patient-years. Multivariate analysis revealed significant predictors of HZ development: a long JAKi exposure period, prior HZ or COVID-19 history, and concomitant high-dose corticosteroids use. The interval between JAKi initiation and HZ development was significantly shorter in patients with prior HZ history than in those without (median, 6.5 months versus 33.5 months, p < 0.001), suggesting "biphasic" emergence of HZ. Only one patient who had experienced an HZ episode while receiving JAKi developed recurrent HZ. None of the seventeen patients immunized with the non-live recombinant zoster vaccine developed HZ. Our JAKi-treated patients had elevated HZ risks, a class effect across different JAKi. A long exposure period, prior history of HZ or COVID-19, and concomitant high-dose corticosteroid treatment may further increase the risk. The emergence of HZ shows a biphasic pattern: early HZ development in patients with prior HZ and late development in those without. Key Points • An increased risk of HZ was observed in Taiwanese RA patients treated with JAKi, presenting as a class effect. • Patients with a long JAKi exposure period, prior history of HZ or COVID-19, and concomitant use of high-dose corticosteroids were at high risk of HZ while receiving JAKi therapy. • The interval between JAKi initiation and HZ occurrence was shorter in patients with prior HZ than in those without, showing "biphasic" emergence., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

The ubiquitin-proteasome system (UPS) plays a key role in maintaining cellular protein homeostasis and participates in modulating various cellular functions. Target of rapamycin (TOR), a highly conserved Ser/Thr kinase found across species from yeasts to humans, forms two multi-protein complexes, TORC1 and TORC2, to orchestrate cellular processes crucial for optimal growth, survival, and stress responses. While UPS-mediated regulation of mammalian TOR complexes has been documented, the ubiquitination of yeast TOR complexes remains largely unexplored. Here we report a functional interplay between the UPS and TORC2 in Saccharomyces cerevisiae. Using avo3-2 ts , a temperature-sensitive mutant of the essential TORC2 component Avo3 exhibiting TORC2 defects at restrictive temperatures, we obtained evidence for UPS-dependent protein degradation and downregulation of the TORC2 component Avo2. Our results established the involvement of the E3 ubiquitin ligase Ubr1 and its catalytic activity in mediating Avo2 degradation in cells with defective Avo3. Coimmunoprecipitation revealed the interaction between Avo2 and Ubr1, indicating Avo2 as a potential substrate of Ubr1. Furthermore, depleting Ubr1 rescued the growth of avo3-2 ts cells at restrictive temperatures, suggesting an essential role of Avo2 in sustaining cell viability under heat stress and/or TORC2 dysfunction. This study uncovers a role of UPS in yeast TORC2 regulation, highlighting the impact of protein degradation control on cellular signaling., 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 © 2024 Elsevier Inc. All rights reserved.)

Integration of carbapenemase gene bla IMP into the chromosome of carbapenem-resistant Acinetobacter baumannii (CRAB) has not been reported. The aim of this study was to explore the genomic characteristics of CRAB AB322 isolated from a Taiwanese patient diagnosed with bacteremia in 2011, whose chromosome harbors bla IMP-19 . Disk diffusion and broth microdilution were employed to analyze the antimicrobial susceptibility of AB322 to 14 antimicrobials. Nanopore whole-genome sequencing platform was utilized for AB322 genome sequencing, and conjugation was further performed to investigate the transferability of bla IMP-19 to amikacin-resistant A. baumannii 218 (AB218) and Acinetobacter nosocomialis 254 (AN254). The results showed that AB322 was classified as multidrug-resistant A. baumannii but remained susceptible to ampicillin/sulbactam, colistin, and tigecycline. Whole-genome sequencing revealed the AB322 genome, consisting of a 4,098,985-bp chromosome, a 71,590-bp conjugative plasmid named pAB322-1, and an 8,726-bp plasmid named pAB322-2. Multilocus sequence typing analysis indicated that AB322 belonged to sequence type 1. AB322 chromosome harbored numerous acquired antimicrobial resistance genes, including aph(3')-Ia , aadA1b , aadA1 , aac(6')-Ib3 , aac (3)-Ia , bla ADC-25 , bla OXA-69 , bla IMP-19 , catA1 , sul1 , and tet(A ), conferring resistance to β-lactams, aminoglycosides, chloramphenicol, sulfamethoxazole, and tetracyclines. Moreover, bla IMP-19 was identified to be situated within class 1 integron In240 and an incomplete PHAGE&#95;Salmon&#95;SJ46&#95;NC&#95;031129 on AB322 chromosome. However, conjugation experiments revealed that bla IMP-19 could not be transferred to AB218 and AN254 in our testing conditions. In conclusion, we first report the presence of chromosomal-integrated bla IMP-19 in CRAB, possibly mediated by integron. The future dissemination of bla IMP-19 among different species, leading to carbapenem resistance dissemination, requires close monitoring., Importance: The horizontal transfer of antimicrobial-resistant genes is crucial for the dissemination of resistance, especially as Acinetobacter baumannii has emerged as a clinically significant pathogen. However, in this study, we first report the integration of the bla IMP-19 gene into the chromosome of A. baumannii , and such horizontal transfer may be associated with integron-phage elements. Additionally, it is possible that these DNA fragments carrying antimicrobial-resistant genes could further spread to other pathogens by moving horizontally onto conjugative plasmids., Competing Interests: The authors declare no conflict of interest.

Anti-interferon (IFN)-γ autoantibodies are linked to varicella zoster virus (VZV) infection. Given the elevated risks of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis), we aimed to examine the relationship between anti-IFN-γ autoantibodies with HZ development in JAKi-treated patients. Serum titers of anti-IFN-γ autoantibodies, plasma levels of IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IFN-γ-inducible protein-10 (IP-10) were measured by ELISA. Among the 66 enrolled RA patients, 24 developed new-onset HZ. Significantly lower MCP-1 levels were observed in patients with HZ compared to those without (median, 98.21 pg/mL, interquartile range (IQR) 77.63-150.30 pg/mL versus 142.3 pg/mL, IQR 106.7-175.6 pg/mL, p < 0.05). There was no significant difference in anti-IFN-γ titers, IFN-γ levels, or IP-10 levels between patients with and without HZ. Three of 24 patients with HZ had severe HZ with multi-dermatomal involvement. Anti-IFN-γ titers were significantly higher in patients with severe HZ than in those with non-severe HZ (median 24.8 ng/mL, IQR 21.0-38.2 ng/mL versus 10.5 ng/mL, IQR 9.9-15.0 ng/mL, p < 0.005). Our results suggest an association between reduced MCP-1 levels and HZ development in JAKi-treated RA patients. High-titer anti-IFN-γ autoantibodies may be related to severe HZ in these patients.

Background: To investigate the feasibility of Diffusion Kurtosis Imaging (DKI) in assessing renal interstitial fibrosis induced by hyperuricemia., Methods: A hyperuricemia rat model was established, and the rats were randomly split into the hyperuricemia (HUA), allopurinol (AP), and AP + empagliflozin (AP + EM) groups (n = 19 per group). Also, the normal rats were selected as controls (CON, n = 19). DKI was performed before treatment (baseline) and on days 1, 3, 5, 7, and 9 days after treatment. The DKI indicators, including mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) of the cortex (CO), outer stripe of the outer medulla (OS), and inner stripe of the outer medulla (IS) were acquired. Additionally, hematoxylin and eosin (H&E) staining, Masson trichrome staining, and nuclear factor kappa B (NF-κB) immunostaining were used to reveal renal histopathological changes at baseline, 1, 5, and 9 days after treatment., Results: The HUA, AP, and AP + EM group MK OS and MK IS values gradually increased during this study. The HUA group exhibited the highest MK value in outer medulla. Except for the CON group, all the groups showed a decreasing trend in the FA and MD values of outer medulla. The HUA group exhibited the lowest FA and MD values. The MK OS and MK IS values were positively correlated with Masson's trichrome staining results (r = 0.687, P < 0.001 and r = 0.604, P = 0.001, respectively). The MD OS and FA IS were negatively correlated with Masson's trichrome staining (r = -626, P < 0.0014 and r = -0.468, P = 0.01, respectively)., Conclusion: DKI may be a non-invasive method for monitoring renal interstitial fibrosis induced by hyperuricemia., (© 2024. The Author(s).)

Background: This study aimed to characterize carbapenem-nonsusceptible Acinetobacter (CNSA) isolated from patients with bacteremia from 1997 to 2015., Methods: A total of 173 CNSA (12.3%) was recovered from 1403 Acinetobacter isolates. The presence of selected β-lactamase genes in CNSA was determined by PCR amplification. The conjugation test was used to determine the transferability of metallo-β-lactamase (MBL)-carrying plasmids. Whole genome sequencing in combination with phenotypic assays was carried out to characterize MBL-plasmids., Results: In general, a trend of increasing numbers of CNSA was observed. Among the 173 CNSA, A. baumannii (54.9%) was the most common species, followed by A. nosocomialis (23.1%) and A. soli (12.1%). A total of 49 (28.3%) CNSA were extensively drug-resistant, and all were A. baumannii. The most common class D carbapenemase gene in 173 CNSA was bla OXA-24-like (32.4%), followed by ISAba1-bla OXA-51-like (20.8%), ISAba1-bla OXA-23 (20.2%), and IS1006/IS1008-bla OXA-58 (11.6%). MBL genes, bla VIM-11, bla IMP-1 , and bla IMP-19 were detected in 9 (5.2%), 20 (11.6%), and 1 (0.6%) CNSA isolates, respectively. Transfer of MBL genes to AB218 and AN254 recipient cells was successful for 7 and 6 of the 30 MBL-plasmids, respectively. The seven AB218-derived transconjugants carrying MBL-plasmids produced less biofilm but showed higher virulence to larvae than recipient AB218., Conclusions: Our 19-year longitudinal study revealed a stable increase in CNSA during 2005-2015. bla OXA-24-like , ISAba1-bla OXA-51-like , and ISAba1-bla OXA-23 were the major determinants of Acinetobacter carbapenem resistance. MBL-carrying plasmids contribute not only to the carbapenem resistance but also to A. baumannii virulence., Competing Interests: Declaration of competing interest The authors report that there are no competing interests to declare., (Copyright © 2024. Published by Elsevier B.V.)

Lethal toxin (LT) is the critical virulence factor of Bacillus anthracis , the causative agent of anthrax. One common symptom observed in patients with anthrax is thrombocytopenia, which has also been observed in mice injected with LT. Our previous study demonstrated that LT induces thrombocytopenia by suppressing megakaryopoiesis, but the precise molecular mechanisms behind this phenomenon remain unknown. In this study, we utilized 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced megakaryocytic differentiation in human erythroleukemia (HEL) cells to identify genes involved in LT-induced megakaryocytic suppression. Through cDNA microarray analysis, we identified Dachshund homolog 1 ( DACH1 ) as a gene that was upregulated upon TPA treatment but downregulated in the presence of TPA and LT, purified from the culture supernatants of B. anthracis . To investigate the function of DACH1 in megakaryocytic differentiation, we employed short hairpin RNA technology to knock down DACH1 expression in HEL cells and assessed its effect on differentiation. Our data revealed that the knockdown of DACH1 expression suppressed megakaryocytic differentiation, particularly in polyploidization. We demonstrated that one mechanism by which B. anthracis LT induces suppression of polyploidization in HEL cells is through the cleavage of MEK1/2. This cleavage results in the downregulation of the ERK signaling pathway, thereby suppressing DACH1 gene expression and inhibiting polyploidization. Additionally, we found that known megakaryopoiesis-related genes, such as FOSB , ZFP36L1 , RUNX1 , FLI1 , AHR , and GFI1B genes may be positively regulated by DACH1 . Furthermore, we observed an upregulation of DACH1 during in vitro differentiation of CD34-megakaryocytes and downregulation of DACH1 in patients with thrombocytopenia. In summary, our findings shed light on one of the molecular mechanisms behind LT-induced thrombocytopenia and unveil a previously unknown role for DACH1 in megakaryopoiesis.

Background: Non-alcoholic fatty liver disease (NAFLD) is prevalent among rheumatoid arthritis (RA) patients, but its pathogenesis has rarely been explored. Galectin-9 (Gal-9) interacts with T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3) expressed on hepatocytes and thus regulates T cell proliferation in a murine model of NAFLD. We aimed to examine the pathogenic role of the Gal-9/TIM-3 pathway in RA-NAFLD., Methods: Serum levels of Gal-9, soluble TIM-3 (sTIM-3), fatty acid-binding proteins (FABP)1, and FABP4 were determined by ELISA in forty-five RA patients and eleven healthy participants. Using Oil-red O staining and immunoblotting, we examined the effects of Gal-9 and free fatty acid (FFA) on lipid accumulation in human hepatocytes and FABP1 expression., Results: Serum Gal-9, sTIM-3 and FABP1 level were significantly higher in RA patients (median 5.02 ng/mL, 3.42 ng/mL, and 5.76 ng/mL, respectively) than in healthy participants (1.86 ng/mL, 0.99 ng/mL, and 0.129 ng/mL, all p  < 0.001). They were also significantly higher in patients with moderate-to-severe NAFLD compared with none-to-mild NAFLD ( p  < 0.01; p  < 0.05; and p  < 0.01, respectively). Serum Gal-9 levels were positively correlated with sTIM-3, FABP1, FABP4 levels, and ultrasound-fatty liver score, respectively, in RA patients. Multivariate regression analysis revealed that Gal-9 (cut-off>3.30) was a significant predictor of NAFLD development, and Gal-9 and sTIM-3 were predictors of NAFLD severity (both p  < 0.05). The cell-based assay showed that Gal-9 and FFA could upregulate FABP1 expression and enhance lipid droplet accumulation in hepatocytes., Conclusion: Elevated levels of Gal-9 and sTIM3 in RA patients with NAFLD and their positive correlation with NAFLD severity suggest the pathogenic role of Gal-9 signaling in RA-related NAFLD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Hsu, Peng, Liao, Chang, Chen, Chen and Chen.)

Background: Although the non-alcoholic fatty liver disease (NAFLD) is prevalent in the general population, NAFLD risk in newly diagnosed rheumatoid arthritis (RA) has rarely been explored. In this population-based cohort, we examined NAFLD risk in patients with RA and identified the potential risk factors., Design: Retrospective study., Setting: Taiwan., Participants: 2281 newly diagnosed patients with RA and selected 91 240 individuals without RA to match with patients with RA (1:40) by age, gender, income status and urbanisation level of the residence., Outcomes: In this retrospective study using the 2000-2018 claim data from two-million representative Taiwanese population, we identified and compared the incidence rates (IRs) of NAFLD and alcoholic fatty liver disease (AFLD) between RA and non-RA groups. Using multivariable regression analyses, we estimated adjusted HR (aHR) of NAFLD development in patients with RA compared with individuals without RA, with 95% CIs., Results: The incidences of NALFD and AFLD were not significantly different between individuals with RA and without RA during the 17-year follow-up period. However, patients with RA had significantly increased NAFLD risk during the first 4 years after RA diagnosis, with IR ratio of 1.66 fold (95% CI 1.18 to 2.33, p<0.005), but the risk was reduced after the first 4 years. Multivariable regression analyses revealed that aHR was 2.77-fold greater in patients not receiving disease-modifying anti-rheumatic drugs therapy than in non-RA subjects (p<0.05). Old age, women, low-income status and obesity could significantly predict NAFLD development., Conclusions: We demonstrated elevated risk of NAFLD in patients with RA during the first 4 years after RA diagnosis, and old age, women, low-income status and obesity were significant predictors of NAFLD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To validate the feasibility of intravoxel incoherent motion imaging (IVIM) for monitoring renal injury and uric acid-lowering efficacy in a rat model of hyperuricaemia., Methods: A total of 92 rats were analysed and categorized into 4 groups: control (CON), hyperuricaemia (HUA), allopurinol intervention (ALL), and combined intervention (COM). Eight rats were randomly selected from each group and underwent IVIM scanning on days 0, 1, 3, 5, 7, and 9. Quantitative magnetic resonance values (D, D*, and f values) measured from the different renal anatomical regions. Quantitative histopathological analysis was performed to assess renal tubular injury using neutrophil gelatinase-associated lipocalin (NGAL), and renal fibrosis using alpha-smooth-muscle-actin (α-SMA). Pearson's correlation analysis was used to determine the correlation between IVIM-derived parameters and the expression of NGAL and α-SMA., Results: The D values of the HUA, ALL, and COM groups generally showed a downward trend over time, and this fluctuation was most significant in the HUA group. The D values showed significant intergroup differences at each point, whereas only a few discrepancies were found in the D* and f values. In addition, the renal D value was negatively correlated with the positive staining rates for NGAL and α-SMA (P < .05), except for the lack of correlation between Dos and α-SMA (P > .05)., Conclusion: IVIM could be a noninvasive and potential assessment modality for the evaluation of renal injury induced by hyperuricaemia and its prognostic efficacy., Advances in Knowledge: IVIM could be a surrogate manner in monitoring renal damage induced by hyperuricaemia and its treatment evaluation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by chronic synovitis and the progressive destruction of cartilage and bone. RA is commonly accompanied by extra-articular comorbidities. The pathogenesis of RA and its comorbidities is complex and not completely elucidated. The assembly of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activates caspase-1, which induces the maturation of interleukin (IL)-1β and IL-18 and leads to the cleavage of gasdermin D with promoting pyroptosis. Accumulative evidence indicates the pathogenic role of NLRP3 inflammasome signaling in RA and its comorbidities, including atherosclerotic cardiovascular disease, osteoporosis, and interstitial lung diseases. Although the available therapeutic agents are effective for RA treatment, their high cost and increased infection rate are causes for concern. Recent evidence revealed the components of the NLRP3 inflammasome as potential therapeutic targets in RA and its comorbidities. In this review, we searched the MEDLINE database using the PubMed interface and reviewed English-language literature on the NLRP3 inflammasome in RA and its comorbidities from 2000 to 2023. The current evidence reveals that the NLRP3 inflammasome contributes to the pathogenesis of RA and its comorbidities. Consequently, the components of the NLRP3 inflammasome signaling pathway represent promising therapeutic targets, and ongoing research might lead to the development of new, effective treatments for RA and its comorbidities.

Background: Although several studies have reported the advantages of the surgery-first approach for orthognathic correction of class III deformity, there is no report of the success of this approach for patients with cleft lip and palate. Therefore, the purpose of this study was to evaluate the stability and outcome of bimaxillary surgery for cleft-related dentofacial deformity using a surgery-first approach., Methods: Forty-one patients with unilateral cleft lip and palate who consecutively underwent Le Fort I and bilateral sagittal split osteotomies for skeletal class III deformity were included. Cone-beam computed tomographic scans before surgery, 1 week after surgery, and after orthodontic treatment were used to measure the surgical and postsurgical changes in jaw position by landmarks, and outcomes of jaw protrusion and relation, incisor angle and occlusion, and menton deviation after treatment. Self-report questionnaires regarding satisfaction with overall appearance of the face and seven facial regions were administered after treatment., Results: A clinically insignificant relapse was found in the maxilla (<1 mm) and mandible (<2 mm). There was a significant improvement in the jaw protrusion and relation, incisor angle and occlusion, and menton deviation. Responses from the self-report questionnaires completed after treatment indicated that patient satisfaction was high., Conclusion: These findings demonstrate surgical-orthodontic treatment with a surgery-first approach can successfully improve cleft-related dentofacial deformity in patients with unilateral cleft lip and palate., Clinical Question/level of Evidence: Therapeutic, IV., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Purpose: To analyze the safety of combination treatment comprising drug-eluting bead transarterial chemoembolization (DEB-TACE) and immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC)., Method: In total, 208 HCC patients receiving DEB-TACE were enrolled for this retrospective single-institution study. Among them, 50 patients who received ICIs at an interval less than one month from DEB-TACE were categorized into the DEB-ICI group; the remaining 158 patients were categorized into the DEB group. Albumin-bilirubin (ALBI) score before and at three months after DEB-TACE were recorded to evaluate liver function changes. Adverse events within three months after DEB-TACE were considered TACE-related and were compared between the two groups., Results: The DEB-ICI group had significantly higher incidence of liver abscess than the DEB group (14.0 % versus 5.1 %, p-value = 0.0337). No significant difference in the other TACE-related adverse events and change of ALBI score between the groups. Univariate logistic regression confirmed that combination with ICIs was an independent risk factor for liver abscess after DEB-TACE (odds ratio = 3.0523, 95 % confidence interval: 1.0474-8.8947, p-value = 0.0409); other parameters including subjective angiographic chemoembolization endpoint scale and combined targeted therapy were nonsignificant risk factors in this study population. In the DEB-ICI group, patients who received ICIs before DEB-TACE exhibited a trend toward liver abscess formation compared with those who received DEB-TACE before ICIs (23.8 % versus 6.9 %, p-value = 0.0922)., Conclusions: Combination treatment involving DEB-TACE and ICIs at an interval less than one month increased the risk of liver abscess after DEB-TACE. Greater caution is therefore warranted for HCC patients who receive ICIs and DEB-TACE with this short interval., 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 B.V. All rights reserved.)

Nonlinear frequency mixing is a method to extend the wavelength range of optical sources with applications in quantum information and photonic signal processing. Lithium niobate with periodic poling is the most widely used material for frequency mixing due to its strong second-order nonlinear coefficient. The recent development using nanophotonic lithium niobate waveguides promises to improve nonlinear efficiencies by orders of magnitude thanks to subwavelength optical confinement. However, the intrinsic nanoscale inhomogeneity of nanophotonic lithium niobate waveguides limits the coherent interaction length, leading to low nonlinear efficiencies. Here we show improved second-order nonlinear efficiency in nanophotonic lithium niobate waveguides that breaks the limit imposed by nanoscale inhomogeneity. This is realized by developing the adapted poling approach to eliminate the impact of nanoscale inhomogeneity. We realize an overall second-harmonic efficiency of 10 4 % W -1 (without cavity enhancement), approaching the theoretical performance for nanophotonic lithium niobate waveguides. The ideal square dependence of the nonlinear efficiency on the waveguide length is recovered. Phase-matching bandwidths and temperature tuneability are improved through dispersion engineering. We finally demonstrate a conversion ratio from pump to second-harmonic power greater than 80% in a single-pass configuration with pump power as low as 20 mW. Our work therefore breaks the trade-off between the conversion ratio and pump power, offering a potential solution for highly efficient and scalable nonlinear-optical sources, amplifiers and converters., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Although the "white skin roll" of the lip is often considered a line, it is better defined as the subunit between the vermilion border and the upper lip horizontal groove. In many unilateral cleft lip repair techniques, this structure is approximated between both sides of the cleft without restoration. This study aimed to analyze the white skin roll height in patients with unilateral cleft lip., Methods: This retrospective cohort study included 134 consecutive infants with unilateral cleft lip aged 3-6 months who underwent lip repair in a single institution between January 2019 and July 2021. White skin roll heights at the peak of the Cupid's bow on the non-cleft side (CPHIR), cleft medial element (CPHIL), and cleft lateral element (CPHIL') were measured, and differences in their averages were analyzed., Results: The mean height was 1.70 ± 0.30 mm at CPHIR, 0.98 ± 0.33 mm at CPHIL, and 1.28 ± 0.32 mm at CPHIL.' The mean difference in height between CPHIR-CPHIL, CPHIR-CPHIL,' and CPHIL-CPHIL' groups was significant for each paired sample (p < 0.01). No difference was found between the complete and incomplete clefts or left and right clefts (p > 0.01)., Conclusions: A significantly reduced mean height of the white skin roll was present more markedly on the cleft medial element than on the cleft lateral element. Therefore, we strongly support using a white skin roll flap on the cleft lateral element for unilateral cleft lip repair, embracing the concepts of subunits and lip contour lines., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. All rights reserved.)

Background: Nasoalveolar molding (NAM) has become standard treatment in the authors' craniofacial center. There are two types of presurgical NAM: the Grayson and Figueroa techniques. The Grayson method involves active alveolar molding, and the Figueroa method involves passive alveolar molding. The authors previously found no differences in number of clinic visits, costs, or 6-month postoperative outcome between the two techniques. The authors extended the previous study to evaluate facial growth between these two groups., Methods: In this randomized single-blind study, conducted between May of 2010 and March of 2013, the authors recruited 30 patients with unilateral complete cleft lip and palate and randomized them for Grayson or Figueroa presurgical NAM. Standard lateral cephalometric measurements at 5 years were used to determine facial growth., Results: Twenty-nine patients completed 5 years of follow-up. There were no statistically significant differences in facial cephalometric measurements between the two groups., Conclusion: Presurgical NAM using either a passive or active NAM technique produced similar facial growth patterns after unilateral cleft lip and palate repair., Clinical Question/level of Evidence: Therapeutic, II., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Objective: Describe the first hybrid global simulation-based comprehensive cleft care workshop, evaluate impact on participants, and compare experiences based on in-person versus virtual attendance., Design: Cross-sectional survey-based evaluation., Setting: International comprehensive cleft care workshop., Participants: Total of 489 participants., Interventions: Three-day simulation-based hybrid comprehensive cleft care workshop., Main Outcome Measures: Participant demographic data, perceived barriers and interventions needed for global comprehensive cleft care delivery, participant workshop satisfaction, and perceived short-term impact on practice stratified by in-person versus virtual attendance., Results: The workshop included 489 participants from 5 continents. The response rate was 39.9%. Participants perceived financial factors (30.3%) the most significant barrier and improvement in training (39.8%) as the most important intervention to overcome barriers facing cleft care delivery in low to middle-income countries. All participants reported a high level of satisfaction with the workshop and a strong positive perceived short-term impact on their practice. Importantly, while this was true for both in-person and virtual attendees, in-person attendees reported a significantly higher satisfaction with the workshop (28.63 ± 3.08 vs 27.63 ± 3.93; P  = .04) and perceived impact on their clinical practice (22.37 ± 3.42 vs 21.02 ± 3.45 P  = .01)., Conclusion: Hybrid simulation-based educational comprehensive cleft care workshops are overall well received by participants and have a positive perceived impact on their clinical practices. In-person attendance is associated with significantly higher satisfaction and perceived impact on practice. Considering that financial and health constraints may limit live meeting attendance, future efforts will focus on making in-person and virtual attendance more comparable.

Objectives: Monocyte distribution width (MDW) correlates with volume modifications of circulating monocytes upon activation. Given the crucial role of monocyte activation in the pathogenesis of adult-onset Still's disease (AOSD), we aimed to examine the associations between MDW and disease activity or inflammatory parameters in this disease., Methods: In 58 AOSD patients and 95 other patients with coronavirus disease 2019 (COVID-19) as disease control, MDW and complete blood count were determined using a UniCel DxH800 analyser. C-reactive protein (CRP) levels were measured by nephelometry, and ferritin levels by chemiluminescent immunoassay. AOSD activity was assessed using a modified Pouchot score., Results: MDW was significantly higher in active AOSD patients (median 28.3, interquartile range [IQR] 23.3-32.1) compared with inactive AOSD (19.2, IQR 18.0-20.6, p<0.001) or non-severe COVID-19 patients (23.2, IQR 21.0-25.2, p<0.01). MDW was positively correlated with AOSD activity scores, CRP, and ferritin levels (all p<0.001). Longitudinal follow-up evaluation revealed that median MDW significantly declined (28.3 versus 18.5, p<0.001) along with disease activity, paralleling a decrease in CRP and ferritin levels. Severe COVID-19 and sepsis patients had elevated MDW, which were not different from active AOSD patients. Multivariate analysis revealed MDW as a significant predictor of active AOSD, and MDW threshold at 21.7 could predict an active status with a high sensitivity of 91.3% and specificity of 94.3%., Conclusions: Elevated MDW and its positive correlation with inflammatory parameters in AOSD patients indicate MDW as a novel activity indicator, with a high MDW value above 21.7 linked to a high probability of active AOSD.

Dengue fever, a mosquito-borne disease in tropical and subtropical climates caused by the dengue virus (DENV), has become a major social and economic burden in recent years. However, current primary detection methods are inadequate for early diagnosis of DENV because they are either time-consuming, expensive, or require training. Non-structural protein 1 (NS1) is secreted during DENV infection and is thus considered a suitable biomarker for the development of an early detection method. In the present study, we developed a detection method for the NS1 protein based on a previously reported thio-NAD cycling ELISA (i.e., ultrasensitive ELISA) and successfully achieved a LOD of 1.152 pg/mL. The clinical diagnosis potential of the detection system was also evaluated by using 85 patient specimens, inclusive of 60 DENV-positive and 25 DENV-negative specimens confirmed by the NAAT method. The results revealed 98.3% (59/60) sensitivity and 100% (25/25) specificity, which was in almost perfect agreement with the NAAT data with a kappa coefficient of 0.972. The present study demonstrates the diagnostic potential of using an ultrasensitive ELISA as a low-cost, easy-to-use method for the detection of DENV compared with NAAT and could be of great benefit in low-income countries.

Longitudinal studies on the variations of phenotypic and genotypic characteristics of K. pneumoniae across two decades are rare. We aimed to determine the antimicrobial susceptibility and virulence factors for K. pneumoniae isolated from patients with bacteraemia or urinary tract infection (UTI) from 1999 to 2022. A total of 699 and 1,267  K. pneumoniae isolates were isolated from bacteraemia and UTI patients, respectively, and their susceptibility to twenty antibiotics was determined; PCR was used to identify capsular serotypes and virulence-associated genes. K64 and K1 serotypes were most frequently observed in UTI and bacteraemia, respectively, with an increasing frequency of K20, K47, and K64 observed in recent years. entB and wabG predominated across all isolates and serotypes; the least frequent virulence gene was htrA. Most isolates were susceptible to carbapenems, amikacin, tigecycline, and colistin, with the exception of K20, K47, and K64 where resistance was widespread. The highest average number of virulence genes was observed in K1, followed by K2, K20, and K5 isolates, which suggest their contribution to the high virulence of K1. In conclusion, we found that the distribution of antimicrobial susceptibility, virulence gene profiles, and capsular types of K. pneumoniae over two decades were associated with their clinical source.

Rationale and Objectives: The aim of this study was to investigate the potential of diffusion kurtosis imaging (DKI) to assess the early renal functional undulation of diabetic mellitus (DM)., Materials and Methods: Fifty-seven Sprague-Dawley (SD) rats were randomly divided into two groups and eventually 48 rats were included in this study: the normal control (CON) group and diabetic mellitus (DM) group. Weeks 0, 4, 8, and 12 after the diabetes model was successfully established, all the rats were scanned on the 3.0T MRI. The DKI derived parameters of renal parenchyma, including fractional anisotropy (FA co , FA me ), mean diffusivity (MD co , MD me ), and mean kurtosis (MK co , MK me ) were measured. Their alteration over time was analyzed and then correlated with urine volume (UV), blood urea nitrogen (BUN), and serum creatinine (Scr) using Pearson correlation analysis. Finally, hematoxylin and eosin (H&E) staining was performed on the kidneys of the two groups., Result: There was a decreasing trend in FA, MK, and MD values over time in diabetic rats. Also, the gradually worsening histological damage of kidneys was noted over time in diabetic rats. The cortical FA and MK values and medullary FA, MK and MD values of diabetic rats were significantly lower than those of controls at most time points after DM induction. In addition, negative correlations were revealed between the BUN and FA co (r = -0.43, p = 0.03) or FA me value (r = -0.49, p = 0.01). The cortical MK value was moderately correlated with UV (r = -0.46, p = 0.03) and BUN (r = -0.55, p = 0.01)., Conclusion: The preliminary findings suggest that DKI might be an effective and sensitive tool to assess the early changes of renal function impairment in diabetic rats. The FA values of the cortex and medulla and the MK value of the cortex are sensitive markers in detecting renal injury in diabetic rats., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Objectives: Gingivoperiosteoplasty is often used for reconstruction of alveolar defects in infants with cleft lip and palate. This study aimed to examine outcomes of tertiary gingivoperiosteoplasty, which has not previously been investigated., Materials and Methods: This prospective study included 11 adults with complete cleft lip and palate (n = 12 sites) who consecutively underwent segmental Le Fort I osteotomy and concomitant gingivoperiosteoplasty for correction of skeletal class III deformity, nasoalveolar fistula and alveolar cleft. Outcomes included clinical and radiographic evaluations of gingivoperiosteoplasty at the time of osteotomy (presence of nasoalveolar fistula, residual cleft defect and unsupported root ratio of cleft-adjacent teeth), and determination of influencing factors for the clinical success of alveolar cleft repair. Study variables included age, gender, pre-surgical orthodontic treatment and alveolar cleft width of cleft-adjacent canine and angulation between cleft-adjacent teeth before surgery and 1-week postsurgery., Results: Posttreatment, no nasoalveolar fistula remained. The residual cleft defect decreased significantly (p < 0.01). The unsupported root ratio of cleft-adjacent teeth did not differ (p > 0.05); eight cleft sites reached Bergland I or II (67% success). One-week postsurgery, the minimal alveolar cleft width of cleft-adjacent canine was significantly less in the success group compared with the failed group (p = 0.01)., Conclusions: Tertiary gingivoperiosteoplasty and segmental Le Fort I osteotomy decreased nasoalveolar fistulas and induced alveolar bone formation. The minimal alveolar cleft width immediately after surgery was the major influencing factor of clinical success., Clinical Relevance: Segmental Le Fort I osteotomy with simultaneous gingivoperiosteoplasty efficaciously repairs adult alveolar clefts., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rheumatoid arthritis (RA), a chronic inflammatory disease, carries a significant burden of atherosclerotic cardiovascular diseases (ASCVD). With their heterogeneous composition, high-density lipoprotein (HDL) particles have varied athero-protective properties, and some may even increase ASCVD risk. In this prospective and cross-sectional study, we aimed to examine the relationship between HDL sizes/metabolites and inflammation in RA. Using 1 H-NMR-based lipid/metabolomics, differential HDL-related metabolites were identified between RA patients and healthy control (HC) subjects and between RA patients with and without anti-citrullinated peptide antibodies (ACPA). The correlation between the discriminative HDL-related metabolites and C-reactive protein (CRP) was evaluated in RA patients. RA patients demonstrated higher particle number, lipids, cholesterol, cholesterol ester, free cholesterol, and phospholipids in large/very large-sized HDLs. ACPA-positive patients had higher L-HDL-C and L-HDL-CE but lower small-/medium-sized HDL-TG levels than ACPA-negative patients. An inverse correlation was found between CRP levels and small-sized HDLs. Janus kinase inhibitor treatment was associated with increased serum small-sized HDL-related metabolites and decreased CRP levels. We are the first to reveal the significant associations between RA inflammation and HDL sizes/metabolites. A potential link between ACPA positivity and changes in serum levels of HDL-related metabolites was also observed in RA patients.

Aims: Transforming growth factor-β2 (TGF-β2) plays an important role in pleiotropic functions and has been reported to be involved in the pathogenesis of chronic obstructive lung disease. The role of TGF-β2 in regulating cigarette smoke (CS)-induced lung inflammation and injury has not been investigated, and its underlying mechanism remains unclear., Main Methods: Primary bronchial epithelial cells (PBECs) were treated with cigarette smoke extract (CSE), and the signaling pathway of TGF-β2 regulating lung inflammation was investigated. Mice were exposed to CS and treated with TGF-β2 i.p. or bovine whey protein extract containing TGF-β2 p.o., and the role of TGF-β2 in alleviating lung inflammation/injury was studied., Key Findings: In vitro, we demonstrated that TGF-β2 attenuated CSE-induced IL-8 production from PBECs through the TGF-β receptor I (TGF-βRI), Smad3, and mitogen-activated protein kinase signaling pathways. Selective TGF-βRI inhibitor (LY364947) and antagonist of Smad3 (SIS3) abolished the effect of TGF-β2 on alleviating CSE-induced IL-8 production. In vivo, CS exposure for 4 weeks in mice increased the levels of total protein, inflammatory cell counts, and monocyte chemoattractant protein-1 in bronchoalveolar fluid and induced lung inflammation/injury, as revealed by immunohistochemistry. Administration of TGF-β2 through intraperitoneal injection or oral feeding with bovine whey protein extract containing TGF-β2 significantly reduced CS-induced lung inflammation and injury., Significance: We concluded that TGF-β2 reduced CSE-induced IL-8 production through the Smad3 signaling pathway in PBECs and alleviated lung inflammation/injury in CS-exposed mice. The anti-inflammatory effect of TGF-β2 on CS-induced lung inflammation in humans deserves further clinical study., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Although 1H-nuclear magnetic resonance (NMR)-based lipid/metabolomics has been used to detect atherosclerosis, data regarding lipid/metabolomic signature in rheumatoid arthritis (RA)-related atherosclerosis are scarce. We aimed to identify the distinct lipid/metabolomic profiling and develop a prediction score model for RA patients with subclinical atherosclerosis (SA)., Methods: Serum levels of lipid metabolites were determined using 1H-NMR-based lipid/metabolomics in 65 RA patients and 12 healthy controls (HCs). The occurrence of SA was defined as the presence of carotid plaques revealed in ultrasound images., Results: Compared with HC, RA patients had significantly higher levels of phenylalanine and glycoprotein acetyls (GlycA) and lower levels of leucine and isoleucine. RA patients with SA had significantly higher levels of phenylalanine, creatinine, and glycolysis&#95;total and lower levels of total lipid in HDL(HDL&#95;L) than RA patients without SA. The Lasso logistic regression analysis revealed that age, creatinine, HDL&#95;L, and glycolysis&#95;total were significant predictors for the presence of SA. The prediction scoring algorithm was built as ( -0.657 + 0.011*Age + 0.004*Creatinine -0.120*HDL&#95;L + 0.056*glycolysis-related measures), with AUC 0.90, sensitivity 83.3%, and specificity 87.2%. Serum phenylalanine levels were significantly decreased, and the levels of HDL&#95;L and HDL&#95;Particle were significantly increased in 20 RA patients, paralleling the decrease in disease activity score for 28-joints., Conclusions: With 1H-NMR-based lipid/metabolomics, distinct profiling of lipid metabolites was identified between RA patients and HC or between RA patients with and without SA. We further developed a scoring model based on lipid/metabolomics profiling for predicting RA-associated SA.

Optical isolators are an essential component of photonic systems. Current integrated optical isolators have limited bandwidths due to stringent phase-matching conditions, resonant structures, or material absorption. Here, we demonstrate a wideband integrated optical isolator in thin-film lithium niobate photonics. We use dynamic standing-wave modulation in a tandem configuration to break Lorentz reciprocity and achieve isolation. We measure an isolation ratio of 15 dB and insertion loss below 0.5 dB for a continuous wave laser input at 1550 nm. In addition, we experimentally show that this isolator can simultaneously operate at visible and telecom wavelengths with comparable performance. Isolation bandwidths up to ∼100 nm can be achieved simultaneously at both visible and telecom wavelengths, limited only by the modulation bandwidth. Our device's dual-band isolation, high flexibility, and real-time tunability can enable novel non-reciprocal functionality on integrated photonic platforms.

Introduction: The diagnosis of adult-onset Still's disease (AOSD) is often delayed due to its clinical heterogeneity and lack of pathognomic features. Hence, there is an unmet need for an efficient diagnostic process. The major aim of this study was to compare the differences in disease outcomes between two groups of AOSD patients with and without implementation of the streamlined diagnostic process (SDP)., Methods: Of 172 febrile patients with skin rash and/or arthralgia, 112 individuals had AOSD. The tentative diagnosis of AOSD or non-AOSD was made with or without the SDP implementation. The selection criteria for AOSD outcomes analysis were as follows: (1) age at study entry older than 20 years, (2) fulfillment of the Yamaguchi criteria for AOSD diagnosis, and (3) a follow-up period longer than 6 months after initiation of therapy. Three outcome parameters were evaluated, including diagnosis lag period, the proportion of "early diagnosis," and the proportion of achieving disease remission after a 6-month therapy., Results: The SDP was implemented for expediting AOSD diagnosis in 41 (36%) enrolled patients (SDP-implemented group). The diagnosis lag period was significantly shorter in the SDP-implemented group (median 2.0 weeks, interquartile range [IQR] 1.0-2.5 weeks) than in the non-SDP-implemented group (4.0 weeks, IQR 2.0-6.0 weeks, p < 0.001). A significantly higher proportion of "early diagnosis" was also found in the SDP-implemented group (75.6%) compared with the non-SDP-implemented group (33.8%, p < 0.001). We revealed a significantly higher proportion of achieving remission in the SDP-implemented group (85.4%) compared with the non-SDP-implemented group (67.6%, p < 0.05). Logistic regression analysis revealed SDP implementation as a potential predictor of achieving disease remission., Conclusions: Implementing an SDP for expediting diagnosis could improve outcomes for AOSD patients. This diagnostic process increased the early diagnosis rate and led to a higher disease remission rate. However, the beneficial effects of SDP implementation need further external validation., (© 2022. The Author(s).)

Objective: To evaluate the efficacy of drug-eluting beads loaded with irinotecan (DEBIRI) in colorectal cancer (CRC) patients with synchronous liver-only metastases non-responsive to bevacizumab-based chemotherapy (BBC)., Methods: Fifty-eight patients were enrolled in this study. Treatment response to BBC and DEBIRI were determined by the morphological criteria and Choi's criteria, respectively. Progression-free survival (PFS) and overall survival (OS) were recorded. The correlation between pre-DEBIRI CT parameters and treatment response to DEBIRI was analyzed., Results: CRC patients were divided into the BBC responsive group (R group) ( n = 16) and the non-responsive group ( n = 42), which was further divided into the NR group (23 patients who did not receive DEBIRI) and the NR+DEBIRI group (19 patients who received DEBIRI after failing BBC). Among the R, NR and NR+DEBIRI groups, the median PFS were 11, 12, and 4 months, respectively ( p < 0.01); median OS were 36, 23, and 12 months, respectively ( p = 0.01). In the NR+DEBIRI group, 33 metastatic lesions were treated with DEBIRI, of which 18 (54.5%) reached objective response. The receiver operating characteristic curve showed that the contrast enhancement ratio (CER) before DEBIRI could predict objective response (AUC = 0.737, p < 0.01)., Conclusion: In CRC patients, DEBIRI can achieve acceptable objective response for liver metastases non-responsive to BBC. However, this locoregional control does not prolong survival. The pre-DEBIRI CER can predict OR in these patients., Advances in Knowledge: DEBIRI can act as an acceptable locoregional management in CRC patients with liver metastases non-responsive to BBC, and the pre-DEBIRI CER is a potential indicator of locoregional control.

Background: Escherichia coli is the leading pathogen responsible for urinary tract infection (UTI) and recurrent UTI (RUTI). Few studies have dealt with the characterization of host and bacteria in RUTI caused by E. coli with genetically identical or different strains. This study aimed to investigate the host and bacterial characteristics of E. coli RUTI based on molecular typing., Results: Patients aged 20 years or above who presented with symptoms of UTI in emergency department or outpatient clinics between August 2009 and December 2010 were enrolled. RUTI was defined as patients had 2 or more infections in 6 months or 3 or more in 12 months during the study period. Host factors (including age, gender, anatomical/functional defect, and immune dysfunction) and bacterial factors (including phylogenicity, virulence genes, and antimicrobial resistance) were included for analysis. There were 41 patients (41%) with 91 episodes of E. coli RUTI with highly related PFGE (HRPFGE) pattern (pattern similarity > 85%) and 58 (59%) patients with 137 episodes of E. coli RUTI with different molecular typing (DMT) pattern, respectively. There was a higher prevalence of phylogenetic group B2 and neuA and usp genes in HRPFGE group if the first episode of RUTI caused by HRPFGE E. coli strains and all episodes of RUTI caused by DMT E. coli strains were included for comparison. The uropathogenic E. coli (UPEC) strains in RUTI were more virulent in female gender, age < 20 years, neither anatomical/ functional defect nor immune dysfunction, and phylogenetic group B2. There were correlations among prior antibiotic therapy within 3 months and subsequent antimicrobial resistance in HRPFGE E. coli RUTI. The use of fluoroquinolones was more likely associated with subsequent antimicrobial resistance in most types of antibiotics., Conclusions: This study demonstrated that the uropathogens in RUTI were more virulent in genetically highly-related E. coli strains. Higher bacterial virulence in young age group (< 20 years) and patients with neither anatomical/functional defect nor immune dysfunction suggests that virulent UPEC strains are needed for the development of RUTI in healthy populations. Prior antibiotic therapy, especially the fluoroquinolones, within 3 months could induce subsequent antimicrobial resistance in genetically highly-related E. coli RUTI., (© 2023. The Author(s).)

Background: Neutralizing anti-interferon (IFN)-γ autoantibodies are linked to adult-onset immunodeficiency and opportunistic infections., Methods: To explore whether anti-IFN-γ autoantibodies are associated with disease severity of coronavirus disease 2019 (COVID-19), we examined the titers and functional neutralization of anti-IFN-γ autoantibodies in COVID-19 patients. In 127 COVID-19 patients and 22 healthy controls, serum titers of anti-IFN-γ autoantibodies were quantified using enzyme-linked immunosorbent assay, and the presence of autoantibodies was verified with immunoblotting assay. The neutralizing capacity against IFN-γ was evaluated with flow cytometry analysis and immunoblotting, and serum cytokines levels were determined using the MULTIPLEX platform., Results: A higher proportion of severe/critical COVID-19 patients had positivity for anti-IFN-γ autoantibodies (18.0%) compared with non-severe patients (3.4%, p < 0.01) or healthy control (HC) (0.0%, p < 0.05). Severe/critical COVID-19 patients also had higher median titers of anti-IFN-γ autoantibodies (5.01) compared with non-severe patients (1.33) or HC (0.44). The immunoblotting assay could verify the detectable anti-IFN-γ autoantibodies and revealed more effective inhibition of signal transducer and activator of transcription (STAT1) phosphorylation on THP-1 cells treated with serum samples from anti-IFN-γ autoantibodies-positive patients compared with those from HC (2.21 ± 0.33 versus 4.47 ± 1.64, p < 0.05). In flow-cytometry analysis, sera from autoantibodies-positive patients could also significantly more effectively suppress the STAT1 phosphorylation (median,67.28%, interquartile range [IQR] 55.2-78.0%) compared with serum from HC (median,106.7%, IQR 100.0-117.8%, p < 0.05) or autoantibodies-negative patients (median,105.9%, IQR 85.5-116.3%, p < 0.05). Multivariate analysis revealed that the positivity and titers of anti-IFN-γ autoantibodies were significant predictors of severe/critical COVID-19. Compared with non-severe COVID-19 patients, we reveal that a significantly higher proportion of severe/critical COVID-19 patients are positive for anti-IFN-γ autoantibodies with neutralizing capacity., Conclusion: Our results would add COVID-19 to the list of diseases with the presence of neutralizing anti-IFN-γ autoAbs. Anti-IFN-γ autoantibodies positivity is a potential predictor of severe/critical COVID-19., (© 2023. The Author(s).)

Objective: Neutralizing anti-interferon (IFN)-γ autoantibodies are linked to opportunistic infections (OIs). To explore the association between anti-IFN-γ autoantibodies and OIs in patients with adult-onset Still's disease (AOSD), we aimed to examine the ability of these autoantibodies to blockade signal transducer and activator of transcription (STAT1)-phosphorylation and chemokines production., Methods: Serum titers of anti-IFN-γ autoantibodies were quantified using ELISA in 29 AOSD and 22 healthy controls (HC). The detectable autoantibodies were verified with immunoblotting assay, and their neutralizing capacity against IFN-γ-signaling was evaluated with flow-cytometry analysis and immunoblotting. IFN-γ-mediated production of supernatant chemokines, including monocyte chemoattractant protein-1 (MCP-1) and IFN-γ inducible protein-10 (IP-10), were measured by ELISA., Results: Among 29 AOSD patients, high titers of anti-IFN-γ neutralizing autoantibodies were detectable in two patients with OIs. Immunoblotting assay revealed more effective inhibition of STAT1-phosphorylation in THP-1 cells treated with sera from autoantibody-positive AOSD patients (56.7 ± 34.79%) compared with those from HC (104.3 ±29.51%), which was also demonstrated in flow-cytometry analysis (47.13 ± 40.99 vs. 97.92 ± 9.48%, p < 0.05). Depleted serum IgG from anti-IFN-γ autoAbs-positive AOSD patients with OIs restored phosphorylated STAT-1 upon IFN-γ treatment. Sera from autoantibody-positive AOSD patients more effectively inhibited IFN-γ-mediated production of MCP-1 (45.65 pg/ml) and IP-10 (22.44 pg/ml) than sera from HC (263.1 pg/ml and 104.0 pg/ml, both p < 0.05). Serum samples showing the strongest inhibition of IFN-γ-signaling were from two patients with high-titer autoantibodies and OIs., Conclusion: AOSD patients have a high positive rate and titers of anti-IFN-γ autoantibodies. The remarkable blockade effect of high-titer autoantibodies on IFN-γ-mediated STAT1-phosphorylation and chemokines could make these patients susceptible to OIs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Liao, Chang, Yeo, Chou and Chen.)

(1) Background: This study aimed to determine the postoperative vermillion symmetry between the cleft and non-cleft sides of patients with unilateral cleft lip during the early and late postoperative periods. (2) Methods: 57 patients with complete and 38 with incomplete unilateral cleft lips operated on between 2010 and 2014 were retrospectively evaluated within 1 month (T1), 9 months to 1 ½ years (T2), and more than 4 years (T3). Vermilion heights of the cleft and non-cleft sides were measured from frontal photographs. The Cleft Lip Component Symmetry Index (CLCSI) was used to determine the symmetry of the cleft and non-cleft sides and was then analyzed. (3) Results: Among the 95 patients studied, vermilion height was excessive on the cleft side throughout the three time periods. There was a significant increase in CLCSI from T1 to T2 for both complete and incomplete types, and a significant increase from T1 to T3 only in the incomplete group and no difference from T2 to T3 for both the groups. (4) Conclusions: Even with efforts to obtain a symmetric vermilion height during the primary cheiloplasty, vermilion height excess was noted with time in complete and incomplete cleft types. Secondary revisional vermilion surgery may be performed to achieve symmetry.

Abnormal/cancerous cells within healthy epithelial tissues undergo apical extrusion to protect against carcinogenesis, although they acquire invasive capacity once carcinogenesis progresses. However, the molecular mechanisms by which cancer cells escape from apical extrusion and invade surrounding tissues remain elusive. In this study, we demonstrate a molecular mechanism for cell fate switching during epithelial cell competition. We found that during competition within epithelial cell layers, Src transformation promotes maturation of focal adhesions and degradation of extracellular matrix. Src-transformed cells underwent basal delamination by Src activation within sphingolipid/cholesterol-enriched membrane microdomains/lipid rafts, whereas they were apically extruded when Src was outside of lipid rafts. A comparative analysis of contrasting phenotypes revealed that activation of the Src-STAT3-MMP axis through lipid rafts was required for basal delamination. CUB-domain-containing protein 1 (CDCP1) was identified as an Src-activating scaffold and as a Met regulator in lipid rafts, and its overexpression induced basal delamination. In renal cancer models, CDCP1 promoted epithelial-mesenchymal transition-mediated invasive behavior by activating the Src-STAT3-MMP axis through Met activation. Overall, these results suggest that spatial activation of Src signaling in lipid rafts confers resistance to apical extrusion and invasive potential on epithelial cells to promote carcinogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Adult-onset Still's disease (AOSD) is an autoinflammatory disease driven by the innate immune response. Given the ambiguity in clinical presentation and lack of specific diagnostic biomarkers, AOSD diagnosis is usually delayed in the early stage. Because AOSD is a rare disease with clinical heterogeneity, there is no consensus on its treatment currently. This review summarizes the current research evidence regarding the pathogenic role and the diagnostic or therapeutic potential of interleukin (IL)-18 in AOSD., Areas Covered: We searched the MEDLINE database using the PubMed interface and reviewed English-language literature from 1971 to 2022. This review focusing on IL-18 discusses its pathogenic role and clinical implications in AOSD., Expert Opinion: NLRP3-inflammasome activation with IL-18 overproduction plays a pathogenic role in AOSD. IL-18 is closely linked to the clinical manifestations and disease activity of AOSD and may be a diagnostic biomarker. Given its pathogenic role in AOSD, IL-18 could become a potential therapeutic target. IL-18 binding protein (IL-18BP) negatively regulates the biological activity of IL-18 by inhibiting IL-18 signaling, and a clinical trial revealed that IL-18BP (Tadekinig alfa) treatment was well-tolerated and effective for AOSD. Recently, monoclonal antibodies against IL-18 have been under evaluation in a phase 1b trial.

Botulinum toxin type A (BTA) injections into the subjacent orbicularis oris muscle have been shown to improve appearance and produce narrower cheiloplasty scars. This study was performed to determine the effect of BTA injected at different sites on the unilateral cleft lip scar and cleft side nostril width. A double-blind, randomized prospective trial was conducted involving 64 consecutive patients with unilateral cleft lip undergoing primary cheiloplasty between September 2016 and January 2019. The patients were randomized to receive BTA injections either into the subjacent orbicularis oris muscle (4 points group) or into the bilateral nasolabial fold region (6 points group) during cheiloplasty. The scars were assessed by photographic scar width measurements and Vancouver scar scale assessment tool. The cleft side nostril width was compared to the non-cleft side width. Fifty-six patients completed the trial, 24 in the 4 points group and 31 in the 6 points group. There was no significant difference in scar width or nostril width measurements between the groups at the end of follow-up. The Vancouver scar scale assessment was also similar between the groups. There was no significant difference in scar width or nostril width measurements after cleft lip repair between patients treated with botulinum toxin injections to the subjacent orbicularis oris muscle and patients treated with injections in the nasolabial region., (Copyright © 2021 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Learning analysis provides a new opportunity for the development of online education, and has received extensive attention from scholars at home and abroad. How to use data and models to predict learners' academic success or failure and give teaching feedback in a timely manner is a core problem in the field of learning analytics. At present, many scholars use key learning behaviors to improve the prediction effect by exploring the implicit relationship between learning behavior data and grades. At the same time, it is very important to explore the association between categories and prediction effects in learning behavior classification. This paper proposes a self-adaptive feature fusion strategy based on learning behavior classification, aiming to mine the effective E-learning behavior feature space and further improve the performance of the learning performance prediction model. First, a behavior classification model (E-learning Behavior Classification Model, EBC Model) based on interaction objects and learning process is constructed; second, the feature space is preliminarily reduced by entropy weight method and variance filtering method; finally, combined with EBC Model and a self-adaptive feature fusion strategy to build a learning performance predictor. The experiment uses the British Open University Learning Analysis Dataset (OULAD). Through the experimental analysis, an effective feature space is obtained, that is, the basic interactive behavior (BI) and knowledge interaction behavior (KI) of learning behavior category has the strongest correlation with learning performance.And it is proved that the self-adaptive feature fusion strategy proposed in this paper can effectively improve the performance of the learning performance predictor, and the performance index of accuracy(ACC), F1-score(F1) and kappa(K) reach 98.44%, 0.9893, 0.9600. This study constructs E-learning performance predictors and mines the effective feature space from a new perspective, and provides some auxiliary references for online learners and managers.

Psoriasis is an immune-mediated skin disease with a worldwide prevalence of 2-4% that causes scaling erythematous skin lesions. It is a chronic relapsing and complex multifactorial disease that often necessitates long-term therapy. Despite various novel therapies, psoriasis remains a treatable but non-curable disease. Because the antitussive medication dextromethorphan (DXM) can inhibit murine bone marrow and human monocytes and slow the progression of arthritis in mice with type II collagen-induced arthritis, we explored whether the oral administration of DXM to mice with imiquimod (IMQ)-induced psoriasis can effectively alleviate psoriasis symptoms and improve immune regulation. Herein, we examined the therapeutic effects of DXM on psoriasis and its potential mechanisms of action in an IMQ-induced psoriasis mice model. We found that an oral dose of DXM (10 mg/kg) could more significantly reduce psoriasis symptoms compared with intraperitoneal injection. Seven days after the oral administration of DXM, the Psoriasis Area and Severity Index (PASI) score was significantly decreased compared with that in the vehicle group. Furthermore, DXM treatment also significantly ameliorated the psoriasis symptoms and the histopathological features of psoriasis, including stratum corneum thickening, desquamation, and immune cell infiltration. Additionally, DXM reduced the mRNA levels of the cytokines TNF-α, IL-6, IL-17A, and IL-22 in skin and the percentage of IL-17A and IL-22 producing T cell receptor γδ T cells (TCRγδT). Taken together, our research demonstrated that DXM could inhibit keratinocyte proliferation and alleviate psoriasis symptoms, which suggests the potential application of DXM in the treatment of chronic inflammation and autoimmune diseases.

Patients with immune-mediated inflammatory diseases (IMID) were seldom enrolled in the studies of SARS-CoV-2 vaccines, and real-world data regarding the immunogenicity of different types of vaccines is limited. We aimed to assess the immunogenicity and safety of three types of vaccines (AZD1222, mRNA-1273, and BNT162b2) in 253 patients with IMID and 30 healthcare workers (HCWs). Plasma levels of IgG-antibody against SARS-CoV-2 targeting the receptor-binding domain of spike protein (anti-S/RBD-IgG) were determined by chemiluminescent immunoassay 3-4 weeks after the first-dose and second-dose vaccination. The positive rate and titers of anti-S/RBD-IgG were significantly higher in mRNA-1273 or BNT162b2 than in the AZD1222 vaccine. Immunogenicity was augmented after the second dose of any vaccine type in all IMID patients, suggesting that these patients should complete the vaccination series. Anti-S/RBD-IgG titers after first-dose vaccination were significantly lower in RA patients than pSS patients, but there was no significant difference after second-dose vaccination among five groups of IMID patients. The positive rate and titers of anti-S/RBD-IgG were significantly lower in patients receiving abatacept/rituximab therapy than in those receiving other DMARDs. All three SARS-CoV-2 vaccines showed acceptable safety profiles, and the common AEs were injection site reactions. We identified SLE as a significant predictor of increased autoimmunity and would like to promote awareness of the possibility of autoimmunity following vaccination.