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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.