Search

Tzu-Yi Wu,1 Chia-Hua Chung,2 Chia-Ni Lin,3 Jing-Shiang Hwang,2 Jung-Der Wang3,4 1Institute of Economics, Academia Sinica, Taipei, Taiwan; 2Institute of Statistical Science, Academia Sinica, Taipei, Taiwan; 3Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan Background: The mortality rates for different cancers are no longer an efficient tool for making national policy. The purpose of this study were to quantify the lifetime risks, life expectancies (LEs) after diagnosis, expected years of life lost (EYLL), and lifetime health care expenditures for 19 major cancers in Taiwan. Methods: A total of 831,314 patients with 19 pathologically proven cancers were abstracted from the Taiwan Cancer Registry from 1998 to 2012. They were linked to the National Mortality Registry (1998–2014) and National Health Insurance reimbursement database (1998–2013) for survival and health care costs. We estimated the cumulative incidence rate for ages 0–79 years and the lifetime survival function for patients with different cancer sites. The EYLL was calculated by subtracting the LE of each cancer cohort from that of the age- and sex-matched referents simulated from national life tables. The estimated lifetime cost was calculated by adding up the product of survival probability and mean cost at the corresponding duration-to-date after adjustment for the inflation to the year of 2013. Results: There were 5 cancers with a lifetime risk exceeding 4%: colorectal, liver, lung, and prostate in males, and breast and colorectal in females. Cancers with EYLL of >10 years were: esophageal, intrahepatic bile ducts, liver, pancreas, oral, nasopharyngeal, leukemia, lung, and gallbladder, extrahepatic bile ducts and biliary tract in males, and intrahepatic bile ducts, pancreas, nasopharyngeal, lung, esophageal, leukemia, liver, gallbladder, extrahepatic bile ducts and biliary tract, ovary, and stomach in females. Cancers with lifetime health care expenditures exceeding US$50,000 to the National Health Insurance were as follows: leukemia, kidney, testis, renal pelvis and ureter in males, and renal pelvis and ureter, leukemia, breast, urinary bladder, kidney, ovary, and nasopharyngeal in females. All these impacts should be considered in health policy decisions. Conclusion: The impacts of cancer in Taiwan are very large. Future studies must consider both quality of life and the entire impact from societal perspectives. Keywords: health impacts, incidence rate, expected years of life lost, cancer prevention

Biphenotypic acute leukemias account for 4% to 8% of all acute leukemias. Most of these leukemias are of myeloid--B-cell or myeloid--T-cell lineage. Acute myeloid--natural killer cell leukemia has been recognized recently. We report the first case, to our knowledge, of CD56[sup+] acute leukemia showing unequivocal myeloid and B-cell differentiation in a 20-year-old woman, whose blast cells were positive for myeloperoxidase, CD13, CD33, CD117, terminal deoxynucleotidyl transferase, CD19, CD20, CD22, CD34, HLA-DR, and CD56 but negative for CD3, CD5, CD7, and CD10. Rare Auer rods were identified in the blast cells. Polymerase chain reaction assays showed rearrangement of immunoglobulin heavy-chain gene and absence of Epstein-Barr virus DNA. We propose that this novel form of multilineage leukemia may represent the neoplastic counterpart of a progenitor that can give rise to myeloid, B, and natural killer cells. [ABSTRACT FROM AUTHOR]

Porcine Circovirus type (PCV) 2 is an important pathogen that has been circulating worldwide and has cuased serious economic loss in pig industry. However, both PCV3 and PCV4 are newly emerging viruses. In Taiwan, PCV2 has been one of the critical pathogens in pig frams and PCV3 has been detected since 2016; however, the epidemiolog of PCV3 in Taiwan remains unclear and PCV4 has yet to be identified. Therefore, in order to detect the positive rate of PCV2, to investigate the epidemiolog of PCV3 in the pig farms, and to examine whether pigs were infected with PCV4 in Taiwan, a total of 128 samples from 46 clinical cases of pigs were collected from September 2020 to December 2021. The case detection rates were 54.3 % for PCV2, 43.5 % for PCV3, and 2.2 % for PCV4. The results suggested that the positivity rates for both PCV2 and PCV3 were still high in Taiwan. In addition, PCV3 was detected among cases from all 7 sampled counties and in 11 of the 16 sampling months, suggesting that PCV3 may lead to endemic pig disease in Taiwan. Surprisingly, the PCV4 was also detected, suggesting the first PCV4 case in Taiwan. The complete genomes derived from the identified PCV3 and PCV4 strains were subsequently sequenced followed by phylogenetic analysis. The results suggested that the 17 identified PCV3 strains could be divided into Taiwanese-like and Japanese-like strains. In addition, the amino acid residues at positions 27, 80, and 212 in the identified PCV4 cap protein were asparagine, isoleucine, and methionine, respectively, and thus the identified PCV4 was catalorized into clade PCV4b. Consequently, it is concluded that (i) the prevalence of PCV2 and PCV3 is still high in Taiwanese pigs, (ii) PCV3 has may be an endemic infection in Taiwan and can be classified into Japanese-like and Taiwanese-like strains, (iii) PCV4 was detected for the first time in Taiwanese pigs and can be classified into PCV4b. It remains unclear how PCV2, PCV3, and PCV4 were introduced to Taiwan, and thus continuous investigation of emerging pathogens in pigs is needed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

This study investigated antimicrobial resistance in Salmonella enterica serovar Choleraesuis (S. Choleraesuis) isolates from diseased pigs in Taiwan (2015-2020). Among 272 isolates, florfenicol (96.7%), enrofloxacin (96.3%), doxycycline (91.2%), gentamicin (84.6%), and tiamulin (80.5%) exhibited high resistance. 99.3% of the isolates were resistant to at least one antibiotic, and 97.8% of the isolates were multidrug resistant. This study illustrated that S. Choleraesuis isolates exhibited high resistance to antimicrobials currently used in the Taiwanese swine industry., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024. Published by Elsevier B.V.)

Actinobacillus pleuropneumoniae infection causes a high mortality rate in porcine animals. Antimicrobial resistance poses global threats to public health. The current study aimed to determine the antimicrobial susceptibilities and probe the resistome of A. pleuropneumoniae in Taiwan. Herein, 133 isolates were retrospectively collected; upon initial screening, 38 samples were subjected to next-generation sequencing (NGS). Over the period 2017-2022, the lowest frequencies of resistant isolates were found for ceftiofur, cephalexin, cephalothin, and enrofloxacin, while the highest frequencies of resistant isolates were found for oxytetracycline, streptomycin, doxycycline, ampicillin, amoxicillin, kanamycin, and florfenicol. Furthermore, most isolates (71.4%) showed multiple drug resistance. NGS-based resistome analysis revealed aminoglycoside- and tetracycline-related genes at the highest prevalence, followed by genes related to beta-lactam, sulfamethoxazole, florphenicol, and macrolide. A plasmid replicon (repUS47) and insertion sequences (IS10R and ISVAp11) were identified in resistant isolates. Notably, the multiple resistance roles of the insertion sequence IS10R were widely proposed in human medicine; however, this is the first time IS10R has been reported in veterinary medicine. Concordance analysis revealed a high consistency of phenotypic and genotypic susceptibility to florphenicol, tilmicosin, doxycycline, and oxytetracycline. The current study reports the antimicrobial characterization of A. pleuropneumoniae for the first time in Taiwan using NGS.

In this study, we aimed to validate a novel light field virtual reality (LFVR) system for estimating refractive errors in the human eye. Fifty participants with an average age of 22.12 ± 2.2 years (range 20-30 years) were enrolled. The present study compared spherical equivalent (SE) and focal line measurements (F1 and F2) obtained by the LFVR system with those obtained by established methods, including closed-field and open-field autorefractors, retinoscopy, and subjective refraction. The results showed substantial agreement between the LFVR system and the traditional methods, with intraclass correlation coefficients (ICC) for SE ranging from 82.7% to 86.7% ( p < 0.01), and for F1 and F2 from 80.7% to 86.4% ( p < 0.01). Intra-repeatability for F1 and F2 demonstrated strong agreement, with ICC values of 88.8% and 97.5%, respectively. These findings suggest that the LFVR system holds potential as a primary tool for refractive error measurement in optical care, offering high agreement and repeatability compared to conventional methods.

In this study, we optimized the parameters of diffusion bonding on multi-layered stainless steel 316L and 430 stacks. The preparation process for diffusion bonding is crucial, as the bonding surfaces need to be polished and meticulously cleaned to ensure a smooth bonding process. We fabricated twelve-layer plates consisting of 55 mm × 55 mm × 3 mm and 100 mm × 50 mm × 3 mm dimensions, and the bonding response was investigated by evaluating the tensile strength of the bonding zone under varying bonding conditions, with a bonding temperature ranging from 1000 to 1048 °C, a bond time ranging from 15 to 60 min, pressure ranging from 10 to 25.3 MPa, and under a vacuum environment. SS430 exhibits a significantly higher compression creep rate than SS316L. The compressibility of diffusion welding materials does not impact the diffusion bonding strength. Multi-axial tensile strength tests confirmed strong bonding joint strength in various axes. The tensile strengths of monolithic and Diffusion bonding (DB) specimens tested in parallel are essentially identical. The optimized diffusion bonding parameters (Condition G2C: 1048 °C/25.3 MPa/15 min) are ideal for producing SS316L stainless steel cores in compact heat exchangers, offering a superior bonding quality and reduced costs. These findings have practical implications for the production of stainless steel cores in compact heat exchangers, demonstrating the relevance and applicability of our research.

Background: Ovarian carcinoma (OC) is a fatal malignancy, with most patients experiencing recurrence and resistance to chemotherapy. In contrast to hematogenous metastasizing tumors, ovarian cancer cells disseminate within the peritoneal cavity, especially the omentum. Previously, we reported omental crown-like structure (CLS) number is associated with poor prognosis of advanced-stage OC. CLS that have pathologic features of a dead or dying adipocyte was surrounded by several macrophages is well known a histologic hallmark for inflammatory adipose tissue. In this study, we attempted to clarify the interaction between metastatic ovarian cancer cells and omental CLS, and to formulate a therapeutic strategy for advanced-stage ovarian cancer., Methods: A three-cell (including OC cells, adipocytes and macrophages) coculture model was established to mimic the omental tumor microenvironment (TME) of ovarian cancer. Caspase-1 activity, ATP and free fatty acids (FFA) levels were detected by commercial kits. An adipocyte organoid model was established to assess macrophages migration and infiltration. In vitro and in vivo experiments were performed for functional assays and therapeutic effect evaluations. Clinical OC tissue samples were collected for immunochemistry stain and statistics analysis., Results: In three-cell coculture model, OC cells-derived IL-6 and IL-8 could induce the occurrence of pyroptosis in omental adipocytes. The pyroptotic adipocytes release ATP to increase macrophage infiltration, release FFA into TME, uptake by OC cells to increase chemoresistance. From OC tumor samples study, we demonstrated patients with high gasdermin D (GSDMD) expression in omental adipocytes is highly correlated with chemoresistance and poor outcome in advanced-stage OC. In animal model, by pyroptosis inhibitor, DSF, effectively retarded tumor growth and prolonged mice survival., Conclusions: Omental adipocyte pyroptosis may contribute the chemoresistance in advanced stage OC. Omental adipocytes could release FFA and ATP through the GSDMD-mediate pyroptosis to induce chemoresistance and macrophages infiltration resulting the poor prognosis in advanced-stage OC. Inhibition of adipocyte pyroptosis may be a potential therapeutic modality in advanced-stage OC with omentum metastasis., (© 2024. The Author(s).)

Purpose: Immune checkpoint inhibitors (ICIs) have significantly improved the survival of patients with cancer and provided long-term durable benefit. However, ICI-treated patients develop a range of toxicities known as immune-related adverse events (irAEs), which could compromise clinical benefits from these treatments. As the incidence and spectrum of irAEs differs across cancer types and ICI agents, it is imperative to characterize the incidence and spectrum of irAEs in a pan-cancer cohort to aid clinical management., Design: We queried >400 000 trials registered at ClinicalTrials.gov and retrieved a comprehensive pan-cancer database of 71 087 ICI-treated participants from 19 cancer types and 7 ICI agents. We performed data harmonization and cleaning of these trial results into 293 harmonized adverse event categories using Medical Dictionary for Regulatory Activities., Results: We developed irAExplorer (https://irae.tanlab.org), an interactive database that focuses on adverse events in patients administered with ICIs from big data mining. irAExplorer encompasses 71 087 distinct clinical trial participants from 343 clinical trials across 19 cancer types with well-annotated ICI treatment regimens and harmonized adverse event categories. We demonstrated a few of the irAE analyses through irAExplorer and highlighted some associations between treatment- or cancer-specific irAEs., Conclusion: The irAExplorer is a user-friendly resource that offers exploration, validation, and discovery of treatment- or cancer-specific irAEs across pan-cancer cohorts. We envision that irAExplorer can serve as a valuable resource to cross-validate users' internal datasets to increase the robustness of their findings., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Over the past few decades, gout and diseases like metabolic syndrome (MetS) have become more prevalent. Attempts have been made in Taiwan to identify the genes responsible for gout. A few gene loci, among them SLC2A9 , have been identified using Taiwan Biobank (TWB) data. We, therefore, examined whether MetS could also account for the association between polymorphism SLC2A9 rs3733591 and gout., Methods: The final analysis consisted of 73,558 subjects, of whom 2,709 had gout. To estimate the likelihood of gout occurrence based on rs3733591 and MetS, we used logistic regression models., Results: Rs3733591-TC + CC compared to TT genotype was associated with gout (OR, 1.15; 95% CI, 1.06-1.25). Also associated with gout was MetS (OR, 1.21; 95% CI, 1.10-1.33). A significant interaction was seen between rs3733591 and MetS ( p -value = 0.039). Using rs3733591-TT/no MetS as the reference group, the ORs (95% CI) for gout was 1.24 (1.11-1.38) for TC + CC/no MetS, 1.35 (1.17-1.56) for TT/MetS, and 1.39 (1.22-1.58) for TC + CC/MetS. However, subgroup analysis defined by sex showed no significant associations in women., Conclusion: In summary, metabolic syndrome and SLC2A9 rs3733591 genotypes were interactively associated with gout in Taiwanese men, but not women., 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 Lin, Ho, Hsieh, Hsiao, Nfor and Liaw.)

Background: Porcine circovirus type 2 (PCV2) infection is ubiquitous around the world. Diagnosis of the porcine circovirus-associated disease requires clinic-pathological elements together with the quantification of viral loads. Furthermore, given pig farms in regions lacking access to sufficient laboratory equipment, developing diagnostic devices with high accuracy, accessibility, and affordability is a necessity., Objectives: This study aims to investigate two newly developed diagnostic tools that may satisfy these criteria., Methods: We collected 250 specimens, including 170 PCV2-positive and 80 PCV2-negative samples. The standard diagnosis and cycle threshold (Ct) values were determined by quantitative polymerase chain reaction (qPCR). Then, two point-of-care (POC) diagnostic platforms, convective polymerase chain reaction (cPCR, qualitative assay: positive or negative results are shown) and EZtargex (quantitative assay: Ct values are shown), were examined and analyzed., Results: The sensitivity and specificity of cPCR were 88.23% and 100%, respectively; the sensitivity and specificity of EZtargex were 87.65% and 100%, respectively. These assays also showed excellent concordance compared with the qPCR assay (κ = 0.828 for cPCR and κ = 0.820 for EZtargex). The statistical analysis showed a great diagnostic power of the EZtargex assay to discriminate between samples with different levels of positivity., Conclusions: The two point-of-care diagnostic platforms are accurate, rapid, convenient and require little training for PCV2 diagnosis. These POC platforms can discriminate viral loads to predict the clinical status of the animals. The current study provided evidence that these diagnostics were applicable with high sensitivity and specificity in the diagnosis of PCV2 infection in the field., Competing Interests: Schweitzer Biotech Company (SBC) Ltd. is the sponsor of the project. Hsieh WJ, Lin CC, and Ting JM. are employees of the SBC. However, the authors declare that the research was conducted with integrity, following all ethical guidelines. All other authors declare no competing interests., (© 2024 The Korean Society of Veterinary Science.)

Breast cancer (BC) is the most frequent cancer in women. In female dogs, canine mammary gland tumor (CMT) is also the leading neoplasm. Comparative oncology indicates similar tumor behaviors between human BCs (HBCs) and CMTs. Therefore, this review summarizes the current research in hormone and targeted therapies and describes the future prospects for HBCs and CMTs. For hormone receptor-expressing BCs, the first medical intervention is hormone therapy. Monoclonal antibodies against Her2 are proposed for the treatment of Her2+ BCs. However, the major obstacle in hormone therapy or monoclonal antibodies is drug resistance. Therefore, increasing alternatives have been developed to overcome these difficulties. We systemically reviewed publications that reported inhibitors targeting certain molecules in BC cells. The various treatment choices for humans decrease mortality in females with BC. However, the development of hormone or targeted therapies in veterinary medicine is still limited. Even though some clinical trials have been proposed, severe side effects and insufficient case numbers might restrict further explorations. This difficulty highlights the urgent need to develop updated hormone/targeted therapy or novel immunotherapies. Therefore, exploring new therapies to provide more precise use in dogs with CMTs will be the focus of future research. Furthermore, due to the similarities shared by humans and dogs, well-planned prospective clinical trials on the use of combinational or novel immunotherapies in dogs with CMTs to obtain solid results for both humans and dogs can be reasonably anticipated in the future.

Preeclampsia (PE) remains one of the leading causes of maternal and perinatal morbidity and mortality. However, the exact pathophysiology of PE is still unclear. The recent widely accepted notion that successful pregnancy relies on maternal immunological adaptation is of utmost importance. Moreover, salt-inducible kinase 3 (SIK3) is an AMP-activated protein kinase-related kinase, and it has reported a novel regulator of energy and inflammation, and its expression related with some diseases. To explore whether SIK3 expression correlated with PE, we analyzed SIK3 gene expression and its association with PE through GEO datasets. We identified that SIK3 was significantly downregulated in PE across four datasets ( p < 0.05), suggesting that SIK3 participated in the pathogenesis of PE. We initially demonstrated the significant downregulation of SIK3 in trophoblast cells of PE. SIK3 downregulation was positively correlated with the increased number of CD204(+) cells in in vivo and in vitro experiments. The increased number of CD204(+) cells could inhibit the migration and invasion of trophoblast cells. We then clarified the potential mechanism of PE with SIK3 downregulation: M2 skewing was triggered by trophoblast cells derived via the CCL24/CCR3 axis, leading to an increase in CD204(+) cells, a decrease in phagocytosis, and the production of IL-10 at the maternal-fetal interface of the placenta with PE. IL-10 further contributed to a reduction in the migration and invasion of trophoblast cells. It also established a feedback loop wherein trophoblast cells increased CCL24 production to maintain M2 dominance in the placental environments of PE.

Background: Perampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER., Method: We analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups., Results: Overall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration., Conclusion: PER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: There is no definitive guidance on whether patients with acute intermittent porphyria (AIP) with recurrent attacks need pharmacological prophylactic treatment., Methods: The management strategies for patients with frequent (defined as ≥4 annualized attack rate (AAR) and less frequent attacks (<4 AAR), including treatment for acute attacks and duration of prophylaxis (weekly heme arginate 3 mg/kg body weight and/or investigational drug, givosiran), were summarized. The AAR for the following periods were presented: the first 2 years after diagnosis, before/after prophylaxis, and the most recent 2 years., Results: A total of 29 patients with AIP were included, 19 (34.5%) had <4 AAR and 10 (65.6%) had ≥4 AAR in the first 2 years after diagnosis. All patients experienced reduced attacks during the treatment course, 23 (79.3%) were attack-free during the most recent 2 years. Among the 9 patients who received prophylaxis (7 heme arginate; 1 givosiran, 1 heme arginate followed by givosiran), 5 (55.6%) were attack-free in the most recent 2-year period and prophylaxis was discontinued because there had been no attacks for >1 year. For patients without prophylaxis (n = 20), 18 (90.0%) were attack-free in the most recent 2-year period and 15 (75.0%) experienced attacks only in the first 2 years after diagnosis., Conclusions: Prophylaxis could be considered for patients with AIP with ≥4 biochemically confirmed attacks/year after routine treatment of 1-2 years, during which the severity and frequency of attacks should be closely monitored to determine the necessity of pharmacologic prophylaxis. More studies are needed to reach a consensus on the use of pharmacological prophylaxis and treatment of AIP., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: The clinical value of therapeutic drug monitoring (TDM) for newer anti-seizure medications (ASMs) remains uncertain. This study aimed to assess the impact of newer ASM TDM on clinical decision making in patients with epilepsy., Methods: We retrospectively identified all plasma requests for newer ASM level measurement as part of routine clinical management in the outpatient departments of seven medical institutes across Taiwan between September 2016 and May 2019. Data collected from reviewed medical records included clinical and medication details, indications for TDM requests, test results, interpretation, and impact on patient management., Results: A total of 682 visits with 1051 plasma samples were included. The most frequently analyzed ASMs were levetiracetam (36.1%), oxcarbazepine (18.4%), and lamotrigine (12.0%). Reasons for TDM included poorly controlled seizures (55.3%), concerns about drug-drug interactions (12.3%), and suspicion of drug overdose (10.6%). 68.8% of samples were within the orienting therapeutic range, even for patients with poorly controlled seizures. TDM for non-adherence concerns showed 54.3% below the orienting therapeutic range, while ASM-related adverse events assessment only 8.9% showed levels exceeding the orienting therapeutic range. Following TDM results, 64.2% of cases had medication adjustments, mainly dosage increases. Overall, 55.9% of newer ASM TDM visits showed improved outcomes, including reduced seizures (47.5%) and fewer ASM-related side effects (8.4%)., Conclusions: These findings suggest that appropriate utilization of TDM for newer ASMs provides clinical benefits in adjunct to complement clinical decision making in the management of epilepsy patients in a real-world clinical setting., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (© 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: Attenuation correction (AC) is an important correction method to improve the quantification accuracy of dopamine transporter (DAT) single photon emission computed tomography (SPECT). Chang's method was developed for AC (Chang-AC) when CT-based AC was not available, assuming uniform attenuation coefficients inside the body contour. This study aims to evaluate Chang-AC and different deep learning (DL)-based AC approaches on 99m Tc-TRODAT-1 brain SPECT using clinical patient data on two different scanners., Methods: Two hundred and sixty patients who underwent 99m Tc-TRODAT-1 SPECT/CT scans from two different scanners (scanner A and scanner B) were retrospectively recruited. The ordered-subset expectation-maximization (OS-EM) method reconstructed 120 projections with dual-energy scatter correction, with or without CT-AC. We implemented a 3D conditional generative adversarial network (cGAN) for the indirect deep learning-based attenuation correction (DL-AC μ ) and direct deep learning-based attenuation correction (DL-AC) methods, estimating attenuation maps (μ-maps) and attenuation-corrected SPECT images from non-attenuation-corrected (NAC) SPECT, respectively. We further applied cross-scanner training (cross-scanner indirect deep learning-based attenuation correction [cull-AC μ ] and cross-scanner direct deep learning-based attenuation correction [call-AC]) and merged the datasets from two scanners for ensemble training (ensemble indirect deep learning-based attenuation correction [eDL-AC μ ] and ensemble direct deep learning-based attenuation correction [eDL-AC]). The estimated μ-maps from (c/e)DL-AC μ were then used in reconstruction for AC purposes. Chang's method was also implemented for comparison. Normalized mean square error (NMSE), structural similarity index (SSIM), specific uptake ratio (SUR), and asymmetry index (%ASI) of the striatum were calculated for different AC methods., Results: The NMSE for Chang's method, DL-AC μ , DL-AC, cDL-AC μ , cDL-AC, eDL-AC μ , and eDL-AC is 0.0406 ± 0.0445, 0.0059 ± 0.0035, 0.0099 ± 0.0066, 0.0253 ± 0.0102, 0.0369 ± 0.0124, 0.0098 ± 0.0035, and 0.0162 ± 0.0118 for scanner A and 0.0579 ± 0.0146, 0.0055 ± 0.0034, 0.0063 ± 0.0028, 0.0235 ± 0.0085, 0.0349 ± 0.0086, 0.0115 ± 0.0062, and 0.0117 ± 0.0038 for scanner B, respectively. The SUR and %ASI results for DL-AC μ are closer to CT-AC, Followed by DL-AC, eDL-AC μ , cDL-AC μ , cDL-AC, eDL-AC, Chang's method, and NAC., Conclusion: All DL-based AC methods are superior to Chang-AC. DL-AC μ is superior to DL-AC. Scanner-specific training is superior to cross-scanner and ensemble training. DL-based AC methods are feasible and robust for 99m Tc-TRODAT-1 brain SPECT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Du, Jiang, Lin, Peng, Sun, Chiu, Hung and Mok.)

Two variants of porcine reproductive and respiratory syndrome virus (PRRSV), PRRSV 1 and PRRSV 2, have caused abortion in pregnant sows and respiratory distress in nursery pigs worldwide. PRRSV 2 has been thoroughly researched in Taiwan since 1993; however, the first case of PRRSV 1 was not reported until late 2018. To decipher the genetic characteristics of PRRSV 1 in Taiwan, open reading frame 5 (ORF5) genes of PRRSV 1 strains collected from 11 individual pig farms in 2019-2020 were successfully sequenced. All Taiwanese ORF5 sequences were closely related to Spanish-like PRRSV strains, which are considered to share a common evolutionary origin with the strain used for the PRRSV 1 vaccine. Analyses of amino acid (aa) and non-synonymous substitutions showed that genetic variations resulted in numerously specific codon mutations scattered across the neutralizing epitopes within the ORF5 gene. The PRRSV 1 challenge experiment disclosed the pathogenetic capability of the NPUST2789 isolate in nursery pigs. These findings provide comprehensive knowledge of the molecular diversity of the PRRSV 1 variant in local Taiwanese fields and facilitate the development of suitable immunization programs against this disease.

Background: Serum carcinoembryonic antigen (CEA) is a biomarker commonly used to detect colorectal cancer. CEA levels are affected by many factors, including cardiometabolic diseases, such as cardiovascular diseases (CVDs) and diabetes. Cardiometabolic diseases and cancer share a similar pathological inflammatory pathway, which correlates with an unhealthy lifestyle. Hence, establishing an adequate CEA cut-off value might be a valuable reference for developing precision healthcare programs for cardiometabolic disease prevention. This study aimed to investigate the association between cardiometabolic risks and serum CEA and the underlying factors., Methods: A community-based, cross-sectional study was conducted between March and December 2021 on the western coast of Taiwan. Lifestyle data were assessed using a structured questionnaire. The cardiometabolic biomarkers, serum CEA, urine malondialdehyde, and 1-hydroxypyrene were quantified by the central laboratory of the collaborating hospital. Chi-square and binary multivariable logistic regression implemented in R version 4.0.2 were used to identify factors defining the risk of high serum CEA levels., Results: A total of 6,295 adult residents without cancer-related diseases completed the study. The mean age was 48.6 (SD = 16.4) years, 56% were female, 32% had metabolic syndrome, and 23% and 10% had CVDs and diabetes, respectively. Multivariate logistic regression showed that age ≥ 65 years, male sex, alcohol consumption, smoking, infrequent use of dental floss, fewer remaining teeth, CVDs, diabetes, and oxidative stress were significantly associated with serum CEA ≥ 3 ng/mL. The discriminatory performance of the area under the receiver operating characteristic curve was 0.75 (0.73-0.76), showing that this model was suitable for distinguishing high CEA levels., Conclusion: Our findings highlight the importance of understanding cardiometabolic diseases, unhealthy lifestyles, and oxidative stress, which contribute to high serum CEA. This study demonstrates that CEA, a well-known tumor marker, can help the early detection and prevention of cardiometabolic diseases via personalized lifestyle modification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chang, Weng, Lin, Lin, Huang and Chen.)

Background and Aim: Porcine circovirus 3 (PCV3) was recently reported in Malaysian commercial pig population in 2020 by conventional polymerase chain reaction (PCR), revealing a molecular prevalence of 17.02% in the sampled domestic pig population. This study aims to describe a chromogenic in situ hybridization (ISH) technique using digoxigenin (DIG)-labeled cloned PCV3 open reading frame 1 (ORF1) fragment DNA to detect and localize the PCV3 antigen in formalin-fixed, paraffin-embedded lung, and lymphoid tissue specimens., Materials and Methods: Since PCV3 was mainly detected in lung and lymphoid tissues, we obtained tissue specimens from these organs from the previous Malaysian PCV3 study. Digoxigenin-labeled ISH probes were designed to target a 69 bp region of PCV3 ORF1 spanning from the nucleotide positions (282-350)., Results: Light microscopy analysis revealed that chromogenic staining of PCV3 antigens was visualized within the cytoplasm of pneumocytes and lymphocytes, indicating positive ISH results. The results of molecular detection of PCV3 using PCR and ISH showed a high agreement of 90.91%, including for the negative PCV3 status for all samples., Conclusion: This study reports a chromogenic ISH technique using DIG-labeled probes targeting PCV3 ORF1 to detect PCV3 antigens in lung and lymphoid tissues. Despite the limited availability of PCV3 antibodies, ISH remains relevant for investigating PCV3 replication and pathogenesis and can be used complementarily with PCR for evaluating the localization of antigens in infected tissues., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Tan, et al.)

Pieces of evidence support the view that the accumulation of uremic toxins enhances oxidative stress and downstream regulation of signaling pathways, contributing to both endothelial microangiography and cell dysfunction. This study is to address the impact of protein-binding uremic toxins on the severity of peripheral nerve function in patients with chronic kidney disease (CKD). Fifty-four patients with CKD were included in the Toronto Clinical Neuropathy Score (TCNS), nerve conduction study (NCS), and laboratory studies including protein-binding uremic toxin (indoxyl sulfate [IS] and p-cresyl sulfate [PCS]), oxidative stress (Thiol and thiobarbituric acid reacting substances [TBARS]), and endothelial dysfunction (serum intercellular adhesion molecule 1 [sICAM-1] and serum vascular adhesion molecule 1 [sVCAM-1]) at enrollment. We used composite amplitude scores (CAS) to analyze the severity of nerve conductions on peripheral nerve function. TCNS and CAS were higher in the diabetic CKD group (p = 0.02 and 0.01, respectively). The NCS revealed the compound muscle action potential of ulnar and peroneal nerves and the sensory nerve action potential of ulnar and sural nerves (p = 0.004, p = 0.004, p = 0.004, and p = 0.001, respectively), which was found to be significantly low in the diabetic group. CAS was significantly correlated with age (r = 0.27, p = 0.04), urine albumin-creatinine ratio (UACR) (r = 0.29, p = 0.046), free-form IS (r = 0.39, p = 0.009), sICAM-1 (r = 0.31, p = 0.02), sVCAM-1 (r = 0.44, p < 0.0001), TBARS (r = 0.35, p = 0.002), and thiols (r = −0.28, p = 0.045). Linear regression revealed that only TBARS and free-form IS were strongly associated with CAS. The mediation analysis shows that the sVCAM-1 level serves as the mediator between higher IS and higher CAS. IS and oxidative stress contribute to the severity of peripheral nerve dysfunction in patients with CKD, and chronic glycemic impairment can worsen the conditions.

Background/purpose: This study aimed to investigate the in vitro susceptibilities of carbapenem-non-susceptible Pseudomonas aeruginosa (CNSPA) and Acinetobacter baumannii (CNSAB) isolates to cefiderocol, novel β-lactamase inhibitor (BLI) combinations, new tetracycline analogues, and other comparative antibiotics., Methods: In total, 405 non-duplicate bacteremic CNSPA (n = 150) and CNSAB (n = 255) isolates were collected from 16 hospitals in Taiwan between 2018 and 2020. Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method, and susceptibilities were interpreted according to the relevant guidelines or in accordance with results of previous studies and non-species-related pharmacokinetic/pharmacodynamic data., Results: Among the isolates tested, cefiderocol demonstrated potent in vitro activity against CNSPA (MIC 50/90 , 0.25/1 mg/L; 100% of isolates were inhibited at ≤4 mg/L) and CNSAB (MIC 50/90 , 0.5/2 mg/L; 94.9% of isolates were inhibited at ≤4 mg/L) isolates. More than 80% of CNSPA isolates were susceptible to cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, and amikacin, based on breakpoints established by the Clinical and Laboratory Standards Institute. Activities of new BLI combinations varied significantly. Tetracycline analogues, including tigecycline (MIC 50/90 , 1/2 mg/L; 92.5% of CNSAB isolates were inhibited at ≤2 mg/L) and eravacycline (MIC 50/90 , 0.5/1 mg/L; 99.6% of CNSAB isolates were inhibited at ≤2 mg/L) exhibited more potent in vitro activity against CNSAB than omadacycline (MIC 50/90 , 4/8 mg/L)., Conclusions: The spread of CNSPA and CNSAB poses a major challenge to global health. Significant resistance be developed even before a novel agent becomes commercially available. The development of on-site antimicrobial susceptibility tests for these novel agents is of great clinical importance., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

The biochemical identification of carotid artery stenosis (CAS) is still a challenge. Hence, 349 male subjects (176 normal controls and 173 stroke patients with extracranial CAS ≥ 50% diameter stenosis) were recruited. Blood samples were collected 14 days after stroke onset with no acute illness. Carotid plaque score (≥2, ≥5 and ≥8) was used to define CAS severity. Serum metabolites were analyzed using a targeted Absolute IDQ ® p180 kit. Results showed hypertension, diabetes, smoking, and alcohol consumption were more common, but levels of diastolic blood pressure, HDL-C, LDL-C, and cholesterol were lower in CAS patients than controls ( p < 0.05), suggesting intensive medical treatment for CAS. PCA and PLS-DA did not demonstrate clear separation between controls and CAS patients. Decision tree and random forest showed that acylcarnitine species (C4, C14:1, C18), amino acids and biogenic amines (SDMA), and glycerophospholipids (PC aa C36:6, PC ae C34:3) contributed to the prediction of CAS. Metabolite panel analysis showed high specificity (0.923 ± 0.081, 0.906 ± 0.086 and 0.881 ± 0.109) but low sensitivity (0.230 ± 0.166, 0.240 ± 0.176 and 0.271 ± 0.169) in the detection of CAS (≥2, ≥5 and ≥8, respectively). The present study suggests that metabolomics profiles could help in differentiating between controls and CAS patients and in monitoring the progression of CAS.

Background/purpose: Streptococcus pneumoniae causes pneumonia and other invasive diseases, and is a leading cause of mortality in the elderly population. The present study aimed to provide current antimicrobial resistance and epidemiological profiles of S. pneumoniae infections in Taiwan., Methods: A total of 252 nonduplicate S. pneumoniae isolates were collected from patients admitted to 16 hospitals in Taiwan between January 2017 and December 2019, and were analyzed. The minimum inhibitory concentration of antibiotics was determined using the Vitek 2 automated system for antimicrobial susceptibility testing. Furthermore, epidemiological profiles of S. pneumoniae infections were analyzed., Results: Among the strains analyzed, 88% were recognized as invasive pneumococcal strains. According to the Clinical and Laboratory Standards Institute criteria for non-meningitis, the prevalence of penicillin-non-susceptible S. pneumoniae demonstrated a declining trend from 43.6% in 2017 to 17.2% in 2019. However, the rate of penicillin-non-susceptible S. pneumoniae was 85.7% based on the criteria for meningitis. Furthermore, the prevalence of ceftriaxone-non-susceptible S. pneumoniae was 62.7% based on the criteria for meningitis. Isolates demonstrated higher susceptibility toward doripenem and ertapenem than toward meropenem and imipenem. An increased rate of non-susceptibility toward levofloxacin was observed in southern Taiwan (15.1%) and elderly patients (≥65 years; 11.4%). Most isolates were susceptible to vancomycin and linezolid., Conclusion: Empirical treatment with ceftriaxone monotherapy for pneumococcal meningitis should be carefully monitored owing to its high non-susceptibility rate. The susceptibility rates of most isolates to penicillin (used for treating non-meningitis pneumococcal diseases), carbapenems (ertapenem and doripenem), respiratory quinolones (moxifloxacin and levofloxacin), vancomycin, and linezolid suggested the potential of these antibiotics in treating pneumococcal diseases in Taiwan., Competing Interests: Declaration of competing interest None declared., (Copyright © 2021. Published by Elsevier B.V.)

Background/purpose: We estimated loss-of-life expectancy (LE) and lifetime medical expenditures (LME) stratified by stages to evaluate the cost-effectiveness of breast cancer (BC) screening in Taiwan., Methods: We interlinked four national databases- Cancer Registry, Mortality Registry, National Health Insurance Claim, and Mammography Screening. A cohort of 123,221 BC was identified during 2002-2015 and followed until December 31, 2017. We estimated LE and loss-of-LE by rolling extrapolation algorithm using age-, sex-, and calendar-year-matched referents simulated from vital statistics. LME was estimated by multiplying monthly cost with survival probability and adjusted for annual discount rate. We calculated incremental cost-effectiveness ratio (ICER) by comparing the loss-of-LE of those detected by screening versus non-screening after accounting for administration fees and radiation-related excess BC., Results: The LEs of stages I, II, III, and IV were 31.4, 27.2, 20.0, and 5.2 years, respectively, while the loss-of-LEs were 1.2, 4.9, 11.7, and 25.0 years with corresponding LMEs of US$ 73,791, 79,496, 89,962, and 66,981, respectively. The difference in LE between stages I and IV was 26.2 years while that of loss-of-LE was 23.8 years, which implies that a potential lead time bias may exist if diagnosis at younger ages for earlier stages were not adjusted for. The ICER of mammography seemed cost-saving after the coverage exceeded half a million., Conclusion: Mammography could detect BC early and be cost-saving after adjustment for different distributions of age and calendar year of diagnosis. Future studies exploring healthcare expenditure and impaired quality of life for false-positive cases are warranted., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: The association between the biomarkers of environmental exposure, oxidative stress, and health-related behaviors in community residents living in an endemic viral hepatitis area and near petrochemical industrial complexes remains unclear. From a health promotion perspective, healthcare providers must know what to do for residents concerned about their health and living environment, especially for individual-level and modifiable risk factors. Therefore, we aimed to explore the factors associated with urinary 1-hydroxypyrene (1-OHP) and malondialdehyde (MDA)., Methods: A community-based, cross-sectional study was conducted between July 2018 and February 2019 in western coastal Yunlin County, Taiwan. All participants lived within a 10 km radius of a large petrochemical complex and did not work in the factory. This study was conducted with the local hospital through annual community health screening. Biological samples were collected and biomarkers determined and quantified in the central laboratory of the collaborating hospital., Results: A total of 6335 adult residents completed the study. The mean age was 47.7 (SD = 16) years. Out of the total population, 56.4% were female, 30.1% had metabolic syndrome (MetS), and 16.8% and 14.3% had hepatitis B virus antigen (HBsAg) and hepatitis C virus antibody (anti-HCV) positivity, respectively. The median 1-OHP and MDA level was 0.11 and 0.9 μg/g creatinine with an interquartile range of 0.07-0.18, and 0.4-1.5, respectively. The MDA levels correlated with specific diseases. The multivariable ordinal logistic regression model revealed that female sex, smoking, betel nut use, HBsAg, and anti-HCV positivity were associated with higher 1-OHP levels. In men, MetS was associated with higher 1-OHP levels and regular exercise with lower 1-OHP levels. High MDA levels were associated with smoking, betel nut users, HBsAg, and anti-HCV positivity., Conclusions: The findings highlight the importance of initiating individualized health promotion programs for residents near petrochemical factories, especially for adults with substance-use and cardiometabolic risk factors. Furthermore, it is crucial to provide further treatment to patients with viral hepatitis.

Currently, there is no objective biomarker to indicate disease progression and monitor therapeutic effects for amyotrophic lateral sclerosis (ALS). This study aimed to identify plasma biomarkers for ALS using a targeted metabolomics approach. Plasma levels of 185 metabolites in 36 ALS patients and 36 age- and sex-matched normal controls (NCs) were quantified using an assay combining liquid chromatography with tandem mass spectrometry and direct flow injection. Identified candidates were correlated with the scores of the revised ALS Functional Rating Scale (ALSFRS-r). Support vector machine (SVM) learning applied to selected metabolites was used to differentiate ALS and NC subjects. Forty-four metabolites differed significantly between ALS and NC subjects. Significant correlations with ALSFRS-r score were seen in 23 metabolites. Six of them showing potential to distinguish ALS from NC-asymmetric dimethylarginine (area under the curve (AUC): 0.829), creatinine (AUC: 0.803), methionine (AUC: 0.767), PC-acyl-alkyl C34:2 (AUC: 0.808), C34:2 (AUC: 0.763), and PC-acyl-acyl C42:2 (AUC: 0.751)-were selected for machine learning. The SVM algorithm using selected metabolites achieved good performance, with an AUC of 0.945. In conclusion, our findings indicate that a panel of metabolites were correlated with disease severity of ALS, which could be potential biomarkers for monitoring ALS progression and therapeutic effects.

Background/purpose: To quantify savings of loss-of-QALE (quality-adjusted life expectancy) and lifetime medical costs from prevention of different cancers., Methods: We collected nation-wide data on 808,700 new cancer cases of 14 different organ systems and followed them from 1998 to 2014 in Taiwan. We also collected 13,005 cancer patients from a medical center and 47,320 repeated measurements of quality of life (QoL) of EQ-5D to obtain utility values and multiplied them with the corresponding survival rates to calculate QALE. With Kaplan-Meier estimation to survival function to the end of follow-up, we extrapolated to lifetime through a rolling over algorithm on the logit transform of the survival ratio between the index cohort and age-, sex, and calendar year matched referents simulated from vital statistics. Lifetime costs for each cancer were estimated by multiplying survival with average monthly costs after adjustment with annual discount rate. The loss-of-QALE was estimated by the difference in QALE between the index cancer cohort and corresponding referents., Results: The dynamic changes and weighted averages of the QoL utility values of 14 different cancers ranged from 0.82 to 0.95. Successful prevention of liver, lung, esophagus, or nasopharynx cancer would save more than 10 quality-adjusted life years and more than 21,000 USD per case for both genders. Since the saving of loss-of-QALE was adjusted for different age, sex, and calendar-year distributions, it could be used in cost effectiveness evaluation., Conclusion: Savings of loss-of-QALE and lifetime costs could be used for comparison of prevention, diagnosis, treatment and rehabilitation from a lifetime horizon., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

Porcine deltacoronavirus (PDCoV) is a highly transmissible intestinal pathogen that causes mild to severe clinical symptoms, such as anorexia, vomiting, and watery diarrhea in pigs. By comparing the genetic sequences of the spike glycoprotein between historical and current Taiwanese PDCoV strains, we identified a novel PDCoV variant that displaced the PDCoV responsible for the 2015 epidemic. This PDCoV variant belongs to a young population within the US lineage, and infected pigs carry high concentrations of the virus. It also has several critical point mutations and an amino acid insertion at position 52 that may enhance the affinity between the B-cell epitopes located in the N-terminal domain with its complementarity regions, consequently facilitating binding or penetration between the fusion peptide and cellular membrane. Furthermore, viral protein structure prediction demonstrated that these amino acid changes may change the ability of the virus to bind to the receptor, which may consequently alter virus infectivity. Our results hence suggest the emergence of new PDCoV strains in Taiwan with the potential for greater transmission and pathogenesis., (© The Author(s) 2021. Published by Oxford University Press.)

The tumor microenvironment is a well-recognized framework in which immune cells present in the tumor microenvironment promote or inhibit cancer formation and development. A crown-like structure (CLS) has been reported as a dying or dead adipocyte surrounded by a 'crown' of macrophages within adipose tissue, which is a histologic hallmark of the inflammatory process in this tissue. CLSs have also been found to be related to formation, progression and prognosis of some types of cancer. However, the presence of CLSs in the omentum of advanced-stage high-grade serous ovarian carcinoma (HGSOC) has not been thoroughly investigated. By using CD68, a pan-macrophage marker, and CD163, an M2-like polarization macrophage marker, immunohistochemistry (IHC) was performed to identify tumor-associated macrophages (TAMs) and CLSs. This retrospective study analyzed 116 patients with advanced-stage HGSOC who received complete treatment and had available clinical data from July 2008 through December 2016 at National Cheng Kung University Hospital (NCKUH) (Tainan, Taiwan). Based on multivariate Cox regression analysis, patients with omental CD68 + CLSs had poor OS (median survival: 24 vs. 38 months, p = 0.001, hazard ratio (HR): 2.26, 95% confidence interval (CI): 1.41-3.61); patients with omental CD163 + CLSs also had poor OS (median survival: 22 vs. 36 months, HR: 2.14, 95%CI: 1.33-3.44, p = 0.002). Additionally, patients with omental CD68 + or CD163 + CLSs showed poor PFS (median survival: 11 vs. 15 months, HR: 2.28, 95%CI: 1.43-3.64, p = 0.001; median survival: 11 vs. 15 months, HR: 2.17, 95%CI: 1.35-3.47, respectively, p = 0.001). Conversely, the density of CD68 + or CD163 + TAMs in ovarian tumors was not associated with patient prognosis in advanced-stage HGSOC in our cohort. In conclusion, we, for the first time, demonstrate that the presence of omental CLSs is associated with poor prognosis in advanced-stage HGSOC.

Objectives: This study aimed to evaluate the efficacy of long-term weekly prophylactic heme arginate (HA) infusions in reducing attack frequency and severity in female AIP patients. Methods: We report the results of five female AIP patients with frequent recurrent attacks (>9/year) before and after institution of weekly prophylaxis with heme arginate (3 mg/kg body weight). All five cases had confirmed disease-associated mutations in the porphobilinogen deaminase gene, and all had received genetic and clinical counseling about AIP. Results: In the five included patients, average annual attack rate (AAR) in the year prior to HA prophylaxis was 11.82 (range 9.03-17.06), and average total HA usage was 32.60 doses (range: 13.71-53.13). After 2.58-14.64 years of HA prophylaxis, average AAR was reduced to 2.23 (range 0.00-5.58), and attack severity (i.e., doses required per attack) was reduced from 2.81 to 1.39 doses/attack. Liver and renal function remained stable during weekly administration of HA prophylaxis. The most common complications were port-A catheter-related events. No other complications or safety concerns occurred with long-term use of HA prophylaxis. Conclusion: Our study demonstrated women with AIP receiving weekly prophylactic HA infusions resulted in fewer episodes that required acute HA treatment while maintaining stable renal and liver function. Weekly prophylactic HA infusions effectively prevent frequent porphyric attacks and reduce attack severity., 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 © 2021 Kuo, Lin and Tang.)

This study aims to present the serum metabolite profiles of patients with acute intermittent porphyria (AIP) and identify specific metabolites that could potentially discriminate between AIP, asymptomatic HMBS mutation carriers, and healthy individuals. The study cohort included 46 female participants: 21 AIP patients, 5 asymptomatic carriers, and 20 'normal' participants (without HMBS gene mutation). Serum samples were analyzed for 157 selected metabolites or clinical variables using an assay combining liquid chromatography MS/MS and direct flow injection. AUC analysis was used to distinguish unique variables between the three groups. A total of 15 variables differed significantly between the AIP and normal control group (VIP score > 1.0 and p < 0.05 with FDR correction). In AIP patients, the levels tyrosine, valine, and eGFR were significantly lower, and the levels of sphingomyelin C16:0, C24:0, C24:1, phosphatidylcholine diacyl C32:1, C36:1, C36:3, ornithine, sarcosine, citrulline, blood urea nitrogen AST, and ALT were significantly higher. The AUC of these 15 variables in discriminating between normal and AIP patients ranged between 0.73 and 0.94 ( p < 0.05). In conclusion, serum metabolic profiles differ between normal individuals and patients carrying the HMBS mutation. The unique metabolites associated with AIP identified in this study may be useful for monitoring the development of AIP symptoms.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus in humans, has expanded globally over the past year. COVID-19 remains an important subject of intensive research owing to its huge impact on economic and public health globally. Based on historical archives, the first coronavirus-related disease recorded was possibly animal-related, a case of feline infectious peritonitis described as early as 1912. Despite over a century of documented coronaviruses in animals, the global animal industry still suffers from outbreaks. Knowledge and experience handling animal coronaviruses provide a valuable tool to complement our understanding of the ongoing COVID-19 pandemic. In this review, we present an overview of coronaviruses, clinical signs, COVID-19 in animals, genome organization and recombination, immunopathogenesis, transmission, viral shedding, diagnosis, treatment, and prevention. By drawing parallels between COVID-19 in animals and humans, we provide perspectives on the pathophysiological mechanisms by which coronaviruses cause diseases in both animals and humans, providing a critical basis for the development of effective vaccines and therapeutics against these deadly viruses.

Porcine deltacoronavirus (PDCoV), a highly transmissible intestinal pathogen, causes mild to severe clinical symptoms, such as anorexia, vomiting and watery diarrhea, in piglets and/or sows. Since the first report of PDCoV infection in Hong Kong in 2012, the virus has readily disseminated to North America and several countries in Asia. However, to date, no unified phylogenetic classification system has been developed. To fill this gap, we classified historical PDCoV reference strains into two major genogroups (G-I and G-II) and three subgroups (G-II-a, G-II-b and G-II-c). In addition, no genetic research on the whole PDCoV genome or spike gene has been conducted on isolates from Taiwan so far. To delineate the genetic characteristics of Taiwanese PDCoV, we performed whole-genome sequencing to decode the viral sequence. The PDCoV/104-553/TW-2015 strain is closely related to the G-II-b group, which is mainly composed of PDCoV variants from China. Additionally, various mutations in the Taiwanese PDCoV (104-553/TW-2015) strain might be linked to the probability of recombination with other genogroups of PDCoVs or other porcine coronaviruses. These results represent a pioneering phylogenetic characterization of the whole genome of a PDCoV strain isolated in Taiwan in 2015 and will potentially facilitate the development of applicable preventive strategies against this problematic virus.

Importance: There are different clinical practices regarding ultrasonography screening intervals for hepatocellular carcinoma (HCC) despite recommendations from international guidelines., Objective: To evaluate whether ultrasonography screening using intervals suggested by international guidelines is associated with cancer stage shifting, reductions in mortality, and improved quality of life (QoL) for patients with HCC., Design, Setting, and Participants: This nationwide comparative effectiveness research study estimated lifetime survival functions using interlinkages of 3 databases from Taiwan-the Taiwan National Health Insurance, Taiwan National Cancer Registry, and National Mortality Registry-combined with QoL measurements obtained from National Cheng Kung University Hospital. In total, 114 022 patients listed as having newly diagnosed HCC from 2002 through 2015 in the Taiwan National Cancer Registry were followed up until 2017. The QoL values of 1059 patients with HCC who visited National Cheng Kung University Hospital were prospectively measured with the European QoL-5 dimensions questionnaire from 2011 through 2019. Patients were categorized based on the time between their last ultrasonography screening and the index date (90 days prior to HCC diagnosis) as 1 of 5 subcohorts: 6 months (0-6 months), 12 months (7-12 months), 24 months (13-24 months), 36 months (25-36 months), and longer than 36 months (no screening in the previous 3 years). Data were analyzed from April 2020 to April 2021., Main Outcomes and Measures: Life expectancy, quality-adjusted life expectancy, and loss of life expectancy or loss of quality-adjusted life expectancy compared with age-, sex-, and calendar year-matched cohorts., Results: There were 59 194 patients with Barcelona Clinic Liver Cancer staging information, including 42 081 men (mean [SD] age, 62.2 [12.6] years) and 17 113 women (mean [SD] age, 69.0 [11.2] years). There was a consistent trend showing that the longer the interval between ultrasonography examinations, the higher the loss of life expectancy and loss of quality-adjusted life expectancy for both sexes. Loss of quality-adjusted life expectancy values for male subcohorts were 10.0 (95% CI, 9.1-10.9) quality-adjusted life-years (QALYs) for ultrasonography screening intervals of 6 months, 11.1 (95% CI, 10.4-11.8) QALYs for 12 months, 12.1 (95% CI, 11.5-12.7) QALYs for 24 months, 13.1 (95% CI, 12.6-13.6) QALYs for 36 months, and 14.6 (95% CI, 14.2-15.0) QALYs for longer than 36 months. Loss of quality-adjusted life expectancy values for female subcohorts were 9.0 (95% CI, 8.3-9.6) QALYs for 6 months, 9.7 (95% CI, 9.2-10.2) QALYs for 12 months, 10.3 (95% CI, 9.8-10.7) QALYs for 24 months, 10.7 (95% CI, 10.2-11.1) QALYs for 36 months, and 11.4 (95% CI, 11.0-11.8) QALYs for longer than 36 months. Patients with underlying hepatitis B virus infection or cirrhosis had the greatest improvement in life expectancy with shorter screening intervals., Conclusions and Relevance: Regular ultrasonography screening with intervals less than 6 to 12 months may be associated with early detection of HCC, save lives, and improve the quality of life for patients with HCC from a lifetime perspective.

Porcine reproductive and respiratory syndrome (PRRS), which is caused by a highly transmissible pathogen called porcine reproductive and respiratory syndrome virus (PRRSV), has caused severe problems, including reproductive disorders in sows and respiratory symptoms in nursery pigs worldwide, since the early 1990s. However, currently available PRRSV vaccines do not supply complete immunity to confront the viral infection. Elicitation of PRRSV-specific neutralizing antibodies (NAbs) during the preinfectious period has been deemed to be a feasible strategy to modulate this virus, especially in farms where nursery pigs are seized with PRRSVs. A total of 180 piglets in a farrow-to-finish farm that had a natural outbreak of PRRS were distributed into three groups based on the different PRRSV NAbs levels in their dams. In the present study, piglets that received superior maternal-transferred NAbs showed delayed and relatively slight viral loads in serum and, on the whole, higher survival rates against wild PRRSV infections. A positive correlation of maternal NAbs between sows and their piglets was identified; moreover, high NAbs titers in piglets can last for at least 4 weeks. These results provide updated information to develop an appropriate immune strategy for breeding and for future PRRSV control under field conditions.

Intensive efforts have been made to eliminate or substantial reduce bacterial adhesion and biofilm formation on titanium implants. However, in the management of peri-implantitis, the methylene blue (MB) photosensitizer commonly used in photoantimicrobial chemotherapy (PACT) is limited to a low retention on the implant surface. The purpose of this study was to assess enhancive effect of water-soluble quaternary ammonium chitosan (QTS) on MB retention on biofilm-infected SLA (sandblasted, large grid, and acid-etched) Ti alloy surfaces in vitro. The effectiveness of QTS + MB with different concentrations in eliminating Gram-negative A. actinomycetemcomitans or Gram-positive S. mutans bacteria was compared before and after PACT. Bacterial counting and lipopolysaccharide (LPS) detection were examined, and then the growth of human osteoblast-like MG63 cells was evaluated. The results indicated that the synergistic QTS + MB with retention ability significantly decreased the biofilm accumulation on the Ti alloy surface, which was better than the same concentration of 1 wt% methyl cellulose (MC). More importantly, the osteogenic activity of MG63 cells on the disinfected sample treated by QTS + MB-PACT modality was comparable to that of sterile Ti control, significantly higher than that by MC + MB-PACT modality. It is concluded that, in terms of improved retention efficacy, effective bacteria eradication, and enhanced cell growth, synergistically, PACT using the 100 μg/mL MB-encapsulated 1% QTS was a promising modality for the treatment of peri-implantitis.

Background: This study aimed to investigate the adding value of MRI over CT for preoperative cytoreductive surgery with hyperthermic intraperitoneal chemotherapies (CRS/HIPEC)., Methods: Imaging and intraoperative peritoneal cancer index (PCI) were calculated in 62 patients with peritoneal metastasis. Predictive models for the completeness of cytoreductive score using PCI data were established using decision tree algorithms., Results: In gastric cancer patients, a large discrepancy and poor agreement was appreciated between CT and surgical PCI, and a nonsignificant difference was noted between MRI and surgical PCI. In colon cancer patients, a better agreement and higher correlation with a smaller error was observed in PCI score using MRI than in that using CT. However, the addition of MRI to CT was limited for appendiceal and ovarian cancer patients. For predicting incomplete cytoreduction, CT models yielded inadequate accuracy while MRI models were more accurate with fair discrimination ability., Conclusions: CT was suitable for estimating PCI and surgery outcome in appendiceal and ovarian cancer patients, while further MRI in addition to CT was recommended for colon and gastric cancer patients. However, for classifying patients with peritoneal carcinomatosis into complete and incomplete cytoreduction, MRI was more effective than CT.

We report the design, synthesis, and biological evaluation of 13 new and 1 known anthraquinone derivatives which exerted cytotoxicity against PC3, A549 and NTUB1 cell lines. The results indicate that, among these 14, compounds-1 and 14 showed the highest growth inhibitory effect on NTUB1 and PC3 cells, respectively. Compound-1 at lower doses targets DNA, induces DNA damage and subsequently triggers G2/M arrest and apoptotic cell death at 24 h. Previously we reported that 14 induced PC3 cell autophagy and in treated PC3 cells, cleaved caspase-3 and cleaved PARP, and survivin did not increase and increase, respectively. The autophagic and necrotic cell deaths mediated by 14-triggered ROS generation. Our study is the first to investigate the biological mechanism of 14 action in detail. We find that when 14 was co-administrated with Bafilomycin A1 (BAF) in PC3 cells, rapid necrotic cell death occurred with no cleaved caspase-3 and cleaved PARP activation and increasing the expression of survivin. We further show that necrotic signaling in these cells coincided with production of reactive oxygen species. In the present study, we developed methods to synthesize five new 14 analogues for studing the structure-activity relationships. This study could provide valuable sight to find new antitumor agents for cancer therapy., (Copyright © 2020. Published by Elsevier Inc.)

Ovarian cancer (OvCa) is the most lethal gynecologic malignancy owing to its high chemoresistance and late diagnosis, which lead to a poor prognosis. Hence, developing new therapeutic modalities is important for OvCa patient treatment. Our previous results indicated that a novel aptamer, Tx-01, can specifically recognize serous carcinoma cells and tissues. Here, we aim to clarify the clinical role and possible molecular mechanisms of Tx-01 in OvCa. Immunostaining and statistical analysis were performed to detect the interaction of Tx-01 and heat shock protein 70/Notch1 intracellular domain (HSP70/NICD) in OvCa. The in vitro and in vivo experiments were carried out to demonstrate the potential mechanisms of Tx-01. Results show that Tx-01 reduced serous OvCa OVCAR3 cell migration and invasion and inhibited HSP70 nuclear translocation by interrupting the intracellular HSP70/NICD interaction. Furthermore, Tx-01 suppressed serous-type OVCAR3 cell tumor growth in vivo . Tx-01 acts as a prognostic factor through its interaction with membrane-bound HSP70 (mHSP70 that locates on the cell surface without direct interaction to NICD) on ascitic circulating tumor cells (CTCs) and is reported to be involved in natural killer (NK) cell recognition and activation. Our data demonstrated that Tx-01 interacted with HSP70 and showed therapeutic and prognostic effects in serous OvCa. Tx-01 might be a potential inhibitor for use in serous OvCa treatment., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Cognitive impairment (CI) is not uncommon in dialysis patients. Various factors have been implicated. This study aims to examine mutual interaction of various clinical factors for CI in patients receiving hemodialysis. A total of 48 hemodialysis patients in outpatient clinic were recruited from 2015 to 2017. Demographics, circulating uremic toxin concentrations, miRNA concentrations, and nerve injury protein concentrations were collected. Clinical dementia rating (CDR) scores were used to stratify the functional scores of the patients. Receiver operating characteristic (ROC) analysis was used to evaluate diagnostic test performance for predicting dichotomous results, and cumulative ROC analysis was used to examine the combined contribution of clinical factors. CDR scale 0 included 15 patients (mean age, 59.1 years); CDR > 0.5 included 33 patients (mean age, 64.0 years). On cumulative ROC analysis, the major predictors of mild CI were hemoglobin, age, sex, homocysteine, neuron-specific enolase (NSE), and miR-486. The cumulative area under the curve (AUC) on combining hemoglobin, age, and miR-486 was the highest (0.897, 95% confidence interval 0.806-0.988). Two dichotomized variables reached 81.82% sensitivity and 86.67% specificity, with the likelihood ratio for positive and negative results being 6.14 and 0.21, respectively. In conclusion, hemoglobin, age, and miR-486 display high-degree combined effects on mild CI in patients receiving hemodialysis.

Background: Survival in hepatocellular carcinoma (HCC) is lower in the USA than in Taiwan. Little is known about the extent to which differences in stage at diagnosis and treatment contribute to this difference. We examined treatment patterns and survival in HCC and analyzed factors driving the difference., Methods: Using a uniform methodology, we identified patients aged 66 years and older with newly diagnosed HCC between 2004 and 2011 in the USA and Taiwan. We compared treatment within 6 months after HCC diagnosis and 2-year stage-specific survival between the two countries., Results: Compared with patients in Taiwan (n = 32,987), patients in the USA (n = 7,003) were less likely to be diagnosed as stage IA (4% vs 8%) and II (13% vs 22%), or receive cancer-directed treatments (41% vs 58%; all p < .001). Stage-specific 2-year survival rates were lower in the USA than in Taiwan (stage IA: 57% vs 77%; stage IB: 38% vs 63%; stage II: 40% vs 57%, stage III: 14% vs 18%; stage IV: 4% vs 5%, respectively; all p < .001 except p = .018 for stage IV). Differences in age and sex (combined), stage, and receipt of treatment accounted for 3.8%, 17.0%, and 16.8% of the survival difference, respectively, leaving 62.5% unexplained., Conclusions: Differential stage at diagnosis and treatment were substantially associated with the survival difference, but approximately two-thirds of the difference remained unexplained. Identifying the main drivers of the difference could help improve HCC survival in the USA., Competing Interests: The authors have declared that no competing interests exist.