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Hsien-Po Huang,1,2 Hsiu-Wen Wang,1 Chia-Hsin Cheng,1 Yi-Shan Chang,1 Ting-Kuang Yeh,1,2 Wei-Hsuan Huang,1 Chia-Wei Liu,1 Chih-Hung Chang,6 Po-Yu Liu,1– 5 Yu-Chun Yen,7 Chien-Hao Tseng1 1Division of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 2Genomic Center for Infectious Diseases, Taichung Veterans General Hospital, Taichung, Taiwan; 3Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 4Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 5Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; 6Department of Computer Science and Communication Engineering, Providence University, Taichung, Taiwan; 7Division of Clinical Informatics, Department of Digital Medicine, Taichung Veterans General Hospital, Taichung, TaiwanCorrespondence: Yu-Chun Yen, Division of Clinical Informatics, Department of Digital Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, Tel +886-4-23592525, ext. 4214, Email jeanycy@vghtc.gov.tw Chien-Hao Tseng, Division of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, Tel +886-4-23592525, ext. 3083, Email tedi3tedi3@vghtc.gov.twPurpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes post-acute sequelae of coronavirus disease 2019 (COVID-19), including pulmonary vasculopathy, increasing thrombotic risk. Screening and treating survivors are essential to reduce associated disabilities. We aim to investigate the clinical characteristics of patients with post-COVID-19 condition and pulmonary embolism, as well as their health-related quality of life one year after COVID-19 diagnosis.Patients and Methods: In our study, we analyzed nine cases of post-COVID-19 condition and pulmonary embolism in a tertiary hospital in Taiwan. Patient characteristics, including age, sex, symptoms, and outcomes, were recorded. One year post-diagnosis, patients underwent follow-up with lab tests, chest X-rays, electrocardiograms, and health-related quality of life (HRQOL) assessments using the EuroQoL 5-Dimension 5-Level (EQ-5D-5L) tool.Results: Post-COVID-19 condition with pulmonary embolism predominantly affects females. Common symptoms include breathlessness and chest pain, and a lung perfusion scan may be useful for diagnosis. The one-year follow-up of five patients mainly showed normal lab results and no active lung lesions. The mean EQ-5D score was 0.928 ± 0.119, and the EQ visual analogue scale (EQ-VAS) was 85.00 ± 11.18. Pain/discomfort was the most reported issue.Conclusion: This research reveals that post-COVID-19 condition with pulmonary embolism affects a significant number of women and those with preexisting conditions like cancer or diabetes. Symptoms overlap also complicates diagnosis. Although many lab results were normal, the elevated risk of pulmonary embolism persists. Lower utility scores and increased anxiety highlight the need for targeted interventions and mental health support. Our study underscores the importance of monitoring pulmonary embolism in patients after COVID-19 infection, given the significant impact on post-COVID-19 condition and overall health outcomes.Keywords: SARS-CoV-2, health related quality of life, pulmonary vasculopathy, EQ-5D

Ya-Chun Liao,1 Yao-Ting Huang,2,* Chien-Hao Tseng,1 Chia-Wei Liu,1 Po-Yu Liu1,3,4,* 1Division of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 2Department of Computer Science and Information Engineering, National Chung Cheng University, Chiayi, Taiwan; 3Department of Post-Baccalaureate Medicine, National Chung Hsing University, Taichung, Taiwan; 4Genome Center for Infectious Diseases, Taichung Veterans General Hospital, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Po-Yu Liu, Division of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Blvd., Xitun District, Taichung, Taiwan, Tel +886-4-2359-2525, Fax +886-4-2359-5046, Email pyliu@vghtc.gov.twPurpose: Burkholderia cepacia complex (Bcc) is a known significant opportunistic pathogen causing morbidity and mortality, particularly in those with cystic fibrosis, chronic granulomatous disease, or immunocompromising host. Mortality of Bcc bloodstream infections among non-cystic fibrosis patients remained high. The antibiotic treatment for Bcc infection is quite challenging due to its intrinsic resistance to most antibiotics, and the resistance to carbapenems was the biggest concern among them. We aimed to realize the mechanism of carbapenem resistance in Bcc.Patients and Methods: Ten strains of Bcc were identified by the MALDI-TOF MS, and the drug susceptibility test was using VITEK 2 system. The Burkholderia cepacia complex genomes were sequenced via Nanopore GridIon. We also downloaded another ninety-five strains of Bcc from the National Center for Biotechnology Information database to evaluate the divergence between carbapenem-resistance and carbapenem-sensitive strains.Results: The genetic organization between carbapenem-sensitive and carbapenem-resistant strains of Bcc showed no difference. However, in the carbapenem-sensitive strain, E151V substitution in PenR was detected. In addition, a novel specific OXA family subgroup, blaOXA-1043 in Burkholderia cenocepacia was discovered.Conclusion: The E151V substitution in PenR may be associated with carbapenem-sensitive in Bcc. Moreover, the V151E mutation in PenR may be related to the activation of PenB, leading to Bcc resistance to carbapenems. Besides, a novel OXA family subgroup, blaOXA-1043, was found in Burkholderia cenocepacia, which differs from the previous OXA family.Keywords: Burkholderia cepacia complex, Burkholderia cenocepacia, carbapenem-resistant, whole-genome sequencing

Po-Hsiu Huang,1,* Yao-Ting Huang,2,* Po-Hsin Lee,3– 6 Chien-Hao Tseng,7 Po-Yu Liu,5– 7 Chia-Wei Liu7 1Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 2Department of Computer Science and Information Engineering, National Chung Cheng University, Chia-Yi, Taiwan; 3Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 4College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 5Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 6Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 7Division of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Po-Yu Liu; Chia-Wei Liu, Tel +886 4 2359 2525, Fax +886 4 2359 2525 2111, Email pyliu@vghtc.gov.tw; chiaweiliu35@gmail.comAbstract: Coinfection in COVID-19 patients is associated with worsening outcome. Among patients with COVID-19, Legionella pneumophila, a common cause of pneumonia, has been reported as a co-occurring respiratory infection. A nonspecific clinical presentation, however, makes an early diagnosis difficult. Bronchoalveolar lavage fluid was collected from a patient suffering from COVID-19 and presenting with pneumonia and sent for metagenomic analysis. Differential abundance analysis was carried out by comparing each taxon reads per million between the bronchoalveolar lavage fluid sample and the negative control. Two replicates of metagenomic sequencing were conducted on bronchoalveolar lavage fluid samples. Within each replicated sequencing, one negative control was sequenced for comparison of taxon abundance in the BALF sample. In both replicates, Legionella pneumophila was the only taxon with significantly higher abundance when compared with the negative control. PCR of the bronchoalveolar further confirmed the presence of L. pneumophila. Several studies have estimated that the incidence of Legionnaires’ disease co-infection in patients with COVID-19 infection is approximately 0% to 1.5%. There are some common characteristics of COVID-19 and co-infection with Legionnaires’ disease, making it difficult to diagnose bacterial infection early. The diagnosis of these cases is important due to the different treatments used. Current diagnostic tests for Legionnaires’ disease include conventional culture, urinary antigen for L. pneumophila serogroup 1, polymerase chain reaction, direct fluorescent antibody stain, and paired serology. The current study demonstrated that metagenomics is a promising approach that facilitated the diagnosis of Legionnaires’ disease.Keywords: Legionnaires’ disease, COVID-19, co-infection, next-generation sequencing

Jen-Yu Hsu,1 Po-Yu Liu,1 Chien-Hao Tseng,1 Chia-Wei Liu,1 Wan-Ting Yang,1 Wei-Hsuan Huang,1 Shu-Yuan Li,1 Ya-Chun Liao,1 Ming-Ju Wu2 1Division of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 407, Taiwan; 2Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan & College of Medicine, National Chung Hsing University, Taichung, 402, TaiwanCorrespondence: Ming-Ju WuDepartment of Internal Medicine, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Blvd, Xitun Dist, Taichung City, 407219, TaiwanTel +886-4-23592525Email wmj530@gmail.comPurpose: The COVID-19 pandemic poses a serious threat to healthcare workers and hospitalized patients. Early detection of COVID-19 cases is essential to control the spread in healthcare facilities. However, real-world data on the screening criteria for hospitalized patients remain scarce. We aimed to explore whether patients with negative results of pre-hospital screening for COVID-19 should be rescreened after admission in a low-prevalence (less than 3% of the world average) setting.Patients and Methods: We retrospectively included patients in central Taiwan who were negative at the first screening but were newly diagnosed with pneumonia or had a body temperature above 38 degrees Celsius during their hospitalization. Each patient might be included as an eligible case several times, and the proportions of cases who were rescreened for COVID-19 and those diagnosed with COVID-19 were calculated. A logistic regression model was constructed to identify factors associated with rescreening. Reverse transcription-polymerase chain reaction tests were used to confirm the diagnosis of COVID-19.Results: A total of 3549 cases eligible for COVID-19 rescreening were included. There were 242 cases (6.8%) who received rescreening. In the multivariable analysis, cases aged 75 years or older, those with potential exposure to SARS-CoV-2, or patients visiting specific departments, such as the Cardiovascular Center and Department of Neurology, were more likely to be rescreened. None was diagnosed with COVID-19 after rescreening. There was no known cluster infection outbreak in the hospital or in the local community during the study period and in the following two months.Conclusion: In Taiwan, a country with a low COVID-19 prevalence, it was deemed safe to rescreen only high-risk hospitalized patients. This strategy was effective and reduced unnecessary costs.Keywords: fever, pneumonia, risk, SARS-CoV-2, screen

Shih-Wei Lee,1,* Yu-Chen Huang,2,3,* Chun-Yu Lin,2,3 Hung-Yu Huang,2,3 Chi-Wei Liu,1 Ming-Tsuen Hsieh,4 Chon-Lin Lee,4– 7 Wen-Yu Chung,8 Kian Fan Chung,9 Chun-Hua Wang,2,3 Han-Pin Kuo10,11 1Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan; 2Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan; 3College of Medicine, Chang Gung Memorial University, Taoyuan, Taiwan; 4Department of Marine Environment and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan; 5Aerosol Science and Research Center, National Sun Yat-Sen University, Kaohsiung, Taiwan; 6Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Department of Applied Chemistry, Providence University, Taichung, Taiwan; 8Department of Computer Science and Information Engineering, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan; 9Experimental Studies, National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UK; 10Pulmonary Medicine Research Center, Taipei Medical University, Taipei, Taiwan; 11Department of Thoracic Medicine, Taipei Medical University Hospital, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Chun-Hua WangDepartment of Thoracic Medicine, Chang Gung Memorial Hospital, 199 Tun-Hwa North Road, Taipei 10507, TaiwanTel +886 3 321 1200 ext 8467Email wchunhua@ms7.hinet.netHan-Pin KuoDepartment of Medicine, Taipei Medical University School of Medicine, 250 Wu-Xing Street, Taipei 11031, TaiwanEmail q8828@ms11.hinet.netPurpose: Exposure to polycyclic aromatic hydrocarbons (PAHs) associated with ambient air particulate matter (PM) poses significant health concerns. Increased acute exacerbation (AE) frequency in asthmatic patients has been associated with ambient PAHs, but which subgroup of patients are particularly susceptible to ambient PAHs is uncertain. We developed a new model to simulate grid-scale PM2.5-PAH levels in order to evaluate whether the severity of asthma as measured by the Global Initiative of Asthma (GINA) levels of treatment is related to cumulative exposure of ambient PAHs.Methods: Patients with asthma residing in the northern Taiwan were reviewed retrospectively from 2014 to 2017. PM2.5 were sampled and analysed for PAHs twice a month over a 72-hour period, in addition to collecting the routinely monitored air pollutant data from an established air quality monitoring network. In combination with correlation analysis and principal component analysis, multivariate linear regression models were performed to simulate hourly grid-scale PM2.5-PAH concentrations (ng/m3). A geographic information system mapping approach with ordinary kriging interpolation method was used to calculate the annual exposure of PAHs (ng/m).Results: Among the 387 patients with asthma aged 18 to 93 (median 62), 97 subjects were treated as GINA step 5 (24%). Asthmatics in GINA 5 subgroup with high annual PAHs exposure were likely to have a higher annual frequency of any AE (1 (0– 12), p< 0.0001). Annual PAHs exposure was correlated with the annual frequency of any exacerbation (r=0.11, p=0.02). This was more significant in the GINA 5 subgroup (r=0.29, p=0.005) and in the GINA 5 subgroup with severe acute exacerbations (r=0.51, p=0.002). Annual PAHs exposure, severe acute exacerbation and GINA steps were independent variables that predict annual frequency of any exacerbation.Conclusion: Asthmatic patients in the GINA 5 subgroup with acute exacerbations were more susceptible to the effect of environmental PAHs on their exacerbation frequency. Reducing environmental levels of PAHs will have the greatest impact on the more severe asthma patients.Keywords: polycyclic aromatic hydrocarbons, asthma acute exacerbation, GINA, hourly grid-scale model

Chunrui Wang,1 Zhe Yuan,1 Wenxiang Huang,1 Li Yan,2 Jun Tang,3 Cheng-wei Liu3 1Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China; 2Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China; 3Department of Infectious Diseases, Key Laboratory of Infectious and Parasitic Diseases in Chongqing, Chongqing 400016, People’s Republic of China Background: Klebsiella pneumoniae (KP) is the most common pathogen isolated in intensive care units (ICUs) and the most frequently encountered carbapenemase-producing Enterobacteriaceae. Increasing antimicrobial drug resistance, especially in carbapenem-resistant KP (CRKP), can limit the choice of antibiotics used for the treatment of infectious diseases and further poses a negative impact on patient outcome. However, the reason behind this increasing resistance is not well known. Patients and methods: A retrospective analysis of laboratory records and clinical cases of KP infection in the ICUs of a hospital from January 2013 to December 2017 was conducted. The disk diffusion method and double-paper synergy test were used to test drug sensitivity for extended-spectrum β-lactamase (ESBL) detection. WHONET5.6 and SPSS 21.0 software were used for statistical analysis. Results: A total of 64.8% (570/847) of patients with KP infection were older than 60 years. The lower respiratory tract was the main infection site, accounting for 70.84% (600/847); the highest rate of ICU admission was for neurosurgery, accounting for 28.69% (243/847). Some 444 multidrug-resistant KP strains were detected, including 69 CRKP and 299 ESBL-producing strains. In the past 5 years, the resistance rate of detected strains to common antibiotics increased to various degrees, particularly carbapenem-resistant strains which increased from 4.76% (9/189) in 2013 to 16.00% (28/175) in 2017. All carbapenem-resistant isolates were resistant to β-lactam antibiotics, and no isolates were resistant to tigecycline. Conclusion: CRKP and ESBLKP prevalence and resistance rates gradually increased in our ICUs in the past 5 years. The reasons for this are manifold. Regular surveillance of resistance, rational use of antibiotics, and other effective infection control measures need to be strengthened to slow down the production of multidrug-resistant bacteria and prevent their spread in ICU settings. Keywords: Klebsiella pneumoniae, antibiotic resistance, carbapenem resistance, intensive care units

Chia Wen Liu,1,2 Wen Jen Lin11Graduate Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei; 2Drug Delivery Department, Biomedical Engineering Research Laboratories, Industrial Technology Research Institute, Hsinchu, TaiwanBackground: This study was performed to develop a functional poly(D,L-lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG)-bearing amino-active end group for peptide conjugation.Methods and results: PLGA was preactivated following by copolymerization with PEG diamine. The resulting amphiphilic PLGA-PEG copolymer bearing 97.0% of amino end groups had a critical micelle concentration of 3.0 × 10-8 mol/L, and the half-effective inhibition concentration (IC50) of the prepared PLGA-PEG nanoparticles was >100 mg/mL, which was much higher than that of PLGA nanoparticles (1.02 ± 0.37 mg/mL). The amphiphilic properties of PLGA-PEG spontaneously formed a core-shell conformation in the aqueous environment, and this special feature provided the amino group on the PEG chain scattered on the surface of PLGA-PEG nanoparticles for efficient peptide conjugation. The peptide-conjugated PLGA-PEG nanoparticles showed three-fold higher uptake than peptide-free PLGA-PEG nanoparticles in a SKOV3 cell line with high expression of epidermal growth factor receptor. Both peptide-conjugated and peptide-free PLGA-PEG nanoparticles were used as nanocarriers for delivery of doxorubicin. Although the rate of release of doxorubicin from both nanoparticles was similar, drug release at pH 4.0 (500 U lipase) was faster than at pH 7.4. The IC50 of doxorubicin-loaded peptide-conjugated PLGA-PEG nanoparticles in SKOV3 cells (0.05 ± 0.03 µg/mL) was much lower (by 62.4-fold) than that of peptide-free PLGA-PEG nanoparticles (3.12 ± 1.44 µg/mL).Conclusion: This in vivo biodistribution study in SKOV3 tumor-bearing mice was further promising in that accumulation of doxorubicin in tumor tissue was in the order of peptide-conjugated PLGA-PEG nanoparticles > peptide-free PLGA-PEG nanoparticles > doxorubicin solution.Keywords: amphiphilic copolymer, peptide, nanoparticles, SKOV3 cell, doxorubicin