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This study aimed to determine the perceptions and attitudes of preservice teachers of Chinese as a foreign language (CFL) toward applying information and computer technology (ICT) and image-generative artificial intelligence (image-GAI) tools in CFL teaching from the perspective of drawings. This 2-week study involved 20 preservice CFL teachers from a university in northern Taiwan. Various data were collected, including questionnaire responses and drawings (both hand-drawn and artificial-intelligence-assisted) by preservice teachers. The collected data were analyzed to determine how the experience of using image-GAI tools influenced how preservice CFL teachers perceive ICT-assisted CFL teaching, and how they perceive the potential of image-GAI tools in enhancing their creativity. The results indicated that most conceptions held by the preservice CFL teachers of ICT-assisted Chinese language teaching involved teachers and learners as the primary people involved, and that they tended to adopt a teacher-centered teaching mode. The preservice CFL teachers had positive attitudes toward using image-GAI tools in CFL teaching. However, they were more reserved regarding whether generative AI tools can promote diversity in CFL teaching and enhance the creativity of preservice teachers. The most common elements in the drawings by the preservice teachers were the activities and the people involved in CFL teaching. Two other noteworthy findings were (1) most preservice CFL teachers believed that this new technology (image-GAI tools) better reflected their understanding of ICT and CFL teaching, and (2) that their drawings indicated that having experience of using image-GAI tools influenced their perception of ICT and CFL teaching.

Abstract Human telomerase assembly is a highly dynamic process. Using biochemical approaches, we find that LARP3 and LARP7/MePCE are involved in the early stage of human telomerase RNA (hTR) and that their binding to RNA is destabilized when the mature form is produced. LARP3 plays a negative role in preventing the processing of the 3′-extended long (exL) form and the binding of LARP7 and MePCE. Interestingly, the tertiary structure of the exL form prevents LARP3 binding and facilitates hTR biogenesis. Furthermore, low levels of LARP3 promote hTR maturation, increase telomerase activity, and elongate telomeres. LARP7 and MePCE depletion inhibits the conversion of the 3′-extended short (exS) form into mature hTR and the cytoplasmic accumulation of hTR, resulting in telomere shortening. Taken together our data suggest that LARP3 and LARP7/MePCE mediate the processing of hTR precursors and regulate the production of functional telomerase.

Background: Prior to 2022, Taiwan had effectively contained the domestic COVID-19 epidemic. However, during 2022, the country encountered multiple large outbreaks of COVID-19, with patients experiencing their first or second infection (reinfection) were both predominantly caused by the Omicron variant. Data are lacking on the risk factors and mortality of COVID-19 reinfection in Omicron era. Methods: In this retrospective population-based cohort study, we recruited COVID-19 patients with their first episode confirmed between April 1, 2022 and June 11, 2022. A reinfection patient was defined as an individual who infected again by SARS-CoV-2 with an interval of more than 90 days. Demographic characteristics, severity of underlying diseases, and vaccination status were adjusted to identify risk factors for reinfection and to further evaluate the hazard of all-cause mortality within 30 days between reinfection and non-reinfection patients. Results: There were 28,588 reinfection patients matched with 142,940 non-reinfection patients included in this study. We found that being female, younger in age, having more severe underlying diseases, and not being fully vaccinated against COVID-19 were risk factors for reinfection. After adjusting for confounding factors, reinfection patients were at a significantly higher risk of all-cause mortality within 30 days (aHR = 4.29, 95% CI: 3.00–6.12, p

With the rapid advancement of technology, there is an increasing need for quick and accurate analysis of vehicle accident severity, determination of accident liability, assessment of vehicle damage extent, and efficient calculation of insurance compensation. This study proposes an innovative approach for vehicle damage assessment by utilizing smartphones equipped with Light Detection and Ranging (LiDAR) technology. High-precision scans of vehicles are conducted in two stages: an initial comprehensive exterior scan of the undamaged vehicle, followed by a scan of the same model post-collision. The obtained point cloud data is processed using 3D reconstruction techniques to create virtual vehicle models. We apply the Iterative Closest Point (ICP) algorithm and Singular Value Decomposition (SVD) methods, along with a proposed deep learning neural network optimization model, to perform point cloud alignment between the pre-collision and post-collision vehicle models. The proposed method enhances the alignment accuracy by refining the transformation parameters, effectively handling nonlinear deformations caused by collisions. Key performance indicators, including Root Mean Square Error (RMSE), relative translation, and relative rotation angles, are used to quantify the extent of vehicle damage. Experimental results demonstrate that the proposed method significantly reduces the relative rotation from approximately 4.03° to 0.04° and the RMSE from about 1.27 units to 0.29 units compared to the traditional ICP and SVD methods, indicating a substantial improvement in alignment precision and damage assessment accuracy. The contributions of this study lie in integrating LiDAR technology with advanced point cloud processing algorithms and a deep learning optimization model for vehicle damage assessment, demonstrating high precision and cost-effectiveness. This method not only enhances the accuracy and efficiency of damage assessment but also reduces costs, offering significant practical value for rapid accident evaluation and insurance claims processing. By providing improved accuracy and reliability in damage assessments, this study significantly contributes to the fields of automotive safety, insurance, and repair.

Background: Taiwan experienced a relatively low incidence of COVID-19 before 2022. However, from April 2022 to March 2023, the country was struck by a nationwide outbreak that occurred in three waves. Despite the considerable magnitude of the epidemic, the epidemiological characteristics of this outbreak have yet to be clearly understood. Methods: This was a nationwide, population-based, retrospective cohort study. We recruited patients who had been confirmed as domestically-acquired COVID-19 patients from April 17, 2022, to March 19, 2023. The three epidemic waves were analyzed in terms of numbers of cases, cumulative incidence, numbers of COVID-19-related deaths, mortality, gender, age, residence, SARS-CoV-2 variant sub-lineages, and reinfection status. Results: The numbers of COVID-19 patients (cumulative incidence per million population) were 4,819,625 (207,165.3) in the first wave, 3,587,558 (154,206.5) in the second wave, and 1,746,698 (75,079.5) in the third wave, showing a progressive decline. The numbers of COVID-19-related deaths and mortalities also decreased throughout the three waves. The coverage of vaccination was observed to increase over time. Conclusion: During the three waves of COVID-19 epidemic, the numbers of cases and deaths gradually declined, while the vaccine coverage increased. It may be appropriate to consider easing restrictions and returning to normality. However, continued monitoring of the epidemiological situation and tracking the emergence of new variants are crucial to prevent the possibility of another epidemic.

Objectives: The aim of this study was to investigate the prognostic value of reclassified new type III monomicrobial gram-negative necrotizing fasciitis (NF) and the microbial factors associated with an increased risk of mortality. Methods: This study included 235 NF cases treated at National Taiwan University Hospital. We compared the mortality risk of NF caused by different causal microorganisms and examined the bacterial virulence genes profile and antimicrobial susceptibility pattern associated with an increase in mortality risk. Results: Type III NF (n = 68) had a mortality risk two-fold higher than type I (polymicrobial, n = 64) or type II (monomicrobial gram-positive, n = 79) NF (42.6% vs 23.4% or 19.0%, P = 0.019 and 0.002, respectively). Mortality differed by causal microorganism (Escherichia coli [61.5%], Klebsiella pneumoniae [40.0%], Aeromonas hydrophila [37.5%], Vibrio vulnificus [25.0%], polymicrobial [23.4%], group A streptococci [16.7%], and Staphylococcus aureus [16.2%], in decreasing rank, P

Despite never imposing a lockdown, Taiwan achieved COVID-19 zero, with reporting only 56 local coronavirus disease 2019 (COVID-19) cases after testing 126,987 individuals in 2020, and further contained a large outbreak rapidly and successfully in 2021. At the onset of the COVID-19 pandemic, our infectious disease modeling results indicated that testing and contact tracing alone would fail to contain the pandemic. However, by supplementing this approach with general public surgical mask-wearing, the reproduction number (R0) could be suppressed to less than 1. This would effectively contain the virus's spread within Taiwan, particularly when combined with strict border control measures to prevent the overwhelming influx of imported COVID-19 cases and ensure the capacity of the medical and public health systems remains resilient. These modeling results became the theoretical basis behind the highly successful Taiwan model against COVID-19 during 2020–2021, supporting by negative excess mortality, seroepidemiological surveys, and molecular epidemiological analyses. This is a public health triumph demonstrating that a democratic and humane approach to the COVID-19 pandemic is not only feasible but highly effective. It also highlights the crucial role of infectious disease modeling in assisting the formulation of a successful national pandemic response.

Abstract Background Tobacco use and secondhand smoke (SHS) are risk factors of kidney stone disease (KSD). The hypothesis is that tobacco produces chemicals that increase oxidative stress and vasopressin, which leads to decreased urine output, and contributes to stone formation. The aim of this study was to examine the effects of smoking and SHS on the development of KSD. Materials and methods We analyzed a total of 25,256 volunteers with no history of KSD participated in the Taiwan Biobank. The presence of underlying and follow-up KSD was surveyed by a self-administrated questionnaire. They were classified into three groups on the basis of smoking and SHS exposure, accessed with survey questionnaires; never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups. Results KSD was noted in 352 (2.0%), 50 (3.3%) and 240 (4.1%) subjects in the never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups, respectively, with a mean follow-up of 4 years. The odds ratio (OR) of KSD was higher in the never-smokers with SHS exposure (OR, 1.622; 95% confidence interval [95% CI], 1.225 to 2.255) and ever-smokers groups (OR, 1.282; 95% CI, 1.044 to 1.574) than in the never-smokers with no SHS exposure group after adjustment of confounders. In addition, never-smokers with SHS exposure had similar effects on the development of KSD than ever-smokers (OR, 1.223; 95% CI, 0.852 to 1.756). Conclusion Our study suggests that both smoking and SHS are a risk factor for developing KSD and that the impact of SHS is not inferior to that of smoking. Trial registration The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20,210,058).

Penile enlargement has been a controversial issue throughout history. We presented a patient who had undergone a procedure involving the injection of subcutaneous liquid silicone over the penile shaft four years prior. He developed long-term negative consequences from inflammatory granulomas. The patient's condition worsened over time, causing pain and impairing his sexual function. Eventually, he was diagnosed with penile SCC caused by chronic inflammation. Although it is rare, it is important to be aware of this probability because, compared to penile granuloma resection for symptom relief, penile SCC requires a comprehensive survey and more aggressive surgical intervention.

Abstract Because longwave (LW) absorption by greenhouse gases and clouds is more significant than the LW scattering effect by clouds, most climate models neglect cloud LW scattering to save computational costs. Ignoring cloud LW scattering directly overestimates outgoing longwave radiation (OLR). This study included ice‐cloud LW scattering treatment in the Exascale Energy Earth System Model (E3SM) version 2 and ran fully‐coupled simulations, prescribed sea surface temperature simulations, and offline radiative transfer calculations to comprehensively assess the impact of ice‐cloud LW scattering on global climate simulation. The instantaneous effect due to ice‐cloud LW scattering reduces the OLR by ∼1 W/m2 on the global average and 2 W/m2 on the tropical average. Tropospheric warming and high cloud amount reduction act to partially compensate for such instantaneous OLR reduction caused by the inclusion of LW scattering. When the simulation reaches the equilibrium, the surface warms by 0.66 K on average with respect to the simulation without LW scattering, with the Arctic surface temperature differences more than twice as large as that of the global mean. The impact of including LW scattering on the simulated climate change in response to 4 × CO2 is also assessed. While including the cloud LW scattering does not significantly modify radiative forcing and total radiative feedback under such a scenario, it results in a 10% more positive cloud feedback.

Abstract Progressive massive pulmonary fibrosis among coal miners has unexpectedly increased. It would likely due to the greater generation of smaller rock and coal particles produced by powerful equipment used in modern mines. There is limited understanding of the relationship between micro- or nanoparticles with pulmonary toxicity. This study aims to determine whether the size and chemical characteristics of typical coal-mining dust contribute to cellular toxicity. Size range, surface features, morphology, and elemental composition of coal and rock dust from modern mines were characterized. Human macrophages and bronchial tracheal epithelial cells were exposed to mining dust of three sub- micrometer and micrometer size ranges at varying concentrations, then assessed for cell viability and inflammatory cytokine expression. Coal had smaller hydrodynamic size (180–3000 nm) compared to rock (495–2160 nm) in their separated size fractions, more hydrophobicity, less surface charge, and consisted of more known toxic trace elements (Si, Pt, Fe, Al, Co). Larger particle size had a negative association with in-vitro toxicity in macrophages (p

RECQ4 mutations contribute to multiple developmental diseases and tumorigenesis. Here the authors describe how a highly oncogenic RECQ4 mutation alters the control of DNA synthesis, leading to abnormal DNA content and cell growth.

Abstract Hoyeraal-Hreidarsson syndrome (HHS) is the most severe form of dyskeratosis congenita (DC) and is caused by mutations in genes involved in telomere maintenance. Here, we identified male siblings from a family with HHS carrying a hemizygous mutation (c.1345C > G, p.R449G), located in the C-terminal nuclear localization signal (NLS) of the DKC1 gene. These patients exhibit progressive cerebellar hypoplasia, recurrent infections, pancytopenia due to bone marrow failure, and short leukocyte telomere lengths. Single-cell RNA sequencing analysis suggested defects in the NLRP3 inflammasome in monocytes and the activation and maturation of NK cells and B cells. In experiments using induced pluripotent stem cells (iPSCs) from patients, DKC1_R449G iPSCs had short telomere lengths due to reduced levels of human telomerase RNA (hTR) and increased cytosolic proportions of DKC1. Treatment with dihydroquinolizinone RG7834 and 3′deoxyanosine cordycepin rescued telomere length in patient-derived iPSCs. Together, our findings not only provide new insights into immunodeficiency in DC patients but also provide treatment options for telomerase insufficiency disorders.

Background: This study aims to explore the clinical correlates of myocardial deformations using speckle-tracking algorithm and to determine the prognostic utility of such measures in asymptomatic ethnic Chinese population. Methods: Global longitudinal (GLS), circumferential strain (GCS), and torsion were analyzed using featured tissue-tracking algorithm among 4049 symptom-free ethnic Chinese population. Hypertrophy (LVH) was classified into 4 tiers: indeterminate, dilated, thick and thick/dilated, by gender-stratified partition of end-diastolic volume index (EDVi) and LV mass/EDV0.67. Results: LVH (7.3%) showed substantially lower GLS (−20.3 ± 1.82% vs. −18.9 ± 2.08%) yet higher torsion (2.20 ± 0.90 vs. 2.39 ± 1.01, p

Summary: The arginine dependency of cancer cells creates metabolic vulnerability. In this study, we examine the impact of arginine availability on DNA replication and genotoxicity resistance. Using DNA combing assays, we find that limiting extracellular arginine results in the arrest of cancer cells at S phase and a slowing or stalling of DNA replication. The translation of new histone H4 is arginine dependent and influences DNA replication. Increased proliferating cell nuclear antigen (PCNA) occupancy and helicase-like transcription factor (HLTF)-catalyzed PCNA K63-linked polyubiquitination protect arginine-starved cells from DNA damage. Arginine-deprived cancer cells display tolerance to genotoxicity in a PCNA K63-linked polyubiquitination-dependent manner. Our findings highlight the crucial role of extracellular arginine in nutrient-regulated DNA replication and provide potential avenues for the development of cancer treatments.

Abstract Background The urachus is the embryological remnant of the cloaca and allantois. Failure of its regression can cause diseases any time after birth. It is difficult to differentiate an abscess from urachal adenocarcinoma based on the clinical presentation and image findings. Cystitis glandularis reflects chronic irritation of the bladder urothelium, and tumor-like florid cystitis glandularis can be misdiagnosed as malignancy. We report a patient with concurrent urachal abscess and florid cystitis glandularis which increased the resemblance of malignancy. Case presentation A 57-year-old female was incidentally found to have a heterogeneous pelvic mass abutting the urinary bladder. A cystoscopy examination revealed protruding tumors located in the bladder dome. Her blood test results were all normal, and urinalysis showed microscopic hematuria. Urachal cancer was diagnosed and en bloc excision of the umbilicus, tumor, and the involved bladder dome was performed. Pathology revealed urachal abscess with concurrent cystitis glandularis within the urinary bladder. No malignancy was identified in the resected specimen. Conclusions It is challenging to distinguish urachal abscess from a malignant tumor based on the clinical presentation and imaging studies. As in our case, the coexistence of urachal abscess and tumor-like florid cystitis glandularis increased the resemblance to a malignancy. This is the first reported case of the concurrence of these two disease entities, and emphasizes that the detection of bladder tumors on cystoscopy is not sufficient to make the diagnosis of urachal cancer with bladder involvement.

Background/purpose: Limited data are available on the role of illicit non-injecting drug use in a prolonged HIV outbreak that predominantly affected men who have sex with men (MSM) in Taiwan since 2006. We aimed to assess associations between specific types of drug use and incident HIV infections in this outbreak. Methods: We conducted a retrospective case–control study among MSM clients at voluntary counselling and testing (VCT) service at National Taiwan University Hospital (Taipei, Taiwan). We used BED IgG-capture enzyme immunoassay to identify incident HIV infection (cases), individually matched to HIV-negative MSM clients (controls) by HIV testing date. We used a structured questionnaire to obtain the information on illicit drug use and sexual risk behaviors. Results: From a total of 15,305 MSM client visits during 2006–2015, 387 cases were matched to 1012 controls. Use of inhaled nitrites (adjusted odds ratio [aOR] 2.1), MDMA (aOR 2.9), amphetamines (aOR 1.6), and ketamine (aOR 1.5) were independently associated with incident HIV infection. Polydrug (≥2 drugs) use was associated with the highest risk (aOR 4.3; 95% CI 2.6–7.2). While the proportion of MSM VCT clients who reported use of any recreational drug remained stable during 2006–2015 (average: 9.7%, P: 0.38), there was a shift in specific types of drug use, from MDMA/ketamine to inhaled nitrites/amphetamine, after 2011 (all Ps

Background/Purpose: Heavy metals impair renal function, causing chronic kidney disease (CKD), and the petrochemical industry is one of the major environmental metal emission sources. This study aimed to investigate the relationship between renal function and metal exposure among the Taiwanese residents living near a petrochemical industry site. Methods: We recruited residents near the No. 6 Naphtha Cracking Complex, and they were categorized into a high-exposure (HE) group (N = 190) in Taisi Village and a low-exposure (LE) group (N = 1184) in other villages of Dacheng Township in Changhua County of Taiwan. The urinary nickel, chromium, and vanadium levels of the study subjects were measured and the levels were standardized by urine creatinine, and the estimated glomerular filtration rates (eGFRs) were calculated to estimate renal function by one-time health data. Linear regression models were applied to illustrate the correlations between the distance to the complex and urinary metal levels and renal function; linear and logistic regression models were applied to evaluate the associations between urinary metal levels and renal function indicators. Results: The study subjects living closer to the petrochemical complex had significantly higher urinary nickel, chromium, and vanadium levels and worse renal function than study subjects living farther away. The urinary nickel and chromium levels of the study subjects were associated with their renal function indicators. When the subject's urinary nickel level increased 1-fold, the eGFR level significantly decreased by 0.820 ml/min/1.73 m2. Conclusion: Residents living closer to the petrochemical industry were exposed to higher metal levels and had worse renal function, and the nickel exposure of residents was potentially related to their decline in renal function.

Potato common scab, which is mainly caused by the bacterium Streptomyces scabies, occurs in key potato growing regions worldwide. It causes necrotic or corky symptoms on potato tubers and decreases the economic value of potato. At present, there is no recommended chemical or biological control for combating potato common scab in Taiwan. It can only reduce the occurrence by cultivation control, but the efficacy is limited. Previously we found that Bacillus amyloliquefaciens Ba01 could control potato common scab in pot assay and in the field. The potential anti-S. scabies mechanism was associated with surfactin secretion, but further molecular dissection was not conducted. Thus, in this study we aimed to determine whether surfactin is the main compound active against S. scabies by knocking out the srf gene cluster in Ba01. The cloning plasmid pRY1 was transformed to Ba01 by electroporation for in-frame deletion. Two independent Δsrf mutants were obtained and confirmed by specific primers and mass spectrometry. The swarming ability and S. scabies inhibition was significantly decreased (P

Objective: In Spring 2020, South Korea applied non-lockdown social distancing (avoiding mass gathering and non-essential social engagement, without restricting the movement of people who were not patients or contacts), testing-and-isolation (testing), and tracing-and-quarantine the contacts (contact tracing) to successfully control the first large-scale COVID-19 outbreak outside China. However, the relative contributions of these two interventions remain uncertain. Methods: We constructed an SEIR model of SARS-CoV-2 transmission (disproportionately through superspreading events) and fit the model to outbreak data in Daegu, South Korea, from February to April 2020. We assessed the effect of non-lockdown social distancing (population-wide control measures) and/or testing-contact tracing (individual-specific control measures), alone or combined, in terms of the basic reproductive number (R0) and the trajectory of the epidemic. Results: The point estimate for baseline R0 is 3.6 (sensitivity analyses range: 2.3 to 5.6). Combined interventions of non-lockdown social distancing and testing-contact tracing can suppress R0 to less than one and rapidly contain the epidemic, even under the worst scenario with a high baseline R0 of 5.6. In contrast, either intervention alone will fail to suppress R0. Non-lockdown social distancing alone just postpones the peak of the epidemic, while testing-contact tracing alone only flattens the curve but does not contain the outbreak. Conclusions: To successfully control a large-scale COVID-19 outbreak, both non-lockdown social distancing and testing-contact tracing must be implemented. The two interventions are synergistic.

Abstract Background Malignant obstruction and associated hydronephrosis is a common complication of advanced cervical cancer. Percutaneous nephrostomy (PCN) followed by antegrade stenting is often required to relieve obstruction as retrograde access fails in considerable proportion of such patients. Reno-pleural fistula is a rare complication of PCN which creates a patent connection between the renal collecting system and the thoracic cavity, and urine accumulation in the pleural space can cause pleural effusion (i.e., urinothorax). Upward or downward migration is a complication of indwelling ureteric stents. Further migration with extrusion outside of the urinary tract is uncommon. Herein we present an unprecedented case in adult of ureteric stent upward migration through a reno-pleural fistula into the thoracic cavity managed by thoracoscopy. Case presentation A 66-year-old female was diagnosed of advanced stage cervical cancer with suspicious bladder invasion. Given her bilateral hydronephrosis with impaired renal function, she underwent bilateral PCN and subsequent antegrade ureteric stenting. However, she presented with dyspnea, right back pain, and oliguria four days after bilateral PCN catheter removal. Computed tomography reported massive right pleural effusion and an intrathoracic ureteric stent within reno-pleural fistula. Thoracoscopy with thoracostomy was performed to remove the ureteric stent and urine in right pleural space. A week later, urinothorax had resolved and right PCN was performed again. She was discharged after regaining normal renal function with right PCN and a left ureteric stent in place. Conclusions A reno-pleural fistula can serve as a route for ureteric stent migration and that continuous drainage of urine can cause urinothorax once the stent reaches the thoracic cavity. Anytime a supracostal approach is used for PCN, even when using small caliber catheters, clinicians should pay special attention given the risk of pleural injury and subsequent complications.

Objective To investigate different parameters derived from the quantity and quality of perinephric fat, and to compare their effectiveness in predicting the malignant pathology of renal tumours. Methods Data from patients diagnosed with renal tumour between April 2014 and December 2020 were retrospectively reviewed, and patients were categorized into malignant or benign tumour groups. Fat parameters, including perinephric fat volume (PFV), perinephric fat area (PFA), perinephric fat thickness (PFT), and Mayo adhesive probability (MAP) score were measured using abdominal computed tomography scans. Between-group differences were assessed by analysis of variance and χ 2 -test. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the performance of perinephric fat parameters in diagnosing malignancy. Results A total of 109 patients were included. MAP score, PFV, PFA, and PFT were significantly increased in the malignant versus benign tumour group, and after correction for body mass index (BMI), the indexed PFV/BMI, PFA/BMI, and PFT/BMI values remained significantly higher in the malignant tumour group. All parameters showed fair predictivity of malignancy, with comparable area under the curve values in the ROC curve. Conclusion An increased amount of perinephric fat is predictive of malignant pathology for renal tumours. The predictive accuracy for each perinephric fat parameter remained fair after correcting for BMI.

Background/Purpose: Vancomycin-resistant Enterococcus (VRE), a multidrug-resistant, difficult-to-treat pathogen of healthcare-associated infections (HAIs), is now endemic at many intensive care units (ICUs). Chlorhexidine (CHG) bathing is a simple and highly effective intervention to decrease VRE acquisition, but its effect on VRE-HAIs has not been assessed in prospective studies at ICUs. Methods: This is a cluster quasi-experimental controlled study. Under active VRE surveillance and contact isolation of all identified VRE carriers, four ICUs were assigned to provide 2% CHG bathing for all patients on a daily basis (CHG group) during the intervention period, while another four ICUs were assigned to provide standard care without CHG bathing for all patients (standard care group) during the same period. Results: The CHG group (n = 1501) had a 62% lower crude incidence of VRE-HAIs during the intervention period, compared with the baseline period (1.0 vs. 2.6 per thousand patient-days, P = 0.009), while VRE-HAIs incidence did not change in standard care group (n = 3299) (1.1 vs. 0.5 per thousand patient-days, P = 0.139). In multivariable analyses, CHG bathing was independently associated with a 70% lower risk of VRE-HAIs (adjusted odds ratio [OR] 0.3, 95% confidence interval [CI], 0.2 to 0.7, P = 0.006). In contrast, standard care during the same period had no effect on the risk of VRE-HAIs (adjusted OR 1.8, 95% CI: 0.7 to 4.7, P = 0.259). Conclusion: CHG bathing is a highly effective approach to prevent VRE-HAIs at ICUs, in the context of active VRE surveillance with contact isolation.

Abstract Fibromyalgia syndrome (FM) is a multifactorial disorder whose pathogenesis and diagnosis are poorly understood. This study investigated differential serum proteome profiles in patients with FM and healthy pain-free controls and explored the association between serum proteome and clinical profiles in patients with FM. Twenty patients with FM (according to the American College of Rheumatology criteria, 2010) and 20 healthy pain-free controls were recruited for optimized quantitative serum proteomics analysis. The levels of pain, pressure pain threshold, sleep, anxiety, depression, and functional status were evaluated for patients with FM. We identified 22 proteins differentially expressed in FM when compared with healthy pain-free controls and propose a panel of methyltransferase-like 18 (METTL18), immunoglobulin lambda variable 3–25 (IGLV3–25), interleukin-1 receptor accessory protein (IL1RAP), and IGHV1OR21-1 for differentiating FM from controls by using a decision tree model (accuracy: 0.97). In addition, we noted several proteins involved in coagulation and inflammation pathways with distinct expression patterns in patients with FM. Novel proteins were also observed to be correlated with the levels of pain, depression, and dysautonomia in patients with FM. We suggest that upregulated inflammation can play a major role in the pathomechanism of FM. The differentially expressed proteins identified may serve as useful biomarkers for diagnosis and evaluation of FM in the future.

Here, the authors meta-analyze clinical trials comparing adjuvanted and non-adjuvanted influenza vaccines in children and find that oil-in-water emulsion adjuvant improves the efficacy of inactivated influenza vaccines in healthy immunologically naive children.

The transition dairy cows are challenged by various stresses such as decreased dry matter intake, liver dysfunction, increased inflammation, and oxidative stress, particularly in subtropical regions. These might increase the requirement for vitamin E and trace elements. To examine whether supplementation of vitamin E, selenium or copper, zinc, and manganese complex would help transition dairy cows to achieve greater reproduction performance by overcoming the immune function and postpartum disorders in subtropical Taiwan. A total of 24 Holstein Friesian dairy cows were enrolled in this study and divided into three groups (n = 8 cows/group): treatment 1 supplemented with organic selenium and vitamin E (SeE), treatment 2 supplemented with organic copper, zinc, and manganese complex (CZM) and control (CON). The results showed SeE supplementation improved immune function, reproductive performance, and milk yield, but not negative energy balance status. Supplementation of CZM improved milk yield and energy regulation through antioxidative capacity and immune function, but had no influence on reproductive performance.

BackgroundClostridioides difficile is the leading cause of nosocomial infectious diarrhea. Toll-like receptors (TLRs) are the major components of innate immunity that sense pathogens. The relationship between TLRs and C. difficile infection (CDI) was analyzed in clinical patients and a mouse model.Materials and MethodsA prospective investigation was conducted in medical wards of Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan, from January 2011 to January 2013. Adult patients were followed up for the development of CDI. Single nucleotide polymorphisms (SNPs) of TLR2 and TLR4 were analyzed to assess the relationship between genetic polymorphisms and the development of CDI. A mouse model of CDI was used to investigate the pathogenic role of TLRs in CDI, TLR2 and TLR4 knockout (Tlr2-/- and Tlr4-/-) mice.ResultsIn the prospective study, 556 patients were enrolled, and 6.5% (36) of patients, accounting for 3.59 episodes per 1000 patient-days, developed CDI. Of 539 patients with available blood samples, the TLR2 rs3804099 polymorphism was more often noted in those with CDI than in those without CDI (64.5% vs. 46.1%; P = 0.046) but was not significant in multivariate analysis. Because the TLR2 rs3804099 polymorphism was moderately associated with CDI, the role of TLR2 and TLR4 was further evaluated in a mouse model. Both Tlr2-/- and Tlr4-/- mice showed more severe CDI disease than wild-type mice in terms of body weight change and fecal content five days after oral challenge with C. difficile. Furthermore, Tlr2-/- mice suffered from more severe disease than Tlr4-/- mice, as evidenced by stool consistency, cecum weight, and survival rate.ConclusionThe TLR2 rs3804099 polymorphism is marginally associated with the development of CDI, and the pathogenic role of TLR2 is further supported by a mouse model.

This study aimed to investigate the effect of supplementation with a mixture of molasses and condensed molasses fermentation solubles (M-CMS) in different synchronization diets formulated with different forage sources in an attempt to improve the fermentation efficiency of diets by M-CMS. In the first experiment, three levels of M-CMS (N: 0%; L: 1.75%; and H: 3.50%) were supplied to diets with or without corn silage to evaluate the supplementation effect on the diet with a synchrony index (SI) of 0.80. In the second experiment, diets containing different corn silage levels (60 or 30% of the forage source) were used to evaluate the effects of M-CMS supplementation on higher SI (at 0.88). The in vitro digestibility, fermentation products, microbial crude protein (MCP), and gas kinetic parameters were determined after 48 h of fermentation. The results demonstrated that M-CMS supplementation improved MCP synthesis in both diets with low and high SI, but did not enhance digestibility. M-CMS supplementation was beneficial to the fermentation stability and extent. It also affected the gas kinetic parameters of the fast- and slow-degradation fractions during fermentation. M-CMS supplementation improved MCP synthesis in diets containing less corn silage. The forage source and degradation rate of individual ingredients should be considered simultaneously to enhance the rumen fermentation efficiency. M-CMS provided a practical choice to further improve MCP synthesis and fermentation stability, even in a diet with high SI.

Although numerous epidemiological studies revealed an association between ambient fine particulate matter (PM2.5) exposure and Alzheimer's disease (AD), the PM2.5-induced neuron toxicity and associated mechanisms were not fully elucidated. The present study assessed brain toxicity in 6-month-old female triple-transgenic AD (3xTg-AD) mice following subchronic exposure to PM2.5 via an inhalation system. The treated mice were whole-bodily and continuously exposed to real-world PM2.5 for 3 months, while the control mice inhaled filtered air. Changes in cognitive and motor functions were evaluated using the Morris Water Maze and rotarod tests. Magnetic resonance imaging analysis was used to record gross brain volume alterations, and tissue staining with hematoxylin and eosin, Nissl, and immunohistochemistry methods were used to monitor pathological changes in microstructures after PM2.5 exposure. The levels of AD-related hallmarks and the oxidative stress biomarker malondialdehyde (MDA) were assessed using Western blot analysis and liquid chromatography-mass spectrometry, respectively. Our results showed that subchronic exposure to environmental levels of PM2.5 induced obvious neuronal loss in the cortex of exposed mice, but without significant impairment of cognitive and motor function. Increased levels of phosphorylated-tau and MDA were also observed in olfactory bulb or hippocampus after PM2.5 exposure, but no amyloid pathology was detected, as reported in previous studies. These results revealed that a relatively lower level of PM2.5 subchronic exposure from the environmental atmosphere still induced certain neurodegenerative changes in the brains of AD mice, especially in the olfactory bulb, entorhinal cortex and hippocampus, which is consistent with the nasal entry and spreading route for PM exposure. Systemic factors may also contribute to the neuronal toxicity. The effects of PM2.5 after a more prolonged exposure period are needed to establish a more comprehensive picture of the PM2.5-mediated development of AD.

There is a strong association between animal abuse and interpersonal violence; therefore, veterinarians may encounter both. Dealing with animal abuse cases is beneficial for advancing animal welfare and the overall public health. Veterinarians play an important role in identifying and responding to this relationship. This study estimated the incidence of animal abuse encountered by veterinarians, examined veterinarians’ awareness of the relationship between animal abuse and human abuse, examined veterinarians’ attitudes towards how they deal with abuse cases, and related demographic characteristics to their attitudes of intervention and the frequency of encountering abuse cases. An anonymous self-administered questionnaire was designed and distributed through social media. Our results show that respondents’ motivation to interfere for animal abuse cases was positively related to their moral or legal responsibility, willingness to assist, and agreement of mandatory reporting. Our results indicated that respondents who believed they had been provided with adequate training were more willing to deal with animal abuse, more capable of distinguishing abuse cases, and did not believe that dealing with abuse cases was beyond their ability. However, more than 60% of our respondents self-evaluated that the animal cruelty awareness training courses were insufficient. Hence, in addition to the traditional role of veterinarians, identifying and responding to animal cruelty should be enhanced through education.

ABSTRACT Streptococcus pyogenes (group A Streptococcus [GAS]) is an important human pathogen causing a broad spectrum of diseases and associated with significant global morbidity and mortality. Almost all GAS isolates express a surface hyaluronic acid capsule, a virulence determinant that facilitates host colonization and impedes phagocyte killing. However, recent epidemiologic surveillance has reported a sustained increase in both mucosal and invasive infections caused by nonencapsulated GAS, which questions the indispensable role of hyaluronic acid capsule in GAS pathogenesis. In this study, we found that pilus of M4 GAS not only significantly promotes biofilm formation, adherence, and cytotoxicity to human upper respiratory tract epithelial cells and keratinocytes, but also promotes survival in human whole blood and increased virulence in murine models of invasive infection. T4 antigen, the pilus backbone protein of M4 GAS, binds haptoglobin, an abundant human acute-phase protein upregulated upon infection and inflammation, on the bacterial surface. Haptoglobin sequestration reduces the susceptibility of nonencapsulated M4 GAS to antimicrobial peptides released from activated neutrophils and platelets. Our results reveal a previously unappreciated virulence-promoting role of M4 GAS pili, in part mediated by co-opting the biology of haptoglobin to mitigate host antimicrobial defenses. IMPORTANCE Group A Streptococcus (GAS) is a strict human pathogen causing more than 700 million infections globally each year. The majority of the disease-causing GAS are encapsulated, which greatly guarantees survival and dissemination in the host. Emergence of the capsule-negative GAS, such as M4 GAS, in recent epidemiologic surveillance alarms the necessity to elucidate the virulence determinants of these pathogens. Here, we found that M4 pili play an important role in promoting M4 GAS adherence and cytotoxicity to human pharyngeal epithelial cells and keratinocytes. The same molecule also significantly enhanced M4 GAS survival and replication in human whole blood and experimental murine infection. T4 antigen, which composes the backbone of M4 pili, was able to sequester the very abundant serum protein haptoglobin to further confer M4 GAS resistance to antibacterial substances released by neutrophils and platelets.

BACKGROUND:Undiagnosed tuberculosis (TB) patients hospitalized because of comorbidities constitute a challenge to TB control in hospitals. We aimed to assess the impact of introducing highly sensitive fluorescent microscopy for examining sputum smear to replace conventional microscopy under a high TB risk setting. METHODS:We measured the impact of switch to fluorescent microscopy on the smear detection rate of culture-confirmed pulmonary TB, timing of respiratory isolation, and total non-isolated infectious person-days in hospital at a high-caseload medical center (approximately 400 TB cases annually) in Taipei. Multivariable Cox regression was applied to adjust for effects of covariates. The effect attributable to the improved smear detection rate was determined using causal mediation analysis. RESULTS:After switch to fluorescence microscopy, median non-isolated infectious duration decreased from 12.5 days to 3 days (P

Background: Doxycycline possesses antibacterial activity against Clostridioides difficile and anti-inflammatory effects. Materials and Methods: The influence of doxycycline on the development of CDI was studied in an established animal model of CDI using C57BL/6 mice. Results: Mice intraperitoneally administered doxycycline had higher cecum weight (1.3 ± 0.1 vs. 0.5 ± 0.1 g; p < 0.001) and less body weight reduction (0.7 ± 0.5 g vs. −17.4 ± 0.2 g; p < 0.001) than untreated mice infected with C. difficile. Oral doxycycline, metronidazole, or vancomycin therapy resulted in less body weight reduction in mice with CDI than in untreated mice (1.1 ± 0.1 g, 1.3 ± 0.2 g, 1.2 ± 0.1 g, vs. 2.9 ± 0.3 g; p < 0.001). Doxycycline therapy led to lower expression levels of inflammatory cytokines, such as macrophage inflammatory protein-2 (0.4 ± 0.1 vs. 2.9 ± 1.3, p = 0.02), and higher levels of zonula occludens-1 (1.2 ± 0.1 vs. 0.8 ± 0.1, p = 0.02) in colonic tissues than in untreated mice. Conclusions: Concurrent intraperitoneal administration of doxycycline and oral C. difficile challenge does not aggravate the disease severity of CDI, and oral doxycycline may be a potential therapeutic option for CDI.

This article reviews the current developments in genus Dehalococcoides as key dechlorinating bacteria in chlorinated ethene contaminated sites. The presence of chlorinated ethenes in environment had been a concern for more than five decades as it represents significant threat to human and ecological health due to its extreme toxicity. This review elucidates the kinetics of Dehalococcoides spp. growth and compound utilization in dechlorination of chlorinated ethenes compounds. The metabolic pathways in physiology of Dehalococcoides spp. are important in the transformation of chlorinated species. The potential of isolates and its reductive dehalogenase genes are seen to infer activities of Dehalococcoides spp. that would be used to the development of engineered systems. This system is helpful in making decision on bioremediation option to treat the contaminated groundwater. Hence, the role of Dehalococcoides spp. in chlorinated ethene biodegradation is controlled by kinetics in complex ways. Therefore, intensive in-situ characterization and understanding the microbial growth on dechlorination evaluation are essential to develop a consistent and rational engineered system. This is to achieve a successful bioremediation strategies for sites contaminated with chlorinated ethenes.

Abstract Clinical management of Clostridium difficile infection is still far from satisfactory as bacterial spores are resistant to many chemical agents and physical treatments. Certain types of nanoparticles have been demonstrated to exhibit anti-microbial efficacy even in multi-drug resistance bacteria. However, most of these studies failed to show biocompatibility to the mammalian host cells and no study has revealed in vivo efficacy in C. difficile infection animal models. The spores treated with 500 µg/mL Fe3-δO4 nanoparticles for 20 minutes, 64% of the spores were inhibited from transforming into vegetative cells, which was close to the results of the sodium hypochlorite-treated positive control. By cryo-electron micro-tomography, we demonstrated that Fe3-δO4 nanoparticles bind on spore surfaces and reduce the dipicolinic acid (DPA) released by the spores. In a C. difficile infection animal model, the inflammatory level triple decreased in mice with colonic C. difficile spores treated with Fe3-δO4 nanoparticles. Histopathological analysis showed a decreased intense neutrophil accumulation in the colon tissue of the Fe3-δO4 nanoparticle-treated mice. Fe3-δO4 nanoparticles, which had no influence on gut microbiota and apparent side effects in vivo, were efficacious inhibitors of C. difficile spore germination by attacking its surface and might become clinically feasible for prophylaxis and therapy.

The back-end intelligent system of Internet of Things (IoT) needs the powerful computing ability to support its service, and therefore, IoT is often constructed on the cloud platform. However, the resources for cloud computing are limited, and different types of services will have different demands for the resources. This paper proposed a service-oriented virtual machine (VM) placement strategy in cloud data center and divided the roles of VM into Web role, worker role, and storage according to the function types. On the basis of service orientation and in consideration of communication overhead between VMs in the data center, the genetic algorithm was used to conduct the optimal configuration for different types of VMs under the situation of limited resources to achieve the minimum communication overhead and total power consumption. The proposed cloud VM placement strategy is also suitable for the intelligent computing platform of IoT back end.

This paper proposes a robot peer reciprocal learning system in which robot peers can not only cooperatively accomplish a difficult task but also help each other to learn better. In this system, each robot is an independent individual and has the ability to make individual decisions. They can communicate about image information, individual decisions, and current state to formulate mutual decisions and motions. For learning a new concept, we propose a mutual learning method, which allows the robots to learn from each other by exchanging weights in their neural network concept learning system. The simulation results show that the robots can learn from each other to build general concepts from limited training, while improving both of their performances at the same time. Finally, we design two cooperative tasks, which require the robots to formulate mutual sequential motions and keep communicating to manage their motions. The robotic experiments demonstrate that the proposed robot peer reciprocal learning system can help robots achieve difficult tasks in appropriate and cooperative ways, just as humans do.

Current antibiotic treatments fail to eliminate the Clostridium difficile (C. difficile) spores and induce dysbiosis and intestinal inflammation via off-target effect, which causes refractory C. difficile infection raise an unmet need for a spore-specific antimicrobial treatment. We developed a sporicidal and antimicrobial vancomycin-loaded spore-targeting iron oxide nanoparticle (van-IONP) that selectively binds to C. difficile spores. Cryo-electron microscopy showed that vancomycin-loaded nanoparticles can target and completely cover spore surfaces. They not only successfully delayed the germination of the spores but also inhibited ∼50% of vegetative cell outgrowth after 48 h of incubation. The van-IONPs also inhibited the interaction of spores with HT-29 intestinal mucosal cells in vitro. In a murine model of C. difficile infection, the van-IONP significantly protected the mice from infected by C. difficile infection, reducing intestinal inflammation, and facilitated superior mucosal viability compared with equal doses of free vancomycin. This dual-function targeted delivery therapy showed advantages over traditional therapeutics in treating C. difficile infection.

Enterovirus 71 (EV71) has emerged as a neurological virus causing life-threatening diseases in young children and infants. Although EV71 vaccines in development have presented promising results in several clinical trials, the identified key antigen for improving the broad protective efficacy of EV71 vaccines has not been well investigated. In this report, we show that different multiplicities of infection (MOIs) of the B4(E59) virus significantly affect EV71 vaccine production in a serum-free microcarrier bioreactor system. The antigens produced from high MOIs of 10-1 and 10-2 exhibited higher yield and more infectious full particle (FP) contents in the EV71 vaccines than those produced with low MOIs of 10-4 and 10-6, leading to better cross-neutralizing efficacy. The C4(E36) neutralization results showed that only antisera raised from EV71 FPs provided substantial neutralizing titers against C4(E36), whereas empty particles (EPs) of EV71 conferred no efficacy. Competitive ELISA showed that anti-FP mainly binds to FPs and that 20% of antibodies bind to EPs, whereas most anti-EP binds EPs, with only 10% antibodies binding to FPs. VP1-adsorbed anti-FP lost most of the virus neutralization efficiency, suggesting that the VP1 subunit of FP is the major immunogenic antigen determining the ability of the EV71 vaccine to elicit cross-neutralizing antibodies against EV71 virus subtypes. These findings demonstrate that the high-MOI production approach is significantly correlated with FP productivity, thereby improving the cross-neutralization efficacy of an EV71 vaccine and providing the basis for a better vaccine design against widespread EV71 viruses.

The tumor microenvironment plays a critical role in the control of metastasis. The epithelial–mesenchymal transition (EMT) is strongly associated with tumor metastasis, and consists of several protein markers, including E-cadherin and vimentin. We discovered that chrysophanol causes oral cancer cell apoptosis and the inhibition of migration/invasion and EMT. However, the detailed mechanisms of chrysophanol and its role in oral cancer with respect to the tumor microenvironment remain unknown. In the clinic, proinflammatory cytokines, such as IL-6 and IL-8, exhibit a higher expression in patients with oral cancer. However, the effect of chrysophanol on the production of IL-6 and IL-8 is unknown. We evaluated the expression of IL-6 and IL-8 in human SAS and FaDu oral cancer cell lines in the presence or absence of chrysophanol. The migration and invasion abilities were also determined using a Boyden chamber assay. Our results showed that treatment with chrysophanol significantly decreased the expression of IL-6 and IL-8, as well as the invasion ability of oral cancer cells. Moreover, chrysophanol also attenuated the EMT by increasing the expression of E-cadherin and reducing the expression of vimentin. Mechanistically, chrysophanol inhibited IL-6- and IL-8-induced invasion and STAT3 phosphorylation. IL-6 and IL-8 promote EMT and cell invasion, which is potentially related to the STAT3 signaling pathway in oral cancer. These findings provide insight into new aspects of chrysophanol activity and may contribute to the development of new therapeutic strategies for oral cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

This paper aims to propose a strategy for the flight control of quad-rotors under single rotor failure conditions. The proposed control strategy consists of two stages—fault detection (FD) and fault tolerant control (FTC). A dual observer-based strategy for FD and fault estimation is developed. With the combination of the results from both observers, the decision making in whether a fault actually happened or the observed anomaly was caused by an external disturbance could be distinguished. Following the FD result, a control strategy for normal flight, as well as the abnormal one, is presented. The FTC considers a real-time coordinate transformation scheme to manipulate the target angles for the quad-rotor to follow a prescribed trajectory. When a rotor fault happens, it is going to be detected by the dual observers and then the FTC is activated to stabilize the system such that the trajectory following task can still be fulfilled. Furthermore, in order to achieve robust flight in the presence of external wind perturbation, the sliding mode control (SMC) theory is further integrated. Simulations illustrate the effectiveness and feasibility of the proposed method.

Clostridium difficile infection (CDI) is the leading cause of nosocomial infection in hospitalized patients receiving long-term antibiotic treatment. An excessive host inflammatory response is believed to be the major mechanism underlying the pathogenesis of C. difficile infection, and various proinflammatory cytokines such as IL-1β are detected in patients with C. difficile infection. IL-1β is known to be processed by caspase-1, a cysteine protease that is regulated by a protein complex called the inflammasome, which leads to a specialized form of cell death called pyroptosis. The function of inflammasome activation-induced pyroptosis is to clear or limit the spread of invading pathogens via infiltrated neutrophils. Here, we focused on inflammasome activation induced by intact C. difficile to re-evaluate the nature of inflammasome activation in CDI pathogenesis, which could provide information that leads to an alternative therapeutic strategy for the treatment of this condition in humans. First, we found that caspase-1-dependent IL-1β production was induced by C. difficile pathogens in macrophages and increased in a time-dependent manner. Moreover, intracellular toxigenic C. difficile was essential for ATP-P2X7 pathway of inflammasome activation and subsequent caspase-1-dependent pyroptotic cell death, leading to the loss of membrane integrity and release of intracellular contents such as LDH. Notably, we also observed that bacterial components such as surface layer proteins (SLPs) were released from pyroptotic cells. In addition, pro-IL-1β production was completely MyD88 and partially TLR2 dependent. Finally, to investigate the role of the caspase-1-dependent inflammasome in host defense, we found that colonic inflammasome activation was also induced by CDI and that caspase-1 inhibition by Ac-YVAD-CMK led to increased disease progression and C. difficile load. Taken together, the present results suggest that MyD88 and TLR2 are critical component in pro-IL-1β production and intracellular C. difficile following the ATP-P2X7 pathway of inflammasome activation and pyroptosis, which play important roles in host defense through the utilization of inflammation-mediated bacterial clearance mechanisms during C. difficile infection.

Dementia is a common neurological disease that substantially affects public health. A previous study revealed that dementia occurs when the body's immune system attacks the cells of the brain, indicating that dementia may be similar to autoimmune rheumatic diseases (ARDs). In the current retrospective cohort study, we focused on middle-aged ARD patients (45 years or older) to investigate the association between ARDs in middle-aged people and dementia by using a nationwide population-based database in Taiwan.Our study analyzed the medical data of the Taiwanese population from 2001 to 2012, with a follow-up period extending until the end of 2011. We identified middle-aged patients with ARDs by using the Taiwan National Health Insurance Research Database. We selected a comparison cohort from the general population that was randomly frequency-matched by age (in 5-year increments), sex, and index year and further analyzed the dementia risk by using a Cox regression model that considers sex, age, and comorbidities.The study enrolled 34,660 middle-aged ARD patients (77% female, mean age = 59.8 years) and 138,640 controls. The risk of developing dementia was 1.18 times higher for middle-aged patients with ARDs compared with patients without ARDs after adjustment for age, sex, and comorbidities. Among the patients with ARDs, the subgroups with rheumatoid arthritis, systemic lupus erythematosus, and Sjögren syndrome (SS) were associated with a significantly higher dementia risk (adjusted hazard ratio [HR] 1.14, 95% confidence index [CI] 1.06-1.32; adjusted HR 1.07, 95% CI 0.86-1.34; adjusted HR 1.46, 95% CI 1.32-1.63, respectively). Furthermore, primary SS and secondary SS patients had the highest risks of dementia among all the ADR subgroups (adjusted HR 1.35, 95% CI 1.18-1.54; adjusted HR 1.67, 95% CI 1.43-1.95 respectively).This nationwide retrospective cohort study demonstrated that dementia risk is significantly higher in middle-aged patients with ARDs compared with the general population.

Virus-encoded microRNAs (miRNAs) have been shown to regulate a variety of biological processes involved in viral infection and viral-associated pathogenesis. Epstein-Barr virus (EBV) is a herpesvirus implicated in nasopharyngeal carcinoma (NPC) and other human malignancies. EBV-encoded miRNAs were among the first group of viral miRNAs identified. To understand the roles of EBV miRNAs in the pathogenesis of NPC, we utilized deep sequencing technology to characterize the EBV miRNA transcriptome in clinical NPC tissues. We obtained more than 110,000 sequence reads in NPC samples and identified 44 EBV BART miRNAs, including four new mature miRNAs derived from previously identified BART miRNA precursor hairpins. Further analysis revealed extensive sequence variations (isomiRs) of EBV miRNAs, including terminal isomiRs at both the 5' and 3' ends and nucleotide variants. Analysis of EBV genomic sequences indicated that the majority of EBV miRNA nucleotide variants resulted from post-transcriptional modifications. Read counts of individual EBV miRNA in NPC tissue spanned from a few reads to approximately 18,000 reads, confirming the wide expression range of EBV miRNAs. Several EBV miRNAs were expressed at levels similar to highly abundant human miRNAs. Sequence analysis revealed that most of the highly abundant EBV miRNAs share their seed sequences (nucleotides 2-7) with human miRNAs, suggesting that seed sequence content may be an important factor underlying the differential accumulation of BART miRNAs. Interestingly, many of these human miRNAs have been found to be dysregulated in human malignancies, including NPC. These observations not only provide a potential linkage between EBV miRNAs and human malignancy but also suggest a highly coordinated mechanism through which EBV miRNAs may mimic or compete with human miRNAs to affect cellular functions.