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Bo-Yang Tsai,1,* Pei-Jane Tsai,1– 4,* Ching-Chi Lee,5,6 Chun-Wei Chiu,7 Yi-Hsin Lai,4 Jen-Chieh Lee,6 Wen-Chien Ko,6,8 Yuan-Pin Hung6– 9 1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Centers of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; 5Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 6Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 7Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan; 8Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 9Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan*These authors contributed equally to this workCorrespondence: Yuan-Pin Hung; Wen-Chien Ko, Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan, Email yuebin16@yahoo.com.tw; winston3415@gmail.comIntroduction: Nucleotide-binding domain leucine-rich repeat protein (NLRP) is critical in the inflammasome-activation pathway, which is important for host survival and the clearance of Clostridioides difficile. Therefore, the influence of NLRP1 polymorphisms on C. difficile colonization (CdC) or infection (CDI) was analyzed.Materials and Methods: A prospective cohort study consisted of hospitalized adults was conducted from January 2011 to January 2013. Single nucleotide polymorphisms (SNPs) of NLRP1, including rs12150220, rs2670660, rs6502867, rs878329, rs8182352, rs3744717, and rs11078571, were incorporating in analyses. The episodes of CdC and CDI were the primary and secondary outcome, respectively.Results: Of the total of 509 eligible patients, 376 (73.9%) had neither CdC nor CDI, 104 (21.8%) had CdC without developing CDI, and 29 (4.3%) developed CDI during the study period. Through multivariate analyses, comorbid diabetes mellitus (adjusted odds ratio [AOR] 1.59, P=0.04) and CC genotype in NLRP1 rs3744717 (AOR 1.70, P=0.02) were recognized as the risk factor of CdC. After adjusting the independent predictors of CDI, in terms of comorbid diabetes mellitus (AOR 3.18, P=0.005) and prior exposure to ceftazidime/ceftriaxone (AOR 2.87, P=0.04) or proton pump inhibitors (AOR 3.86, P=0.001), patients with CC+GC genotype in NLRP1, rs878329 (AOR 2.39, P=0.03) remained a higher risk of CDI.Conclusion: For hospitalized adults, the association of CC genotype in NLRP1 rs3744717 and CdC as well as the CC+GC genotype in NLRP1 rs878329 and CDI was respectively evidenced. We believed the prompt identification of patients having specific genotype in NLRP1 would prevent and improve the quality of care in CDI.Keywords: Clostridioides difficile infection, colonization, nucleotide-binding domain leucine-rich repeat protein 1, NLRP1, inflammasome, polymorphism

Ching-Chi Lee,1– 3,* Chun-Wei Chiu,4,* Jen-Chieh Lee,1 Pei-Jane Tsai,5– 7 Wen-Chien Ko,1,8 Yuan-Pin Hung1,4,8,9 1Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan; 2Graduate Institute of Medical Sciences, College of Health Sciences, Chang Jung Christian University, Tainan, 711, Taiwan; 3Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan; 4Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, 700, Taiwan; 5Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, College of Medicine, Tainan, 704, Taiwan; 6Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan; 7Centers of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; 8Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan; 9Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan*These authors contributed equally to this workCorrespondence: Yuan-Pin Hung, Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan, Email yuebin16@yahoo.com.tw Wen-Chien Ko, Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, Email winston3415@gmail.comIntroduction: The risk factors and clinical impact of carbapenem-resistant Enterobacterales (CRE) coinfection among hospitalized patients with Clostridioides difficile infection (CDI) were analyzed in this study.Materials and Methods: A clinical study was performed at the medical wards of Tainan Hospital, Ministry of Health and Welfare in southern Taiwan. Patients with CDI between January 2013 and April 2020 were included.Results: Among 238 patients included for analysis, 22 (9.2%) patients developed CRE coinfections within 14 days before or after the onset of CDI. CDI patients with CRE coinfection had longer hospitalization stays (103.0 ± 97.0 days vs 42.5 ± 109.6 days, P = 0.01) than those without CRE coinfection. In the multivariate analysis, age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.01– 1.10, P = 0.02) was independently associated with CRE coinfection. In contrast, underlying old stroke (OR 0.15, 95% CI 0.03– 0.70, P = 0.02) was negatively linked to CRE coinfection.Conclusion: Among patients with CDI, CRE coinfections were associated with prolonged hospitalization for CDI. Age was an independent risk factor for CRE coinfection among patients with CDI.Keywords: carbapenem-resistant Enterobacterales, Clostridioides difficile infection, age, hypertension, recurrence, prolonged hospitalization

Ching-Chi Lee,1,2,&ast; Jen-Chieh Lee,2,&ast; Chun-Wei Chiu,3 Pei-Jane Tsai,4– 6 Wen-Chien Ko,2,7 Yuan-Pin Hung2,3,7,8 1Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan; 2Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan; 3Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, 700, Taiwan; 4Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan; 5Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 6Centers of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; 7Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan; 8Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan&ast;These authors contributed equally to this workCorrespondence: Yuan-Pin Hung, Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, 700, Taiwan, Email yuebin16@yahoo.com.tw Wen-Chien Ko, Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan, Email winston3415@gmail.comIntroduction: The influence of corticosteroid therapy before or after the onset of Clostridioides difficile infections (CDIs) on the clinical outcomes of adults with hospital-onset CDIs was investigated.Materials and Methods: A clinical study was conducted on the medical wards of a teaching hospital between January 2013 and April 2020. Adults (aged ≥ 20 years) with hospital-onset CDIs (ie, symptom onset at least 48 hours after hospitalization) were included. “Corticosteroid therapy during acute CDIs” was defined as the receipt of a corticosteroid at the prednisolone equivalent (PE) dose of ≥ 10 mg for at least 48 hours within one week after the CDI diagnosis. “Prior corticosteroid exposure” was defined as the receipt of a corticosteroid at the PE dose of ≥ 5 mg PE for at least 48 hours within one month before the CDI diagnosis.Results: Of the 243 adults with hospital-onset CDIs, patients (44, 18.1%) who received corticosteroid therapy during acute CDIs were more likely to have prior corticosteroid exposure (86.4% vs 11.9%, P < 0.001) and CDI episodes in intensive care units (31.8% vs 10.8%, P =0.001). Of note, a crucial association between corticosteroid therapy during acute CDIs and CDI recurrence was evidenced (13.6% vs 1.5%, P =0.002). Prior corticosteroid exposure was not associated with favorable CDI outcomes in terms of successful treatment (78.3% vs 74.9%, P =0.89), in-hospital crude mortality (17.4% vs 24.0%, P =0.61), or CDI recurrence (4.3% vs 5.3%, P = 1.00). However, for 177 patients without prior corticosteroid exposure, corticosteroid therapy during acute CDIs was linked to a higher proportion of CDI recurrence (33.3% vs 5.3%, P =0.046).Conclusion: Corticosteroid therapy during acute CDIs might impact the recurrence of CDIs, particularly in those with a lack of prior corticosteroid exposure.Keywords: steroid, prednisolone, Clostridioides difficile, diarrhea, recurrence, intensive care unit, immunosuppression

Ching-Chi Lee,1,2,&ast; Jen-Chieh Lee,2,&ast; Chun-Wei Chiu,3 Pei-Jane Tsai,4– 6 Wen-Chien Ko,2,7 Yuan-Pin Hung2,3,7 1Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan; 2Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan; 3Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, 700, Taiwan; 4Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan; 5Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 6Centers of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; 7Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan&ast;These authors contributed equally to this workCorrespondence: Yuan-Pin Hung, Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, 700, Taiwan, Email yuebin16@yahoo.com.tw Wen-Chien Ko, Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan, Email winston3415@gmail.comIntroduction: A leukocyte count ≥ 15,000 cells/mL and serum creatinine of > 1.5 mg/dL have been reported as two important predictors of severe CDI. However, the association of the differential ratios of blood leukocytes, and the prognosis of Clostridioides difficile infection (CDI) is not clear.Materials and Methods: A clinical study was conducted at medical wards of Tainan Hospital, Ministry of Health and Welfare in southern Taiwan between January 2013 and April 2020. Hospitalized adults (aged ≥ 20 years) with hospital-onset CDI (ie, symptom onset after at least 48 hours of admission) were included.Results: A total of 235 adults with an average age of 75.7 years and female predominance (51.5%), including 146 (62%) adults with non-severe CDI and 87 (38%) severe CDI, were included for analysis. Patients with severe CDI had a higher crude in-hospital mortality rate than patients with non-severe CDI (35.6% vs 18.5%, P = 0.005). Multivariate analysis revealed no association between a leukocyte count > 15,000 cell/mL at the onset of CDI and in-hospital mortality (odds ratio [OR] 1.66, P = 0.21). In contrast, a neutrophil ratio > 75% (OR 2.65, P = 0.02), serum creatinine > 1.5 mg/L (OR 3.42, P = 0.03), and CDI caused by isolates harboring the tcdC gene (OR 3.54, P = 0.02) were independently associated with in-hospital mortality. Patients with a neutrophil ratio > 85%, 80– 85%, or 75– 80% of serum leukocytes had a higher mortality rate (34.8%, 30.3%, or 34.4%, respectively) than patients with a neutrophil ratio of 70– 75% or ≤ 75% (12.5% or 13.9%, respectively).Conclusion: Serum creatinine > 1.5 mg/L, a high neutrophil ratio of blood leukocytes (> 75%), and the causative C. difficile harboring the tcdC gene was independent prognostic predictors in hospitalized adults with CDI.Keywords: Clostridioides difficile, leukocyte, differential ratio, neutrophil, prognosis, mortality

Yuan-Pin Hung,1–3,* Pei-Jane Tsai,4,* Yuan-Ti Lee,5,6 Hung-Jen Tang,7 Hsiao-Ju Lin,1–3 Hsiu-Chuan Liu,1 Jen-Chieh Lee,2 Bo-Yang Tsai,4 Po-Ren Hsueh,8 Wen-Chien Ko2,9,10 1Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan; 2Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; 3Graduate Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan; 4Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 5Institute of Medicine and School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 6Division of Infectious Diseases, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 7Department of Internal Medicine, Chi-Mei Hospital, Tainan, Taiwan; 8Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; 9Center of Infection Control, National Cheng Kung University Hospital, Tainan, Taiwan; 10Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan *These authors contributed equally to this work Objectives: The information of antimicrobial susceptibility, toxin gene, and ribotype distribution of toxigenic Clostridium difficile isolates in Taiwan remain limited. Patients and methods: The study was conducted from January 2015 to December 2016 in 5 hospitals in Taiwan. Adults aged ≥20 years with a hospital stay for >5 days were included, and those with colectomy or intestinal infection due to other enteropathogens were excluded. Multiplex PCR was used to detect tcdA, tcdB, cdtA, cdtB, and tcdC deletions, and antimicrobial susceptibility for metronidazole, vancomycin, doxycycline, and tigecycline was investigated. Ribotypes of those isolates with tcdC deletion and tcdA+/tcdB+ were determined. Results: Of 1112 C. difficile isolates collected from adults at 5 hospitals, 842 were toxigenic, including 749 (89.0%) tcdA+/tcdB+ isolates and 93 (11.0%) tcdA−/tcdB+. Of the toxigenic isolates, 76 (9.0%) had a tcdC deletion and were cdtA+/cdtB+, indicative of hypervirulence, and RT078 lineage, including RT126, RT127, and RT078, predominated (n=53, 76.3%). Similar to the susceptibility data in Asia countries, metronidazole or vancomycin resistance was rare, noted in 1.2% or 2.1%, respectively. Reduced doxycycline susceptibility (minimum inhibitory concentration [MIC] of ≥8 mg/L) was more common among RT078 lineage than non-RT078 lineage (75.9%, 44/58 vs 6.0%, 47/784; P

High relapse rate during abstinence is a defining characteristic of drug addiction. We previously found that opioid seeking progressively increases after voluntary abstinence induced by adverse consequences of oxycodone seeking (crossing an electric barrier). Functional MRI revealed that this effect is associated with changes in functional connectivity within medial orbitofrontal cortex (mOFC)- and dorsomedial striatum (DMS)-related circuits. Here, we used a pharmacological manipulation and fMRI to determine the causal role of mOFC and DMS in oxycodone seeking after electric barrier-induced abstinence. We trained rats to self-administer oxycodone (6 h/day, 14 days). Next, we induced voluntary abstinence by exposing them to an electric barrier for 2 weeks. We inactivated the mOFC and DMS with muscimol+baclofen (GABA a and GABA b receptor agonists) and then tested them for relapse to oxycodone seeking on abstinence days 1 or 15 without the electric barrier or oxycodone. Inactivation of DMS (p < 0.001) but not mOFC decreased oxycodone seeking before or after electric barrier-induced abstinence. Functional MRI data revealed that DMS inactivation decreased cerebral blood volume levels in DMS and several distant cortical and subcortical regions (corrected p < 0.05). Furthermore, functional connectivity of DMS with several frontal, sensorimotor, and auditory regions significantly increased after DMS inactivation (corrected p < 0.05). Finally, an exploratory analysis of an existing functional MRI dataset showed that DMS inactivation restored voluntary abstinence-induced longitudinal changes in DMS functional connectivity with these brain regions (p < 0.05). Results indicate a role of DMS and related brain circuits in oxycodone seeking after voluntary abstinence, suggesting potential targets for intervention., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: This study comprehensively investigates the changes in healthcare utilization among chronic patients with regular outpatient visits to hospitals after the occurrence of Covid-19. The research examines whether patients altered their originally regular medical attendance frequencies due to the pandemic and explores potential negative impacts on the health conditions of those irregular attendees post-pandemic., Methods: Data for this study were sourced from a database at a medical center in Taiwan. The subjects were chronic patients with regular hospital outpatient visits before the Covid-19 outbreak. The study tracked medical utilization patterns from 2017 to 2022 for different patient characteristics and outpatient behaviors, employing statistical methods such as Repeated Measures ANOVA and Generalized Estimating Equation to analyze changes in healthcare utilization and health status during the post-pandemic period., Results: The results reveal that, compared to the regular group, chronic patients with irregular outpatient visits during the post-pandemic period exhibited a decrease of 5.85 annual outpatient visits, a reduction of NT$20,290.1 in annual medical expenses, and a significantly higher abnormality rate in average biochemical test results by 0.9%., Conclusions: The findings contribute to understanding the impact of the Covid-19 pandemic on healthcare utilization and health conditions among outpatient chronic disease populations. In response to the new medical landscape in the post-pandemic era, proactive suggestions are made, including providing telemedicine outpatient services and referral-based medical care to meet the needs of the target population, ensuring a continuous and reassuring healthcare model for chronic patients, and mitigating the operational impacts of public health emergencies on hospitals., (© 2024. The Author(s).)

Introduction: Antimicrobial therapy plays a crucial role in the management of CDI patients. However, the standard agent for treating CDIs is limited to oral fidaxomicin or vancomycin. For patients made nil by mouth, there is a clinically urgent and essential need to develop an intravenous antibiotic., Methods: For C. difficile with the lowest MIC of nemonoxacin and vancomycin, the inhibitory effects were tested using the kinetic time-kill assay and ex vivo co-culture model. The effectiveness of nemonoxacin and vancomycin in inhibiting spore germination, the sporicidal activity, and the treatment of mice with CDIs were compared., Results: For clinical isolates and laboratory strains, lower MICs of nemonoxacin against C. difficile than levofloxacin and ciprofloxacin were observed, even in those harboring point mutations in the quinolone-resistance determining region. Although nemonoxacin failed to suppress spore outgrowth and germination in C. difficile , it exhibited an effective inhibitory effect against C. difficile in the kinetic time-kill assay and the ex vivo co-culture model. Mice receiving intraperitoneal nemonoxacin had less weight loss, higher cecum weight, a longer colon length, and lower expression of the tcdB gene, compared with untreated mice. Notably, there were no significant differences observed in weight loss, cecum weight, colon length, or tcdB gene expression between mice treated with vancomycin and those treated with any dose of nemonoxacin. Similarly, no significant differences were found between mice receiving combination therapy of intraperitoneal nemonoxacin plus oral vancomycin and those treated with intraperitoneal nemonoxacin or oral vancomycin alone., Discussion: The potential role of nemonoxacin, which can be administered parenterally, for treating CDIs was evidenced through the in vitro , ex vivo , and mouse models., 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 Lee, Yan, Wu, Ko, Tsai and Hung.)

Phosphatase and tensin homolog (PTEN) is vital for B cell development, acting as a key negative regulator in the PI3K signaling pathway. We used CD23-cre to generate PTEN-conditional knockout mice (CD23-cKO) to examine the impact of PTEN mutation on peripheral B cells. Unlike mb1-cre-mediated PTEN deletion in early B cells, CD23-cKO mutants exhibited systemic inflammation with increased IL-6 production in mature B cells upon CpG stimulation. Inflammatory B cells in CD23-cKO mice showed elevated phosphatidylinositol 3-phosphate [PI(3)P] levels and increased TLR9 endosomal localization. Pharmacological inhibition of PI(3)P synthesis markedly reduced TLR9-mediated IL-6. Single-cell RNA-sequencing (RNA-seq) revealed altered endocytosis, BANK1, and NF-κB1 expression in PTEN-deficient B cells. Ectopic B cell receptor (BCR) expression on non-inflammatory mb1-cKO B cells restored BANK1 and NF-κB1 expression, enhancing TLR9-mediated IL-6 production. Our study highlights PTEN as a crucial inflammatory checkpoint, regulating TLR9/IL-6 axis by fine-tuning PI(3)P homeostasis. Additionally, BCR downregulation prevents the differentiation of inflammatory B cells in PTEN deficiency., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

This study investigated particle and volatile organic compound (VOC) emission rates (ER) from 3D pens, which are increasingly popular in children's toys. Nine filaments and two 3D pens were evaluated using a flow tunnel, a scanning mobility particle sizer, a proton-transfer-reaction time-of-flight mass spectrometer for particles, and a thermal desorption-gas chromatography-mass spectrometer for VOCs. Results showed that the ERs varied with the pen type, filament, and brand. The particle ER was highest for acrylonitrile butadiene styrene (ABS), followed by polylactic acid (PLA) and polycaprolactone (PCL). Notably, ERs of 83 % and 33 % of ABS and PLA filaments exceeded the maximum allowable particle ER (MAER; 5 × 10 9 particles/min) for 3D printers but were lower than the VOC MAER (173 μg/min in the office). Different filaments emitted diverse VOCs; ABS emitted styrene and benzene, PLA emitted lactide, and PCL emitted phenol. While particle ERs from 3D pens were comparable to those from printers, the total VOC ERs from 3D pens were slightly lower. Caution is warranted when using 3D pens because of potential health risks, especially their prolonged use, proximity to the breathing zone, and usage by children. This study highlights the need for considering particles and VOCs when assessing the safety of 3D pens, emphasizing awareness of potential hazards, particularly in child-oriented settings., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chungsik Yoon reports financial support was provided by Korea Environmental Industry and Technology Institute. Chungsik Yoon reports financial support was provided by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea. If there are other authors, they 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. Published by Elsevier B.V.)

Background: Though the artificial neural network (ANN) technique has been used to predict noise-induced hearing loss (NIHL), the established prediction models have primarily relied on cross-sectional datasets, and hence, they may not comprehensively capture the chronic nature of NIHL as a disease linked to long-term noise exposure among workers., Methods: A comprehensive dataset was utilized, encompassing eight-year longitudinal personal hearing threshold levels (HTLs) as well as information on seven personal variables and two environmental variables to establish NIHL predicting models through the ANN technique. Three subdatasets were extracted from the afirementioned comprehensive dataset to assess the advantages of the present study in NIHL predictions., Results: The dataset was gathered from 170 workers employed in a steel-making industry, with a median cumulative noise exposure and HTL of 88.40 dBA-year and 19.58 dB, respectively. Utilizing the longitudinal dataset demonstrated superior prediction capabilities compared to cross-sectional datasets. Incorporating the more comprehensive dataset led to improved NIHL predictions, particularly when considering variables such as noise pattern and use of personal protective equipment. Despite fluctuations observed in the measured HTLs, the ANN predicting models consistently revealed a discernible trend., Conclusions: A consistent correlation was observed between the measured HTLs and the results obtained from the predicting models. However, it is essential to exercise caution when utilizing the model-predicted NIHLs for individual workers due to inherent personal fluctuations in HTLs. Nonetheless, these ANN models can serve as a valuable reference for the industry in effectively managing its hearing conservation program., Competing Interests: All authors declare that they have no conflict of interest., (© 2024 Occupational Safety and Health Research Institute. Published by Elsevier B.V. on behalf of Institute, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency.)

Introduction: Angiotensin-converting enzyme 2 (ACE2) played an important role in the renin-angiotensin-aldosterone system (RAAS) and it was proved to be renoprotective in renal disease. Urinary angiotensin-converting enzyme 2 (uACE2) has been shown to reflect renal injury in human and experimental studies, but its role in feline kidney disease remains unknown., Aims: Our objectives involve comparing uACE2 concentrations and activities in cats across CKD stages with healthy controls, investigating the relationship between uACE2 concentrations, activities, and clinicopathological data in feline CKD patients, and assessing the predictive abilities of both for CKD progression., Methods: A retrospective, case-control study. The concentration and activity of uACE2 were measured by commercial ELISA and fluorometric assay kits, respectively. The concentration was adjusted to give uACE2 concentration-to-creatinine ratios (UACCRs)., Results: In total, 67 cats consisting of 24 control and 43 chronic kidney disease (CKD), including 24 early-stage CKD and 19 late-stage CKD, were enrolled in this study. UACCR values were significantly higher in both early-stage (2.100 [1.142-4.242] x 10 -6 ) and late-stage feline CKD (4.343 [2.992-5.0.71] x 10 -6 ) compared to healthy controls (0.894 [0.610-1.076] x 10 -6 ; p  < 0.001), and there was also significant difference between-early stage group and late-stage group ( p = 0.026). Urinary ACE2 activity (UAA) was significantly lower in CKD cats (1.338 [0.644-2.755] x pmol/min/ml) compared to the healthy cats (7.989 [3.711-15.903] x pmol/min/ml; p  < 0.001). UACCR demonstrated an independent, positive correlation with BUN ( p  < 0.001), and UAA exhibited an independent, negative correlation with plasma creatinine ( p  < 0.001). Both UACCR and UAA did not yield significant results in predicting CKD progression based on the ROC curve analysis., Conclusion and Clinical Importance: uACE2 concentration and activity exhibit varying changes as renal function declines, particularly in advanced CKD cats., 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 Kuo, Hsu, Wu, Jan, Tsai and Lee.)

Background: A new sublineage of emm1 group A Streptococcus (GAS), M1 UK , has emerged in Europe, North America, and Australia. Notably, a significant portion of emm1 isolates in Asia, particularly in Hong Kong and mainland China, acquired scarlet fever-associated prophages following the 2011 Hong Kong scarlet fever outbreak. However, the presence of the M1 UK sublineage has not yet been detected in Asia., Methods: This study included 181 GAS isolates (2011-2021). The emm type of these isolates were determined, and 21 emm1 isolates from blood or pleural fluid (2011-2021) and 10 emm1 isolates from throat swabs (2016-2018) underwent analysis. The presence of the scarlet fever-associated prophages and the specific single nucleotide polymorphisms of the M1 UK clone were determined by polymerase chain reaction and the genome sequencing., Results: The M1 UK lineage strains from throat swab and blood samples were identified. One of the M1 UK strain in Taiwan carried the scarlet fever-associated prophage and therefore acquired the ssa, speC, and spd1 toxin repertoire. Nonetheless, the increase of M1 UK was not observed until 2021, and there was a reduction in the diversity of emm types in 2020-2021, possibly due to the COVID-19 pandemic restriction policies in Taiwan., Conclusions: Our results suggested that the M1 UK lineage clone has introduced in Taiwan. In Taiwan, the COVID-19 restrictions were officially released in March 2023; therefore, it would be crucial to continuously monitor the M1 UK expansion and its related diseases in the post COVID-19 era., Competing Interests: Declaration of conflict of interest The authors affirm no conflict of interest relative to any source of funding, sponsorship, or financial benefit., (Copyright © 2024. Published by Elsevier B.V.)

Background: This study evaluated the utility of using Accreditation Council for Graduate Medical Education (ACGME) Milestones as a formative assessment tool for the fifth- and sixth-grade medical students' performance in their internal medicine (IM) clerkship and the same students' performance in their post-graduate year (PGY) IM training., Methods: Retrospective data were collected from 65 medical students completing the two-year IM clerkship in the academic years 2019 and 2020 and 26 of the above students completing their PGY-1 training at the same university hospital in the academic year 2021. Data included the assessment results of 7 of the ACGME IM Milestones, information on admitted patients assigned to the students, and surveys of the students' satisfaction., Results: The analysis included 390 assessment results during the IM clerkship and 78 assessment results during the PGY-1 training. Clinical teachers commonly rated level 3 to medical students in the IM clerkship, with PC-2 subcompetency receiving the lowest rating among seven subcompetencies. The levels of most subcompetencies showed stationary in the two-year IM clerkship. Significant improvement was observed in all subcompetencies during the PGY-1 training. The medical students in the second-year IM clerkship expressed higher satisfaction with implementing Milestones than in their first-year IM clerkship and perceived Milestones assessments' usefulness as learning feedback., Conclusions: Using ACGME Milestones as a formative assessment tool in the IM clerkship yielded promising outcomes. Longitudinal follow-up of subcompetencies facilitated tracking students' development and providing constructive feedback., (© 2024. The Author(s).)

Background: Occupational exposure to artificial stone, a popular material used for countertops, can cause accelerated silicosis, but the precise relationship between silica dose and disease development is unclear., Objectives: This study evaluated the impact of silica exposure on lung function and chest imaging in artificial stone manufacturing workers., Methods: Questionnaire and spirometry assessments were administered to workers in two plants. A high-exposure subset underwent further evaluation, including chest CT and DLco. Weighting factors, assigned as proxies for silica exposure, were based on work tasks. Individual cumulative exposures were estimated using area concentration measurements and time spent in specific areas. Exposure-response associations were analyzed using linear and logistic regression models., Results: Among 65 participants, the mean cumulative silica exposure was 3.61 mg/m 3 -year (range 0.0001 to 44.4). Each 1 mg/m 3 -year increase was associated with a 0.46% reduction in FVC, a 0.45% reduction in FEV1, and increased lung function abnormality risk (aOR = 1.27, 95% CI = 1.03-1.56). Weighting factors correlated with cumulative exposures (Spearman correlation = 0.59, p < 0.0001), and weighted tenure was associated with lung function abnormalities (aOR = 1.04, 95% CI = 1.01-1.09). Of 37 high-exposure workers, 19 underwent chest CT, with 12 (63%) showing abnormal opacities. Combining respiratory symptoms, lung function, and chest X-ray achieved 91.7% sensitivity and 75% specificity for predicting chest CT abnormalities., Conclusion: Lung function and chest CT abnormalities occur commonly in artificial stone workers. For high-exposure individuals, abnormalities on health screening could prompt further chest CT examination to facilitate early silicosis detection., (© 2024. The Author(s).)

Clostridioides difficile is a Gram-positive, anaerobic, and spore-forming bacterial member of the human gut microbiome. The primary virulence factors of C. difficile are toxin A and toxin B. These toxins damage the cell cytoskeleton and cause various diseases, from diarrhea to severe pseudomembranous colitis. Evidence suggests that bacteriophages can regulate the expression of the pathogenicity locus (PaLoc) genes of C. difficile. We previously demonstrated that the genome of the C. difficile RT027 strain NCKUH-21 contains a prophage-like DNA sequence, which was found to be markedly similar to that of the φCD38-2 phage. In the present study, we investigated the mechanisms underlying the φNCKUH-21-mediated regulation of the pathogenicity and the PaLoc genes expression in the lysogenized C. difficile strain R20291. The carriage of φNCKUH-21 in R20291 cells substantially enhanced toxin production, bacterial motility, biofilm formation, and spore germination in vitro. Subsequent mouse studies revealed that the lysogenized R20291 strain caused a more severe infection than the wild-type strain. We screened three φNCKUH-21 genes encoding DNA-binding proteins to check their effects on PaLoc genes expression. The overexpression of NCKUH-21&#95;03890, annotated as a transcriptional regulator (phage transcriptional regulator X, PtrX), considerably enhanced toxin production, biofilm formation, and bacterial motility of R20291. Transcriptome analysis further confirmed that the overexpression of ptrX led to the upregulation of the expression of toxin genes, flagellar genes, and csrA. In the ptrX-overexpressing R20291 strain, PtrX influenced the expression of flagellar genes and the sigma factor gene sigD, possibly through an increased flagellar phase ON configuration ratio., Competing Interests: Declaration of Interest Statement The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Severe soft tissue infections caused by Aeromonas dhakensis, such as necrotizing fasciitis or cellulitis, are prevalent in southern Taiwan and around the world. However, the mechanism by which A. dhakensis causes tissue damage remains unclear. Here, we found that the haemolysin Ahh1, which is the major virulence factor of A. dhakensis, causes cellular damage and activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome signalling pathway. Deletion of ahh1 significantly downregulated caspase-1, the proinflammatory cytokine interleukin 1β (IL-1β) and gasdermin D (GSDMD) and further decreased the damage caused by A. dhakensis in THP-1 cells. In addition, we found that knockdown of the NLRP3 inflammasome confers resistance to A. dhakensis infection in both THP-1 NLRP3 -/- cells and C57BL/6 NLRP3 -/- mice. In addition, we demonstrated that severe soft-tissue infections treated with antibiotics combined with a neutralizing antibody targeting IL-1β significantly increased the survival rate and alleviated the degree of tissue damage in model mice compared control mice. These findings show that antibiotics combined with therapies targeting IL-1β are potential strategies to treat severe tissue infections caused by toxin-producing bacteria., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Avanafil is a second-generation phosphodiesterase type 5 (PDE5) inhibitor, and offers a rapid onset of action (15 minutes). Its real-world data, including treatment satisfaction, are still lacking., Aim: The study sought to investigate the treatment outcomes of avanafil and the factors impacting treatment satisfaction in a real-world setting., Methods: Between November 2021 and February 2023, erectile dysfunction (ED) patients prescribed avanafil were consecutively enrolled in this phase 4, open-label, cross-sectional, observational study. At each follow-up visit (4-week intervals), participants completed a questionnaire for assessing the use and treatment-emergent adverse events of avanafil, ED severity, and treatment satisfaction., Outcomes: The outcome measures included the Sexual Health Inventory for Men (SHIM), and Erectile Dysfunction Inventory of Treatment Satisfaction., Results: Among 234 patients enrolled, 112 (47.9%) patients had follow-up visits and answered the questionnaire. Treatment with avanafil significantly improved the mean SHIM total score from 10.2 ± 5.6 at baseline to 17.5 ± 6.2 ( P  < .001). Of the patients treated with avanafil, 71.4% (n = 80 of 112) reported a >4-point improvement in the SHIM total score, and 33.1% (n = 37 of 112) reported normal erectile function. The proportion of patients satisfied with avanafil treatment (defined as Erectile Dysfunction Inventory of Treatment Satisfaction index score ≥60) was 87.5%. Several physical factors (younger age, lower waist circumference, and lower level of low-density lipoprotein), and sexual function factors (shorter duration of ED, higher SHIM total score at baseline, PDE5 inhibitor treatment naive, and acquired premature ejaculation) tended to contribute to satisfaction with avanafil treatment. Treatment-emergent adverse events occurred in 41.1% of patients, and all were mild in severity., Clinical Implications: This study identifies the factors associated with treatment satisfaction of avanafil, which may ultimately lead to better treatment outcomes., Strengths and Limitations: This is the first study to provide real-world evidence of avanafil for ED treatment, and validated questionnaires were used to assess erectile function and treatment satisfaction. However, the limitations of this study include single-center observational study design, small sample size, and short-term follow-up., Conclusion: Avanafil is an effective treatment for ED, and satisfaction rate is high in an outpatient setting. The awareness of identified factors related to patient satisfaction may improve treatment outcomes., Competing Interests: All the authors declared no any conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

We report on a unique photonic quantum source chip highly integrating four-stage photonic elements in a lithium niobate (LN) waveguide circuit platform, where an aperiodically poled LN (APPLN) electro-optic (EO) polarization mode converter (PMC) is sandwiched between two identical type-0 PPLN spontaneous parametric down-converters (SPDCs), followed by an EO phase controller (PC). These core nonlinear optic and EO building blocks on the chip are systematically characterized stage by stage to show its high performance as an integrated quantum source. The APPLN EO PMC, optimally constructed by a genetic algorithm, is characterized to have a broad bandwidth (>13 nm), benefiting an efficient control of broadband type-0 SPDC photon pairs featuring a short correlation time. We demonstrate an efficient conversion of the |VV› photon-pair state generated from the first PPLN SPDC stage to the |HH› state through the APPLN EO PMC stage over its operating bandwidth, a broadband or broadly tunable polarization-entangled state can thus be possibly produced via the superposition of the |VV› state generated from the other PPLN SPDC on the third stage of the chip. Such a state can be further manipulated into two of the Bell states if the relative phases between the two polarization states can be properly modulated through the EO PC on the fourth stage of the chip. Such a multifunction integrated quantum photonic source chip can be of high value to developing a compact, efficient, and high-speed quantum information processor.

Extracellular vesicles (EVs) can be released from gram-positive bacteria and would participate in the delivery of bacterial toxins. Streptococcus pyogenes (group A Streptococcus , GAS) is one of the most common pathogens of monomicrobial necrotizing fasciitis. Spontaneous inactivating mutation in the CovR/CovS two-component regulatory system is related to the increase of EVs production via an unknown mechanism. This study aimed to investigate whether the CovR/CovS-regulated RopB, the transcriptional regulator of GAS exoproteins, would participate in regulating EVs production. Results showed that the size, morphology, and number of EVs released from the wild-type strain and the ropB mutant were similar, suggesting RopB is not involved in controlling EVs production. Nonetheless, RopB-regulated SpeB protease degrades streptolysin O and bacterial proteins in EVs. Although SpeB has crucial roles in modulating protein composition in EVs, the SpeB-positive EVs failed to trigger HaCaT keratinocytes pyroptosis, suggesting that EVs did not deliver SpeB into keratinocytes or the amount of SpeB in EVs was not sufficient to trigger cell pyroptosis. Finally, we identified that EV-associated enolase was resistant to SpeB degradation, and therefore could be utilized as the internal control protein for verifying SLO degradation. This study revealed that RopB would participate in modulating protein composition in EVs via SpeB-dependent protein degradation and suggested that enolase is a potential internal marker for studying GAS EVs.

Background: Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection relies on immunity generated after primary infection. However, humoral immunity following primary infection with the Omicron variant is not well understood., Methods: We prospectively recruited children <19 years with virologically-confirmed SARS-CoV-2 infection at National Cheng Kung University Hospital from February 2022 to September 2022 during the first wave of Omicron BA.2 outbreak in Taiwan. Serum samples were collected one month after acute infection to measure anti-spike protein receptor binding domain antibody levels and surrogate virus neutralizing antibody (NAb) levels against wild type disease and variants., Results: Of the 164 patients enrolled, most were under 5 years (65.2%) with a diagnosis of upper respiratory tract infection. Children under 6 months with maternal coronavirus disease 2019 (COVID-19) vaccination had higher levels of both anti-SARS-CoV-2 spike antibody (119.0 vs 27.4 U/ml, p < 0.05) and anti-wild type NAb (56.9% vs 27.6% inhibition, p = 0.001) than those without. Children aged 5-12 years with prior vaccination had higher anti-spike antibody, anti-wild type, and anti-Omicron BA.2 NAb levels than those without (all p < 0.05). In previously naïve children without maternal or self-vaccination, those 6 months to 2 years had the highest antibody levels. Multivariable linear regression analysis showed age was the only independent factor associated with antibody level., Conclusions: In our study, children aged 6 months to 2 years have the highest antibody responses to SARS-CoV-2 Omicron variant infection. Age and prior vaccination are the main factors influencing the immunogenicity of SARS-CoV-2 infection., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Aims: The aim of this study is to clarify the role of NLRP3 inflammasome in phosphate burden-induced vascular smooth muscle cell (VSMC) calcification., Main Methods: VSMC calcification was induced using a high concentration of inorganic phosphate. After pharmacological inhibition or genetic silencing of the NLRP3 inflammasome, pyroptosis, or potassium efflux, the cells were examined by RT-qPCR, immunofluorescence, and western blotting to identify the NLRP3-mediated pathway for VSMC calcification., Key Findings: Calcified VSMCs with α-smooth muscle actin (α-SMA) disarray presented features of pyroptosis, including caspase-1 maturation, cleaved gasdermin D (GSDMD), and a high supernatant level of lactate dehydrogenase A. Pharmacological inhibitions of caspase-1 and pyroptosis attenuated VSMC calcification, whereas interleukin-1β receptor antagonism did not. Unlike canonical NLRP3 activation, osteogenic VSMCs did not upregulate NLRP3 expression. However, NLRP3 genetic silencing or inhibitions, which targets different domains of the NLRP3 protein, could ameliorate VSMC calcification by aborting caspase-1 and GSDMD activation. Furthermore, potassium efflux through the inward-rectifier potassium channel, and not through the P2X7 receptor, triggered NLRP3 inflammasome activation and VSMC calcification., Significance: In the present study, we identified a potassium efflux-triggered NLRP3-caspase-1-mediated pyroptotic pathway for VSMC calcification that is unique and different from the canonical NLRP3 inflammasome activation. Therefore, targeting this pathway may serve as a novel therapeutic strategy for vascular calcification., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1-28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m 5 C RNA methylation, including TREX2, and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8 + T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation., Competing Interests: Declaration of interests H.-K.L. is a consultant for Stablix, Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background/purpose(s): Human breastmilk (BM) is important for microbiome maturation in infants across different body sites. Streptococcus and Staphylococcus are considered universally predominant genera in the BM microbiota. However, whether the differential abundance of Streptococcus and Staphylococcus in BM can differentially affect microbiome maturation in infants remains unclear., Methods: We recruited exclusively breastfeeding mothers from among the donors of the human milk bank established at National Cheng-Kung University Hospital. The donor mothers provided 35 BM samples at three months (3 M; before introducing children to complementary feeding) and 23 BM samples at six months (6 M; after introducing children to complementary feeding) postpartum. At both time points, samples from different body sites, including nasal swabs, oral swabs and stool, were collected from the mothers and their infants., Results: Maternal BMI was inversely associated with coagulase-negative Staphylococcus (CoNS) abundance in breastmilk. Staphylococcus caprae representation in BM CoNS showed a negative correlation with Streptococcus abundance. Network analysis revealed that infants fed Staphylococcus-dominated BM had better gut and nasal microbiota networks than infants fed Streptococcus-abundant BM during early infancy., Conclusion: Our work suggests that maternal metabolic status plays a crucial role in Staphylococcus/Streptococcus competition in BM, which in turn can impact the development of the infant microbiota. Our microbiota co-occurrence network analysis might serve as a helpful bioinformatic tool to monitor microbiota maturation during early infancy., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Varus collapse followed by osteosynthesis for distal femoral fractures with conventional implants has been well documented but is seldom mentioned in fractures managed with locking plates. The purpose of this study was to assess the incidence of varus collapse after treating complex supra-intercondylar fractures of the distal femur (AO type C3) using a Single Plate (SP) or Double Plate (DP) fixation technique., Materials and Methods: We retrospectively reviewed 357 patients with distal femoral fractures who were treated at our hospital between 2006 and 2017. After excluding cases of infection, malignancy, periprosthetic fracture, revision surgery, pediatric fracture, and extra-articular fracture, 54 patients were included in the study. All demographic data and radiological and clinical outcomes were reviewed and analyzed., Results: There were 54 patients enrolled into this study with age from 15 to 85 years old (mean 41.6, SD = 19.9), and 32 of them were open fractures (59%). The patients were further divided into either an SP (n = 15) or a DP group (n = 39). Demographics, including age, sex, injury severity score, and open fracture type, were all compatible between the two groups. The overall nonunion rate was 25.9% (n = 14; 6 from the SP and 8 from the DP group; p = 0.175). The varus collapse rate was 9.3% (n = 5; 4 from the SP and 1 from the DP group (p = 0.018)., Conclusions: The varus collapse rate after osteosynthesis with a single lateral locking plate could be as high as 26.7% in AO type C3 fractures of the distal femur, which would be decreased to 2.6% by adding a medial buttress plate. Surgeons should consider DP fixation to avoid varus collapse in severely comminuted complete intra-articular fractures of the distal femur., (© 2023. The Author(s).)

Clostridioides difficile spores are considered as the major source responsible for the development of C . difficile infection (CDI), which is associated with an increased risk of death in patients and has become an important issue in infection control of nosocomial infections. Current treatment against CDI still relies on antibiotics, which also damage normal flora and increase the risk of CDI recurrence. Therefore, alternative therapies that are more effective against C . difficile bacteria and spores are urgently needed. Here, we designed an oxidation process using H 2 O 2 containing PBS solution to generate Cl - and peroxide molecules that further process Ag and Au ions to form nanoboxes with Ag-Au peroxide coat covering Au shell and AgCl core (AgAu-based nanoboxes). The AgAu-based nanoboxes efficiently disrupted the membrane structure of bacteria/spores of C . difficile after 30-45 min exposure to the highly reactive Ag/Au peroxide surface of the nano structures. The Au-enclosed AgCl provided sustained suppression of the growth of 2 × 10 7 pathogenic Escherichia coli for up to 19 days. In a fecal bench ex vivo test and in vivo CDI murine model, biocompatibility and therapeutic efficacy of the AuAg nanoboxes to attenuate CDI was demonstrated by restoring the gut microbiota and colon mucosal structure. The treatment successfully rescued the CDI mice from death and prevented their recurrence mediated by vancomycin treatment. The significant outcomes indicated that the new peroxide-derived AgAu-based nanoboxes possess great potential for future translation into clinical application as a new alternative therapeutic strategy against CDI., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of The American Institute of Chemical Engineers.)

Objective: This study aimed to identify the characteristics of distortion product otoacoustic emissions (DPOAEs) that can be used to differentiate noise-induced hearing loss (NIHL) from age-related hearing loss. A potential index to detect NIHL was defined in terms of its susceptibility to cumulative noise exposure but not to age., Design: In this cross-sectional cohort study, a job-exposure matrix was used to calculate the cumulative noise exposure. Multivariate linear regression models were used to examine how age and cumulative noise exposure associated with DPOAEs at individual frequencies after adjusting for hypertension, dyslipidaemia, tobacco use and alcohol consumption., Study Sample: The pure-tone audiometry and DPOAEs data collected from 239 male workers in a steel factory., Results: DPOAEs and DPOAE signal-to-noise ratios (SNRs) at all frequencies were found to be correlated with age, and those at 2, 3, 4 and 6 kHz were correlated with both age and noise exposure. The difference between DPOAE SNR at 1 and 3 kHz showed significant correlation with noise exposure but not with age., Conclusions: The results showed that this DPOAE index, the DPOAE SNR at 1 kHz minus the DPOAE SNR at 3 kHz, could add values to audiometric evaluation of NIHL.

Purpose: Osteosynthesis for acetabular fractures with ipsilateral sacroiliac joint (SIJ) injuries remains challenging for orthopedic surgeons, despite the evolution of surgical approaches, such as the pararectus approach, and treatment sequences. The study aimed to describe the details of the treatment of acetabular fracture with ipsilateral SIJ injury by the pararectus approach and to report its surgical outcomes., Methods: We retrospectively assessed patients with acetabular fractures and ipsilateral SIJ injuries undergoing osteosynthesis by the pararectus approach over a three-year period. Evaluation parameters of the quality of reduction of both acetabulum and pelvis injuries were, among others, Matta's criteria, Lefaivre's criteria, inlet/outlet ratios, and maximal gap measured on computed tomography (CT) scans., Results: Ten patients (seven men and three women) were enrolled. Pelvic ring injuries classified as AO B2.3 and acetabular fractures involving two columns were the most common fractures, accounting for 70% and 60%, respectively. Radiological evaluation for pelvic ring injury revealed three excellent and seven good results according to Matta's criteria, as well as five excellent, three good, and one fair results according to Lefaivre's criteria. Inlet and outlet ratios were between 0.84-1.06 and 0.93-1.60, respectively. The distance of the sacroiliac joints significantly improved postoperatively in both axial and coronal views (P = 0.002). Further, the maximal articular gap and step-off of acetabular fractures on axial, coronal, and sagittal view CT scans showed statistically significant improvements after osteosynthesis., Conclusion: Simultaneous reduction and fixation of acetabular fractures with ipsilateral SIJ injuries using the pararectus approach achieved satisfactory radiological outcomes., Level of Evidence: IV., Trial Registration: Retrospectively registered., (© 2022. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: Information regarding the heterologous prime-boost COVID vaccination has been fully elucidated. The study aimed to evaluate both humoral, cellular immunity and cross-reactivity against variants after heterologous vaccination., Methods: We recruited healthcare workers previously primed with Oxford/AstraZeneca ChAdOx1-S vaccines and boosted with Moderna mRNA-1273 vaccine boost to evaluate the immunological response. Assay used: anti-spike RBD antibody, surrogate virus neutralizing antibody and interferon-γ release assay., Results: All participants exhibited higher humoral and cellular immune response after the booster regardless of prior antibody level, but those with higher antibody level demonstrated stronger booster response, especially against omicron BA.1 and BA.2 variants. The pre-booster IFN-γ release by CD4 + T cells correlates with post-booster neutralizing antibody against BA.1 and BA.2 variant after adjustment with age and gender., Conclusions: A heterologous mRNA boost is highly immunogenic. The pre-existing neutralizing antibody level and CD4 + T cells response correlates with post-booster neutralization reactivity against the Omicron variant., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Vaccines are a powerful medical intervention for preventing epidemic diseases. Efficient inactivated or protein vaccines typically rely on an effective adjuvant to elicit an immune response and boost vaccine activity. In this study, we investigated the adjuvant activities of combinations of Toll-like receptor 9 (TLR9) and stimulator of interferon genes (STING) agonists in a SARS-CoV-2 receptor binding domain protein vaccine. Adjuvants formulated with a TLR9 agonist, CpG-2722, with various cyclic dinucleotides (CDNs) that are STING agonists increased germinal center B cell response and elicited humoral immune responses in immunized mice. An adjuvant containing CpG-2722 and 2'3'-c-di-AM(PS)2 effectively boosted the immune response to both intramuscularly and intranasally administrated vaccines. Vaccines adjuvanted with CpG-2722 or 2'3'-c-di-AM(PS)2 alone were capable of inducing an immune response, but a cooperative adjuvant effect was observed when both were combined. CpG-2722 induced antigen-dependent T helper (Th)1 and Th17 responses, while 2'3'-c-di-AM(PS)2 induced a Th2 response. The combination of CpG-2722 and 2'3'-c-di-AM(PS)2 generated a distinct antigen-dependent Th response profile characterized by higher Th1 and Th17, but lower Th2 responses. In dendritic cells, CpG-2722 and 2'3'-c-di-AM(PS)2 showed a cooperative effect on inducing expression of molecules critical for T cell activation. CpG-2722 and 2'3'-c-di-AM(PS)2 have distinct cytokine inducing profiles in different cell populations. The combination of these two agonists enhanced the expression of cytokines for Th1 and Th17 responses and suppressed the expression of cytokines for Th2 response in these cells. Thus, the antigen-dependent Th responses observed in the animals immunized with different vaccines were shaped by the antigen-independent cytokine-inducing profiles of their adjuvant. The expanded targeting cell populations, the increased germinal center B cell response, and reshaped T helper responses are the molecular bases for the cooperative adjuvant effect of the combination of TLR9 and STING agonists., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Pulmonary fibrosis (PF) is a progressive, non-reversible illness with various etiologies. Currently, effective treatments for fibrotic lungs are still lacking. Here, we compared the effectiveness of transplantation of human mesenchymal stem cells from umbilical cord Wharton's jelly (HUMSCs) versus those from adipose tissue (ADMSCs) in reversing pulmonary fibrosis in rats. Bleomycin 5 mg was intratracheally injected to establish a severe, stable, single left lung animal model with PF. On Day 21 post-BLM administration, one single transplantation of 2.5 × 10 7 HUMSCs or ADMSCs was performed. Lung function examination of Injury and Injury+ADMSCs rats displayed significantly decreased blood oxygen saturation and increased respiratory rates, while Injury+HUMSCs rats showed statistical amelioration in blood oxygen saturation and significant alleviation in respiratory rates. Reduced cell number in the bronchoalveolar lavage and lower myofibroblast activation appeared in the rats transplanted with either ADMSCs or HUMSCS than that in the Injury group. However, ADMSC transplantation stimulated more adipogenesis. Furthermore, matrix-metallopeptidase-9 over-expression for collagen degradation, and the elevation of Toll-like receptor-4 expression for alveolar regeneration were observed only in the Injury+HUMSCs. In comparison with the transplantation of ADMSCs, transplantation of HUMSCs exhibited a much more effective therapeutic effect on PF, with significantly better results in alveolar volume and lung function.

Background: Reasons for the increased use of closed reduction and internal fixation (CRIF) for traumatic sacral fractures (SFs) are unclear in the literature. Therefore, we aimed to report the annual changes in the number of patients, mechanisms of injury, fracture patterns, and fixation methods., Methods: In this retrospective study, we extracted data of 271 patients (mean age, 37.5 years) from the trauma register over an 8-year period. Annual records regarding the number of patients, injury mechanisms, fracture types, and treatment options were statistically analyzed to examine the interactions among these factors., Results: The number of patients with SFs increased significantly each year. The rate of admission to the intensive care unit after resuscitation was high (64.9%). Arbeitsgemeinschaft für Osteosynthesefragen (AO) type C pelvic ring injury (PRI), Dennis zone II injury, Roy-Camille type 2 injury, and U/H-type injury were the most common fracture types. Trans-iliac trans-sacral screws were mainly used in AO type B PRI, and their use significantly increased each year. For AO type C PRI, open reduction and internal fixation (ORIF) with rigid fixation was the main treatment, and the use of CRIF with iliosacral screws decreased each year. Stepwise statistical analysis revealed that the increase in AO type B PRI and ORIF for anterior PRI were the factors contributing to the increased use of CRIF for SFs., Conclusions: While the use of osteosynthesis for SFs is increasing, an increased use of CRIF for traumatic SFs has also been observed in clinical practice. This increase can be attributed to the increase in AO type B PRIs and ORIF for anterior PRIs., (© 2022. The Author(s).)

The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an oligomeric complex that assembles in response to exogenous signals of pathogen infection and endogenous danger signals of non-microbial origin. When NLRP3 inflammasome assembly activates caspase-1, it promotes the maturation and release of the inflammatory cytokines interleukin-1B and IL-18. Aberrant activation of the NLRP3 inflammasome has been implicated in various diseases, including chronic inflammatory, metabolic, and cardiovascular diseases. The NLRP3 inflammasome can be activated through several principal mechanisms, including K+ efflux, lysosomal damage, and the production of mitochondrial reactive oxygen species. Interestingly, metabolic danger signals activate the NLRP3 inflammasome to induce metabolic diseases. NLRP3 contains three crucial domains: an N-terminal pyrin domain, a central nucleotide-binding domain, and a C-terminal leucine-rich repeat domain. Protein-protein interactions act as a 'pedal or brake' to control the activation of the NLRP3 inflammasome. In this review, we present the mechanisms underlying NLRP3 inflammasome activation after induction by metabolic danger signals or via protein-protein interactions with NLRP3 that likely occur in metabolic diseases. Understanding these mechanisms will enable the development of specific inhibitors to treat NLRP3-related metabolic diseases.

Background/aims: To understand whether the epidemiology, aetiologies, common pathogens and the antibiotic efficacy against the identified bacteria of periorbital cellulitis in adults have changed recently (2010-2019) compared with the past decade (2000-2009)., Methods: Adult patients (n=224) diagnosed with preseptal cellulitis and orbital cellulitis admitted to Kaohsiung Veterans General Hospital during 2000-2019 were retrospectively reviewed. Demographic and clinical characteristics, isolated pathogens and antibiotic susceptibility tests against the commonly cultured bacteria were analysed., Results: Preseptal cellulitis showed a tendency of female predominance. Patients in their 60s showed an incidence peak; more cases were observed during winter. The most common predisposing factor was dacryocystitis (15.5%-30.5%), followed by hordeolum (15.5%-24.8%). Aetiology of sinusitis (p=0.001) decreased and that of conjunctivitis (p=0.007) increased significantly with time. Culture results of nasopharyngeal swabs and local abscess showed higher positivity rate than conjunctival swab. The most common isolates were methicillin-susceptible Staphylococcus aureus , methicillin-resistant S. aureus , coagulase-negative staphylococci and Pseudomonas aeruginosa . Antibiotics including fluoroquinolones and vancomycin were effective; in contrast, ampicillin/sulbactam and oxacillin showed decreasing efficacy against gram-positive bacteria. For antibiotic treatment against P. aeruginosa , fluoroquinolones, ceftazidime, piperacillin and imipenem were ideal choices., Conclusion: In isolated pathogens, the increasing trend of methicillin-resistant S. aureus detection was compatible with reducing oxacillin efficacy against periorbital infection. In our study, the report of antibiotic efficacy against the most common identified bacteria offered empirical choices for hospitalised patients with periorbital infection before obtaining culture results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Peroxisome proliferator-activated receptor γ (PPARγ) gene mutations in humans and mice lead to whole-body insulin resistance and partial lipodystrophy. It is unclear whether preserved fat depots in partial lipodystrophy are beneficial for whole-body metabolic homeostasis. We analyzed the insulin response and expression of metabolic genes in the preserved fat depots of Pparg C/- mice, a familial partial lipodystrophy type 3 (FPLD3) mouse model resulting from a 75% decrease in Pparg transcripts. Perigonadal fat of Pparg C/- mice in the basal state showed dramatic decreases in adipose tissue mass and insulin sensitivity, whereas inguinal fat showed compensatory increases. Preservation of inguinal fat metabolic ability and flexibility was reflected by the normal expression of metabolic genes in the basal or fasting/refeeding states. The high nutrient load further increased insulin sensitivity in inguinal fat, but the expression of metabolic genes became dysregulated. Inguinal fat removal resulted in further impairment of whole-body insulin sensitivity in Pparg C/- mice. Conversely, the compensatory increase in insulin sensitivity of the inguinal fat in Pparg C/- mice diminished as activation of PPARγ by its agonists restored insulin sensitivity and metabolic ability of perigonadal fat. Together, we demonstrated that inguinal fat of Pparg C/- mice plays a compensatory role in combating perigonadal fat abnormalities.

Group A Streptococcus (GAS) is a strict human pathogen possessing a unique pathogenic trait that utilizes the cooperative activity of NAD + -glycohydrolase (NADase) and Streptolysin O (SLO) to enhance its virulence. How NADase interacts with SLO to synergistically promote GAS cytotoxicity and intracellular survival is a long-standing question. Here, the structure and dynamic nature of the NADase/SLO complex are elucidated by X-ray crystallography and small-angle scattering, illustrating atomic details of the complex interface and functionally relevant conformations. Structure-guided studies reveal a salt-bridge interaction between NADase and SLO is important to cytotoxicity and resistance to phagocytic killing during GAS infection. Furthermore, the biological significance of the NADase/SLO complex in GAS virulence is demonstrated in a murine infection model. Overall, this work delivers the structure-functional relationship of the NADase/SLO complex and pinpoints the key interacting residues that are central to the coordinated actions of NADase and SLO in the pathogenesis of GAS infection., (© 2023. The Author(s).)

High relapse rate is a key feature of opioid addiction. In humans, abstinence is often voluntary due to negative consequences of opioid seeking. To mimic this human condition, we recently introduced a rat model of incubation of oxycodone craving after electric barrier-induced voluntary abstinence. Incubation of drug craving refers to time-dependent increases in drug seeking after cessation of drug self-administration. Here, we used the activity marker Fos, muscimol-baclofen (GABAa + GABAb receptor agonists) global inactivation, Daun02-selective inactivation of putative relapse-associated neuronal ensembles, and fluorescence-activated cell sorting of Fos-positive cells and quantitative polymerase chain reaction to demonstrate a key role of vSub neuronal ensembles in incubation of oxycodone craving after voluntary abstinence, but not homecage forced abstinence. We also used a longitudinal functional magnetic resonance imaging method and showed that functional connectivity changes in vSub-related circuits predict opioid relapse after abstinence induced by adverse consequences of opioid seeking.

As a critical node connecting the forebrain with the midbrain, the lateral habenula (LHb) processes negative feedback in response to aversive events and plays an essential role in value-based decision-making. Compulsive drug use, a hallmark of substance use disorder, is attributed to maladaptive decision-making regarding aversive drug-use-related events and has been associated with dysregulation of various frontal-midbrain circuits. To understand the contributions of frontal-habenula-midbrain circuits in the development of drug dependence, we employed a rat model of methamphetamine self-administration (SA) in the presence of concomitant footshock, which has been proposed to model compulsive drug-taking in humans. In this longitudinal study, functional MRI data were collected at pretraining baseline, after 20 d of long-access SA phase, and after 5 d of concomitant footshock coupled with SA (punishment phase). Individual differences in response to punishment were quantified by a "compulsivity index (CI)," defined as drug infusions at the end of punishment phase, normalized by those at the end of SA phase. Functional connectivity of LHb with the frontal cortices and substantia nigra (SN) after the punishment phase was positively correlated with the CI in rats that maintained drug SA despite receiving increasing-intensity footshock. In contrast, functional connectivity of the same circuits was negatively correlated with CI in rats that significantly reduced SA. These findings suggest that individual differences in compulsive drug-taking are reflected by alterations within frontal-LHb-SN circuits after experiencing the negative consequences from SA, suggesting these circuits may serve as unique biomarkers and potential therapeutic targets for individualized treatment of addiction.

Background/purpose: Although metronidazole is not recommended to treat Clostridioides difficile infection (CDI) in Western countries, it was still to be recommended for the treatment of non-severe CDI among Taiwanese adults in 2020. This controversy in the clinical role of metronidazole therapy for CDI was examined in a prospective clinical study., Methods: The study was conducted from January 2015 to December 2016 in three hospitals in Taiwan. Metronidazole treatment failure (MTF) was defined as the persistence of diarrhea after six days of treatment, medication modification (shifting to oral vancomycin), or death after five days of therapy., Results: Overall, 325 patients receiving metronidazole for CDI were included. The overall MTF rate was 48.6% (158 patients). Leukocyte counts of >15,000 cells/mL in peripheral blood (odd ratio [OR] 1.81; P = 0.04) and congestive heart failure (OR 3.26; P = 0.02) were independently associated with MTF. The MTF rate for patients with leukocyte counts of ≤15,000 cells/mL and no congestive heart failure, leukocyte counts of >15,000 cells/mL and no congestive heart failure, leukocyte counts of ≤15,000 cells/mL and congestive heart failure, and leukocyte counts of >15,000 cells/mL and congestive heart failure were 44.2%, 51.8%, 73.3%, and 66.7%, respectively. Of note, patients who experienced MTF had a higher recurrence rate of CDI than those with metronidazole treatment success (13.9% vs. 6.0%, P = 0.02)., Conclusion: For Taiwanese adults with CDI, the failure rate of metronidazole therapy approached 50%, which suggests the reappraisal of the therapeutic role of metronidazole therapy, especially for patients with leukocytosis or underlying congestive heart failure., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Objectives: Malnutrition and cognitive impairment are associated with poor functional recovery in older adults following hip-fracture surgery. This study examined the combined effects of cognitive impairment and nutritional trajectories on postoperative functional recovery for older adults following hip-fracture surgery., Design: Prospective longitudinal correlational study., Setting and Participants: This study recruited 350 older adults (≥60 years of age) who received hip-fracture surgery at a 3000-bed medical center in northern Taiwan from September 2012 to March 2020., Methods: Participant data were collected over a 2-year period after surgery for nutritional and cognitive status and activities of daily living (ADLs). Participants were grouped by type of nutritional trajectory using group-based trajectory modeling. Generalized estimating equations analyzed associations between trajectory groups/cognitive status at discharge and performance of ADLs., Results: Nutritional trajectories best fit a 3-group trajectory model: malnourished (19%), at-risk of malnutrition (40%), and well-nourished (41%). Nutritional status for the malnourished group declined from 12 months to 24 months following surgery; nutritional status remained stable for at-risk of malnutrition and well-nourished groups. Interactions for cognitive impairment-by-nutritional status were significant: the malnourished + intact cognition subgroup had significantly better ADLs than the malnourished + cognitive impairment subgroup (b = 27.1, 95% confidence interval = 14.0-40.2; P < .001). For at-risk of malnutrition and well-nourished groups, there were no significant differences between cognitive impairment and intact cognition in ADLs. These findings suggest that nutritional status may buffer the negative effect of cognitive impairment on ADLs., Conclusions and Implications: Better nutritional status over time for older adults following hip fracture can protect against adverse influences of cognitive impairment on ADLs during postoperative recovery. Participants with malnutrition and cognitive impairment had the poorest ADLs. These findings suggest interventions tailored to improving nutritional status may improve recovery for older adults following hip-fracture surgery., (Copyright © 2022 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in substantial impacts on all aspects of medical education. Modern health systems must prepare for a wide variety of catastrophic scenarios, including emerging infectious disease outbreaks and human and natural disasters. During the COVID-19 pandemic, while the use of traditional teaching methods has decreased, the use of online-based teaching methods has increased. COVID-19 itself and the accompanying infection control measures have restricted full-scale practice. Therefore, we developed an adapted hybrid model that retained adequate hands-on practice and educational equality, and we applied it with a group of undergraduate medical students participating in a mandatory disaster education course in a military medical school., Methods: The course covered the acquisition of skills used in emergency and trauma scenarios through designated interdisciplinary modules on disaster responses. Several asynchronous and synchronous online webinars were used in this one-credit mandatory disaster and military medicine education course. To allow opportunities for hands-on practice and ensure education equality, the students were divided into 15 groups, with 12 students in each group. The hands-on practice exercises were also recorded and disseminated to the students in the designated area for online learning., Results: A total of 164 3rd-year medical students participated in this mandatory disaster and military medicine course during the COVID-19 pandemic. The satisfaction survey response rate was 96.5%. The students were satisfied with the whole curriculum (3.8/5). Most of the free-text comments regarding the course represented a high level of appreciation. The students felt more confident in the knowledge and skills they gained in hands-on exercises than they did in the knowledge and skills they gained in online exercises. The students showed significant improvements in knowledge after the course., Conclusions: We demonstrated that this adapted hybrid arrangement provided an enhanced learning experience, but we also found that medical students were more confident in their knowledge and skills when they had real hands-on practice., Competing Interests: The authors declare that they have no competing interests. This study was supported by a grant from the Tri-Service General Hospital, National Defense Medical Center, Taiwan (TSGH-E-111208), Ministry of National Defense-Medical Affairs Bureau (MND-MAB-110-121, MND-MAB-C-11111-111050X) and the Ministry of Science and Technology (MOST 108-2314-B-016-047-MY3).

Nicotine exposure is associated with regional changes in brain nicotinic acetylcholine receptors subtype expression patterns as a function of dose and age at the time of exposure. Moreover, nicotine dependence is associated with changes in brain circuit functional connectivity, but the relationship between such connectivity and concomitant regional distribution changes in nicotinic acetylcholine receptor subtypes following nicotine exposure is not understood. Although smoking typically begins in adolescence, developmental changes in brain circuits and nicotinic acetylcholine receptors following chronic nicotine exposure remain minimally investigated. Here, we combined in vitro nicotinic acetylcholine receptor autoradiography with resting state functional magnetic resonance imaging to measure changes in [ 3 H]nicotine binding and α4ß2 subtype nicotinic acetylcholine receptor binding and circuit connectivity across the brain in adolescent (postnatal Day 33) and adult (postnatal Day 68) rats exposed to 6 weeks of nicotine administration (0, 1.2 and 4.8 mg/kg/day). Chronic nicotine exposure increased nicotinic acetylcholine receptor levels and induced discrete, developmental stage changes in regional nicotinic acetylcholine receptor subtype distribution. These effects were most pronounced in striatal, thalamic and cortical regions when nicotine was administered during adolescence but not in adults. Using these regional receptor changes as seeds, resting state functional magnetic resonance imaging identified dysregulations in cortico-striatal-thalamic-cortical circuits that were also dysregulated following adolescent nicotine exposure. Thus, nicotine-induced increases in cortical, striatal and thalamic nicotinic acetylcholine receptors during adolescence modifies processing and brain circuits within cortico-striatal-thalamic-cortical loops, which are known to be crucial for multisensory integration, action selection and motor output, and may alter the developmental trajectory of the adolescent brain. This unique multimodal study significantly advances our understanding of nicotine dependence and its effects on the adolescent brain., (Published by Oxford University Press on behalf of the Guarantors of Brain 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Clostridioides difficile is a major causative pathogen of nosocomial antibiotic-associated diarrhea and severe colitis. Despite the use of vancomycin and fidaxomicin as standard drugs for the treatment of C. difficile infection (CDI), clinical relapse rates remain high. Therefore, new alternative therapeutics to treat CDI are urgently required. The nuclear receptor, peroxisome proliferator-activated receptor-γ (PPAR-γ), is mainly expressed in the adipose tissue and modulates lipid metabolism and insulin sensitization. Previous studies have shown that PPAR-γ is highly expressed in colonic tissues and regulates tight junction function in epithelial cells. However, the role of PPAR-γ in CDI pathogenesis remains unclear. In this study, we used a mouse model of CDI and found that both expression levels of PPAR-γ and the tight junction protein, occludin, were decreased in colonic tissues. Furthermore, to investigate the role of PPAR-γ in CDI, we used PPAR-γ defective mice and found that intestinal permeability and bacterial dissemination in these mice were significantly higher than those in wild-type mice during CDI. Administration of the PPAR-γ agonist, pioglitazone, to activate PPAR-γ activity improved the phenotypes of CDI, including bodyweight loss, inflammation, and intestinal integrity. Taken together, these results demonstrate that PPAR-γ is a potential therapeutic target in CDI, as it modulates colonic inflammation and integrity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lai, Wu, Tsai, Hung, Lin, Tsai, Ko and Tsai.)

Prior MALDI mass spectrometry imaging (MALDI-MSI) studies reported significant changes in phosphatidylcholines (PCs), lysophosphatidylcholines (LPCs), and sphingomyelins (SMs) in ischemic rat brains yet overlooked the information on other classes of PLs and SLs and provided very little or no validation on the detected lipid markers. Relative quantitation of four classes of PLs and two classes of SLs in the ischemic and normal temporal cortex (TCX), parietal cortex (PCX), and striatum (ST) of rats was performed with hydrophilic interaction chromatography (HILIC)-tandem mass spectrometry (MS/MS) analyses, and the marker lipid species was identified by multivariate data analysis and validated with additional tissue cohorts. The acquired lipid information was sufficient in differentiating individual anatomical regions under different pathological states, identifying region-specific ischemic brain lipid markers and revealing additional PL and SL markers not reported previously. Validation of orthogonal partial least square discriminating analysis (OPLS-DA) identified ischemic brain lipid markers yielded much higher classification accuracy, precision, specificity, sensitivity, and lower false positive and false negative rates than those from the volcano plot analyses using conventional statistical significance and a fold change of two as the cutoff and provided a wider prospective to ischemia-associated brain lipid changes.

Introduction: The concept of local sleep refers to the phenomenon of local brain activity that modifies neural networks during unresponsive global sleep. Such network rewiring may differ across spatial scales; however, the global and local alterations in brain systems remain elusive in human sleep. Materials and Methods: We examined cross-scale changes of brain networks in sleep. Functional magnetic resonance imaging data were acquired from 28 healthy participants during nocturnal sleep. We adopted both metrics of connectivity (functional connectivity [FC] and regional homogeneity [ReHo]) and complexity (multiscale entropy) to explore the global and local functionality of the neural assembly across nonrapid eye movement sleep stages. Results: Long-range FC decreased with sleep depth, whereas local ReHo peaked at the N2 stage and reached its lowest level at the N3 stage. Entropy exhibited a general decline at the local scale ( Scale 1 ) as sleep deepened, whereas the coarse-scale entropy ( Scale 3) was consistent across stages. Discussion: The negative correlation between Scale-1 entropy and ReHo reflects the enhanced signal regularity and synchronization in sleep, identifying the information exchange at the local scale. The N2 stage showed a distinctive pattern toward local information processing with scrambled long-distance information exchange, indicating a specific time window for network reorganization. Collectively, the multidimensional metrics indicated an imbalanced global-local relationship among brain functional networks across sleep-wake stages.

This is the first report to discover Clostridiodes difficile (C. difficile) ribotype RT126 and RT598 (both ribotypes belong to RT078-lineage) in a river water system in southern Taiwan. Fluoroquinolone resistance was also found. The connection between clinical isolates and those from the environment needs further investigation., (Copyright © 2022. Published by Elsevier B.V.)