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Candida auris is resistant to multiple antifungal agents. This study investigated its antifungal susceptibility and explored FKS1 mutations across the isolates from mice enterically colonized with wild-type C. auris and treated with echinocandin. Resistant C. auris with FKS1 mutations, including S639F, S639Y, D642Y, R1354H, or R1354Y, were isolated and found to be micafungin- and caspofungin-resistant in vivo; however, the MICs of isolates with mutation in R1354 remained below the micafungin breakpoint in vitro., Antimicrobial agents and chemotherapy, 67(4), art. no. e0124322; 2023

Background: Lascufloxacin hydrochloride (LSFX) is a quinolone antibiotic that inhibits DNA gyrase and topoisomerase IV of bacteria, it is anticipated to minimize antibiotic resistance in bacteria. It exhibits antibacterial activity against a relatively wide range of bacterial species, including anaerobic bacteria, and its efficacy and safety against community-acquired pneumonia have been shown; however, its efficacy and safety against nursing and healthcare associated pneumonia (NHCAP) have not been verified. Methods/Design: Here, a single-arm, open-label, uncontrolled study was conducted in which LSFX was administered to patients with NHCAP at 24 facilities. The research subjects (77 cases) were orally administered 75 mg of LSFX once a day for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC) (TOC; 5–10 days after the end of LSFX administration), while the secondary endpoints were the efficacy at the time of end of treatment, early clinical efficacy, microbiological efficacy at the time of TOC and end of treatment, and safety evaluation of LSFX. Discussion: NHCAP is a common pneumonia in clinical settings and a notable pneumonia whose mortality is high compared to community-acquired pneumonia. The present study showed the efficacy and safety of LSFX against NHCAP, which could lead to a larger number of therapeutic options for NHCAP., Medicine, 102(8), art. no. e33092; 2023

Background:We conducted a multicenter study to evaluate the performance of a novel fully automated molecular point-of-care test using transcription-reverse transcription concerted reaction that can detect influenza A and B within 15 min in nasopharyngeal swabs and gargle samples (TRCsatFLU). Methods:Patients who visited or were hospitalized at eight clinics and hospitals with influenza-like illnesses between December 2019 and March 2020 participated in this study. We collected nasopharyngeal swabs from all patients and gargle samples from patients whom the physician judged fit to perform gargling. The result of TRCsatFLU was compared to a conventional reverse transcription-polymerase chain reaction (RT-PCR). If the results of TRCsatFLU and conventional RT-PCR were different, the samples were analyzed by sequencing. Results:We evaluated 233 nasopharyngeal swabs and 213 gargle samples from 244 patients. The average age of the patients was 39.3 ± 21.2. Of the patients, 68.9% visited a hospital within 24 h of symptom onset. The most common symptoms were fever (93.0%), fatigue (79.5%), and nasal discharge (64.8%). All patients in whom the gargle sample was not collected were children. Influenza A or B was detected in 98 and 99 patients in nasopharyngeal swabs and gargle samples using TRCsatFLU, respectively. Four and five patients in nasopharyngeal swabs and gargle samples, respectively, with different TRCsatFLU and conventional RT-PCR results. Influenza A or B was detected using sequencing in all samples with different results. Based on the combined conventional RT-PCR and sequencing results, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of TRCsatFLU for influenza detection in nasopharyngeal swabs were 0.990, 1.000, 1.000, and 0.993, respectively. In the gargle samples, the sensitivity, specificity, PPV, and NPV of the TRCsatFLU for detecting influenza were 0.971, 1.000, 1.000, and 0.974, respectively. Conclusions:The, Virology Journal, 20(1), art. no. 41; 2023

Crizotinib demonstrates dramatic effects for the patients with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase gene (ALK) fusion or c-ros oncogene 1 (ROS-1) fusion-positive lung cancer, with some characteristic toxicities. Although several studies reported that serious esophagitis was induced by crizotinib, the detailed mechanisms and ways to ameliorate the esophagitis have not been clarified. In this report, we report two cases with lung cancer who had been treated with crizotinib and developed severe esophagitis. Polarizing microscope examination clearly revealed that the accumulation of crizotinib-residue in the esophageal biopsy samples at the second anatomical narrowing of the esophagus in both cases. Since it seemed that the accumulation of crizotinib-residue in the esophageal mucosa directly caused the esophageal inflammation, we recommended taking crizotinib with a large amount of water (more than 200 ml) and to stay sitting upright for 30 minutes after intake. After that, the esophagitis gradually improved and the patients could continue taking crizotinib without dose reduction or withdrawal. Our experiences suggest that this crizotinib-induced esophagitis could be easily prevented by proper administration of crizotinib., Acta medica Nagasakiensia, 66(2), pp.99-103; 2023

Background: Thymic epithelial tumors (TETs) are prone to developing in East Asian populations. However, little is known about the genomic profile of TETs in East Asian populations, and the genomic aberrations in TETs have not yet been fully clarified. Thus, molecular targeted therapies for patients with TETs have not been established. This prospective study was conducted to explore the genetic abnormalities of surgically resected TETs in a Japanese cohort and to identify clues for carcinogenesis and potential therapeutic targets in TETs. Methods: Genetic profiles of TETs were investigated using fresh-frozen specimens resected from operable cases with TETs. DNA sequencing was performed using a next-generation sequencing (NGS) gene panel test with Ion Reporter™ and CLC Genomics Workbench 11.0. The mutation sites were further confirmed by Sanger sequencing, digital droplet polymerase chain reaction (ddPCR), and TA cloning for validation. Results: Among 43 patients diagnosed with anterior mediastinal tumors between January 2013 and March 2019, NGS and validation analyses were performed in 31 patients [29 thymomas and two thymic cancers (TCs)] who met the study criteria. Of these, 12 cases of thymoma types A, AB, B1, and B2 harbored the general transcription factor 2-I (GTF2I) mutation (L424H). Conversely, the mutation was not detected in type B3 thymoma or TC, suggesting that the GTF2I mutation existed in indolent types of TETs. Rat sarcoma viral oncogene (RAS) mutations were detected in three cases [Harvey RAS (HRAS) in two cases of type AB thymoma and neuroblastoma RAS (NRAS)] in one case of type B1 thymoma), and additional sex combs like 1 (ASXL1) mutation was present in one case of TC. All RAS mutations were observed in GTF2I-mutated cases. Conclusions: The GTF2I mutation (L424H) is the most frequently occurring mutation in the limited histology of thymoma, consistent with those in the non-Asian population. HRAS and NRAS mutations co-occurred in cases harboring the, Translational Lung Cancer Research, 12(4), pp.707-718; 2023

Background: The lung cancer biopsy specimens obtained by endobronchial ultrasound-guide sheath (EBUS-GS) trans lung biopsy occasionally do not contain cancer cells. It is a problem that there is a possibility that they may not contain cancer cells. Aim of the study: To investigate the proportion of biopsy specimens containing cancer cells in total biopsy specimens. Materials & methods: Patients with lung cancer diagnosed by EBUS-GS were selected. The primary end point was the proportion of specimens containing tumors in the total specimens obtained by EBUS-GS. Results: Twenty-six patients were investigated. The percentage of specimens containing cancer cells in the total specimens was 79.0%. Conclusion: The proportion of biopsy specimens containing cancer cell to all biopsy specimens by EBUS-GS was high, but not 100%., Lung Cancer Management, 11(4), art. no. 0001; 2023

BD Phoenix CPO Detect panels can identify and classify carbapenemaseproducing organisms (CPOs) simultaneously with antimicrobial susceptibility testing (AST) for Gram-negative bacteria. Detection and classification of carbapenemase producers were performed using the BD Phoenix CPO Detect panels NMIC/ID-441 for Enterobacterales, NMIC/ID-442 for nonfermenting bacteria, and NMIC-440 for both. The results were compared with those obtained using comparator methods. A total of 133 strains (32 Klebsiella pneumoniae, 37 Enterobacter cloacae complex, 33 Pseudomonas aeruginosa, and 31 Acinetobacter baumannii complex strains), including 60 carbapenemase producers (54 imipenemases [IMPs] and 6 OXA type), were analyzed. Using panels NMIC-440 and NMIC/ID-441 or NMIC/ID-442, all 54 IMP producers were accurately identified as CPOs (positive percent agreement [PPA], 100.0%; 54/54). Among the 54 IMP producers identified as CPOs using panels NMIC-440 and NMIC/ID-441, 12 and 14 Enterobacterales were not resistant to carbapenem, respectively. Among all 54 IMP producers, 48 (88.9%; 48/54) were correctly classified as Ambler class B using panel NMIC-440. Using panels NMIC-440 and NMIC/ID-442, all four OXA-23-like carbapenemaseproducing A. baumannii complex strains (100.0%, 4/4) were correctly identified as CPOs, and three (75.0%, 3/4) were precisely classified as class D using panel NMIC-440. Both carbapenemase producers harboring the blaISAba1-OXA-51-like gene were incorrectly identified as non-CPOs using panels NMIC-440 and NMIC/ID-442. For detecting carbapenemase producers, the overall PPA and negative percent agreement (NPA) between panel NMIC-440 and the comparator methods were 96.7% (58/60) and 71.2% (52/73), respectively, and the PPA and NPA between panels NMIC/ID-441 or NMIC/ID-442 and the comparator methods were 96.7% (58/60) and 74.0% (54/73), respectively. BD Phoenix CPO Detect panels can successfully screen carbapenemase producers, particularly IMP producers, regardless of the, Microbiology spectrum, 11(3), art. no. e0089723; 2023

Outbreaks of invasive infections, with high mortality rates, caused by multidrug-resistant Candida auris have been reported worldwide. Although hotspot mutations in FKS1 are an established cause of echinocandin resistance, the actual contribution of these mutations to echinocandin resistance remains unknown. Here, we sequenced the FKS1 gene of a caspofungin-resistant clinical isolate ( clade I ) and identified a novel resistance mutation (G4061A inducing R1354H). We applied the clus-tered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to generate a recovered strain (H1354R) in which only this single nucleotide mutation was reverted to its wild-type sequence. We also generated mutant strains with only the R1354H mutation introduced into C. auris wild-type strains (clade I and II) and analyzed their antifungal susceptibility. Compared to their parental strains, the R1354H mutants exhibited a 4- to 16-fold increase in caspofungin minimum inhibitory concentration (MIC) while the H1354R reverted strain exhibited a 4-fold decrease in caspofungin MIC. In a mouse model of disseminated candidiasis, the in vivo therapeutic effect of caspofungin was more closely related to the FKS1 R1354H mutation and the virulence of the strain than its in vitro MIC. The CRISPR-Cas9 system could thus aid in elucidating the mechanism underlying drug resistance in C. auris., Journal of Fungi, 9(5), art. no. 529; 2023

This study aimed to examine the validity of urinary N-terminal titin fragment/creatinine (urinary N-titin/Cr) reflecting muscle damage biomarker in patients with interstitial lung disease. This retrospective study enrolled patients with interstitial lung disease. We measured urinary N-titin/Cr. Furthermore, we measured the cross-sectional areas of the pectoralis muscles above the aortic arch (PMCSA) and erector spinae muscles of the 12th thoracic vertebra muscles (ESMCSA) to assess muscle mass until 1 year. We examined the correlation between urinary N-titin/Cr and the change in muscle mass. We plotted receiver operating characteristic curves to estimate the cut-off points for urinary N-titin/Cr for distinguishing the greater-than-median and smaller-than-median reduction of muscle mass after 1 year. We enrolled 68 patients with interstitial lung disease. The median urinary N-titin/Cr value was 7.0 pmol/mg/dL. We observed significant negative correlations between urinary N-titin/Cr and changes in the PMCSA after 1 year (p < 0.001) and changes in the ESMCSA after 6 months (p < 0.001) and 1 year (p < 0.001). The cut-off points for urinary N-titin/Cr were 5.2 pmol/mg/dL and 10.4 pmol/mg/dL in the PMCSA and ESMCSA, respectively. In summary, urinary N-titin/Cr may predict muscle loss in the long-term and act as a clinically useful biomarker reflecting muscle damage., Scientific Reports, 13(1), art. no. 9723; 2023

We investigated the clinical features of bloodstream infections (BSIs) caused by Klebsiella pneumoniae harboring rmpA and molecular characteristics of the bacteria. We retrospectively investigated adult patients with K. pneumoniae BSI from January 2010 to March 2021 at Nagasaki University Hospital. A matched case–control study in a 1:3 ratio was conducted to clarify the clinical and bacterial characteristics of BSI caused by rmpA-positive K. pneumoniae compared with those caused by rmpA-negative isolates. Antimicrobial susceptibility testing and multilocus sequence typing (MLST) were performed for rmpA-positive isolates. The rmpA was detected in 36 (13.4%) of the 268 isolates. Of these 36 isolates, 31 (86.1%) harbored iucA and 35 (97.2%) each possessed peg-344 and iroB; capsular types were identified as K1 in 9 (25.0%) and K2 in 10 isolates (27.8%). Contrarily, of the 108 rmpA-negative isolates, which were matched for case–control studies, 5 isolates (4.6%) harbored iucA and 1 (0.9%) each possessed peg-344 and iroB; 2 (1.9%) and 3 isolates (2.8%) had K1 and K2 capsular types, respectively. Among the rmpA-positive isolates, ST23/K1 (eight isolates) was the most frequent, followed by ST412/non-K1/K2 (seven isolates), ST86/K2 (five isolates), and ST268/non-K1/K2 (four isolates). In a multivariate analysis using clinical factors, liver abscess positively correlated with rmpA-positive isolates, whereas biliary tract infection and use of anticancer drugs negatively correlated with rmpA-positive isolates in patients with K. pneumoniae BSI. Considering the correlation between rmpA-positive isolates and clinical features, rmpA can be used as a marker for understanding the pathophysiology of K. pneumoniae BSI., Scientific Reports, 13(1), art. no. 6571; 2023

Following an endobronchial examination, a young mine supervisor was treated with antibiotics for a pulmonary nontuberculous mycobacterial infection for approximately one year. However, a review of the radiological findings revealed a different possibility. Accordingly, pulmonary resection was performed, and histopathological analysis revealed numerous yeast-like fungi. Since the patient had stayed in the southwestern United States for two months in 2009, eight years previously, coccidioidomycosis was strongly suspected. The diagnosis of coccidioidomycosis was subsequently confirmed by serology and polymerase chain reaction testing of the excised specimen. Here, we report an educational case that emphasizes the importance of meticulous medical history-taking and awareness of endemic mycoses in other countries in the context of globalization., Japanese Journal of Infectious Diseases, 76(5), pp.314-318; 2023

Sarcoidosis is a systemic inflammatory disease characterized by noncaseating epithelioid cell granulomas. However, certain infections can exhibit similar histological findings. We present a case of a 69-year-old man who was initially diagnosed with sarcoidosis and later was confirmed, through 16S rRNA sequencing, to have disseminated Mycobacterium genavense infection. Acid-fast bacteria were detected in the bone marrow biopsy using Ziehl–Neelsen staining, but routine clinical tests did not provide a definitive diagnosis. The patient tested negative for HIV, anti-interferongamma antibodies, and genetic immunodeficiency disorders. He was treated with multiple drugs, including aminoglycosides and macrolides, but showed no improvement in fever and pancytopenia. However, these clinical signs responded favorably to steroid therapy. We reviewed 17 Japanese cases of M. genavense infection. All cases were in males; 7/17 (41%) were HIV-negative; and 12/17 (71%) had a decreased CD4 count. Genetic analysis confirmed M. genavense isolation, and macrolides were used universally. Mycobacterium genavense infection is challenging to identify and mimics other systemic inflammatory diseases such as sarcoidosis. There are no standard treatment protocols. Our case report and Japanese case review contribute to understanding this rare disease., Microorganisms, 11(9), art. no. 2145; 2023

Background: Mucormycosis is a potentially fatal fungal infection, and there is limited information on its precise epidemiology and treatment practices, including the optimal dosage of liposomal amphotericin B. Methods: A retrospective, multicenter, nationwide analysis of 82 proven and probable cases of mucormycosis was performed. Cases between 2015 and 2022 were collected from 51 hospitals in Japan by hematologists and infectious disease specialists. The study included the epidemiology, treatment details, and association between the dose of liposomal amphotericin B and the outcome. Results: The lungs were the most commonly involved organ (70.7% of cases), and 35.4% of patients had disseminated disease. Rhizopus spp., Cunninghamella spp., and Mucor spp. were the most common organisms. Mortality at 4 weeks was 41.5%. The survivors had a shorter duration of neutropenia (P = .006) and less persistent hyperglycemia (P = .023). The site of infection and species of Mucorales had no detectable effect on survival. Survival did not differ between patients receiving liposomal amphotericin B at 5 mg/kg/d relative to those receiving >5 mg/kg/d (P = .625). Using Cox proportional hazards models and adjusting for confounders, the hazard ratio for the influence of >5 mg/kg/d liposomal amphotericin B on 4-week survival was 0.86 (95% CI, 0.28–2.68; P = .796) compared with 5 mg/kg/d. Conclusions: This study provides important insights into the precise epidemiology and treatment practices of mucormycosis. Treatment with liposomal amphotericin B at doses higher than 5 mg/kg/d did not improve outcomes relative to 5 mg/kg/d., Open Forum Infectious Diseases, 10(10), art. no. ofad480; 2023

Background: Lascufloxacin hydrochloride (LSFX) is a quinolone antibiotic that inhibits DNA gyrase and topoisomerase IV of bacteria, it is anticipated to minimize antibiotic resistance in bacteria. It exhibits antibacterial activity against a relatively wide range of bacterial species, including anaerobic bacteria, and its efficacy and safety against community-acquired pneumonia have been shown; however, its efficacy and safety against nursing and healthcare associated pneumonia (NHCAP) have not been verified. Methods/Design: Here, a single-arm, open-label, uncontrolled study was conducted in which LSFX was administered to patients with NHCAP at 24 facilities. The research subjects (77 cases) were orally administered 75 mg of LSFX once a day for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC) (TOC; 5–10 days after the end of LSFX administration), while the secondary endpoints were the efficacy at the time of end of treatment, early clinical efficacy, microbiological efficacy at the time of TOC and end of treatment, and safety evaluation of LSFX. Discussion: NHCAP is a common pneumonia in clinical settings and a notable pneumonia whose mortality is high compared to community-acquired pneumonia. The present study showed the efficacy and safety of LSFX against NHCAP, which could lead to a larger number of therapeutic options for NHCAP., Medicine, 102(8), art. no. e33092; 2023

Background:We conducted a multicenter study to evaluate the performance of a novel fully automated molecular point-of-care test using transcription-reverse transcription concerted reaction that can detect influenza A and B within 15 min in nasopharyngeal swabs and gargle samples (TRCsatFLU). Methods:Patients who visited or were hospitalized at eight clinics and hospitals with influenza-like illnesses between December 2019 and March 2020 participated in this study. We collected nasopharyngeal swabs from all patients and gargle samples from patients whom the physician judged fit to perform gargling. The result of TRCsatFLU was compared to a conventional reverse transcription-polymerase chain reaction (RT-PCR). If the results of TRCsatFLU and conventional RT-PCR were different, the samples were analyzed by sequencing. Results:We evaluated 233 nasopharyngeal swabs and 213 gargle samples from 244 patients. The average age of the patients was 39.3 ± 21.2. Of the patients, 68.9% visited a hospital within 24 h of symptom onset. The most common symptoms were fever (93.0%), fatigue (79.5%), and nasal discharge (64.8%). All patients in whom the gargle sample was not collected were children. Influenza A or B was detected in 98 and 99 patients in nasopharyngeal swabs and gargle samples using TRCsatFLU, respectively. Four and five patients in nasopharyngeal swabs and gargle samples, respectively, with different TRCsatFLU and conventional RT-PCR results. Influenza A or B was detected using sequencing in all samples with different results. Based on the combined conventional RT-PCR and sequencing results, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of TRCsatFLU for influenza detection in nasopharyngeal swabs were 0.990, 1.000, 1.000, and 0.993, respectively. In the gargle samples, the sensitivity, specificity, PPV, and NPV of the TRCsatFLU for detecting influenza were 0.971, 1.000, 1.000, and 0.974, respectively. Conclusions:The, Virology Journal, 20(1), art. no. 41; 2023

Crizotinib demonstrates dramatic effects for the patients with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase gene (ALK) fusion or c-ros oncogene 1 (ROS-1) fusion-positive lung cancer, with some characteristic toxicities. Although several studies reported that serious esophagitis was induced by crizotinib, the detailed mechanisms and ways to ameliorate the esophagitis have not been clarified. In this report, we report two cases with lung cancer who had been treated with crizotinib and developed severe esophagitis. Polarizing microscope examination clearly revealed that the accumulation of crizotinib-residue in the esophageal biopsy samples at the second anatomical narrowing of the esophagus in both cases. Since it seemed that the accumulation of crizotinib-residue in the esophageal mucosa directly caused the esophageal inflammation, we recommended taking crizotinib with a large amount of water (more than 200 ml) and to stay sitting upright for 30 minutes after intake. After that, the esophagitis gradually improved and the patients could continue taking crizotinib without dose reduction or withdrawal. Our experiences suggest that this crizotinib-induced esophagitis could be easily prevented by proper administration of crizotinib., Acta medica Nagasakiensia, 66(2), pp.99-103; 2023

Candida auris is resistant to multiple antifungal agents. This study investigated its antifungal susceptibility and explored FKS1 mutations across the isolates from mice enterically colonized with wild-type C. auris and treated with echinocandin. Resistant C. auris with FKS1 mutations, including S639F, S639Y, D642Y, R1354H, or R1354Y, were isolated and found to be micafungin- and caspofungin-resistant in vivo; however, the MICs of isolates with mutation in R1354 remained below the micafungin breakpoint in vitro., Antimicrobial agents and chemotherapy, 67(4), art. no. e0124322; 2023

We investigated the clinical features of bloodstream infections (BSIs) caused by Klebsiella pneumoniae harboring rmpA and molecular characteristics of the bacteria. We retrospectively investigated adult patients with K. pneumoniae BSI from January 2010 to March 2021 at Nagasaki University Hospital. A matched case–control study in a 1:3 ratio was conducted to clarify the clinical and bacterial characteristics of BSI caused by rmpA-positive K. pneumoniae compared with those caused by rmpA-negative isolates. Antimicrobial susceptibility testing and multilocus sequence typing (MLST) were performed for rmpA-positive isolates. The rmpA was detected in 36 (13.4%) of the 268 isolates. Of these 36 isolates, 31 (86.1%) harbored iucA and 35 (97.2%) each possessed peg-344 and iroB; capsular types were identified as K1 in 9 (25.0%) and K2 in 10 isolates (27.8%). Contrarily, of the 108 rmpA-negative isolates, which were matched for case–control studies, 5 isolates (4.6%) harbored iucA and 1 (0.9%) each possessed peg-344 and iroB; 2 (1.9%) and 3 isolates (2.8%) had K1 and K2 capsular types, respectively. Among the rmpA-positive isolates, ST23/K1 (eight isolates) was the most frequent, followed by ST412/non-K1/K2 (seven isolates), ST86/K2 (five isolates), and ST268/non-K1/K2 (four isolates). In a multivariate analysis using clinical factors, liver abscess positively correlated with rmpA-positive isolates, whereas biliary tract infection and use of anticancer drugs negatively correlated with rmpA-positive isolates in patients with K. pneumoniae BSI. Considering the correlation between rmpA-positive isolates and clinical features, rmpA can be used as a marker for understanding the pathophysiology of K. pneumoniae BSI., Scientific Reports, 13(1), art. no. 6571; 2023

Background: Thymic epithelial tumors (TETs) are prone to developing in East Asian populations. However, little is known about the genomic profile of TETs in East Asian populations, and the genomic aberrations in TETs have not yet been fully clarified. Thus, molecular targeted therapies for patients with TETs have not been established. This prospective study was conducted to explore the genetic abnormalities of surgically resected TETs in a Japanese cohort and to identify clues for carcinogenesis and potential therapeutic targets in TETs. Methods: Genetic profiles of TETs were investigated using fresh-frozen specimens resected from operable cases with TETs. DNA sequencing was performed using a next-generation sequencing (NGS) gene panel test with Ion Reporter™ and CLC Genomics Workbench 11.0. The mutation sites were further confirmed by Sanger sequencing, digital droplet polymerase chain reaction (ddPCR), and TA cloning for validation. Results: Among 43 patients diagnosed with anterior mediastinal tumors between January 2013 and March 2019, NGS and validation analyses were performed in 31 patients [29 thymomas and two thymic cancers (TCs)] who met the study criteria. Of these, 12 cases of thymoma types A, AB, B1, and B2 harbored the general transcription factor 2-I (GTF2I) mutation (L424H). Conversely, the mutation was not detected in type B3 thymoma or TC, suggesting that the GTF2I mutation existed in indolent types of TETs. Rat sarcoma viral oncogene (RAS) mutations were detected in three cases [Harvey RAS (HRAS) in two cases of type AB thymoma and neuroblastoma RAS (NRAS)] in one case of type B1 thymoma), and additional sex combs like 1 (ASXL1) mutation was present in one case of TC. All RAS mutations were observed in GTF2I-mutated cases. Conclusions: The GTF2I mutation (L424H) is the most frequently occurring mutation in the limited histology of thymoma, consistent with those in the non-Asian population. HRAS and NRAS mutations co-occurred in cases harboring the, Translational Lung Cancer Research, 12(4), pp.707-718; 2023

Outbreaks of invasive infections, with high mortality rates, caused by multidrug-resistant Candida auris have been reported worldwide. Although hotspot mutations in FKS1 are an established cause of echinocandin resistance, the actual contribution of these mutations to echinocandin resistance remains unknown. Here, we sequenced the FKS1 gene of a caspofungin-resistant clinical isolate ( clade I ) and identified a novel resistance mutation (G4061A inducing R1354H). We applied the clus-tered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to generate a recovered strain (H1354R) in which only this single nucleotide mutation was reverted to its wild-type sequence. We also generated mutant strains with only the R1354H mutation introduced into C. auris wild-type strains (clade I and II) and analyzed their antifungal susceptibility. Compared to their parental strains, the R1354H mutants exhibited a 4- to 16-fold increase in caspofungin minimum inhibitory concentration (MIC) while the H1354R reverted strain exhibited a 4-fold decrease in caspofungin MIC. In a mouse model of disseminated candidiasis, the in vivo therapeutic effect of caspofungin was more closely related to the FKS1 R1354H mutation and the virulence of the strain than its in vitro MIC. The CRISPR-Cas9 system could thus aid in elucidating the mechanism underlying drug resistance in C. auris., Journal of Fungi, 9(5), art. no. 529; 2023

BD Phoenix CPO Detect panels can identify and classify carbapenemaseproducing organisms (CPOs) simultaneously with antimicrobial susceptibility testing (AST) for Gram-negative bacteria. Detection and classification of carbapenemase producers were performed using the BD Phoenix CPO Detect panels NMIC/ID-441 for Enterobacterales, NMIC/ID-442 for nonfermenting bacteria, and NMIC-440 for both. The results were compared with those obtained using comparator methods. A total of 133 strains (32 Klebsiella pneumoniae, 37 Enterobacter cloacae complex, 33 Pseudomonas aeruginosa, and 31 Acinetobacter baumannii complex strains), including 60 carbapenemase producers (54 imipenemases [IMPs] and 6 OXA type), were analyzed. Using panels NMIC-440 and NMIC/ID-441 or NMIC/ID-442, all 54 IMP producers were accurately identified as CPOs (positive percent agreement [PPA], 100.0%; 54/54). Among the 54 IMP producers identified as CPOs using panels NMIC-440 and NMIC/ID-441, 12 and 14 Enterobacterales were not resistant to carbapenem, respectively. Among all 54 IMP producers, 48 (88.9%; 48/54) were correctly classified as Ambler class B using panel NMIC-440. Using panels NMIC-440 and NMIC/ID-442, all four OXA-23-like carbapenemaseproducing A. baumannii complex strains (100.0%, 4/4) were correctly identified as CPOs, and three (75.0%, 3/4) were precisely classified as class D using panel NMIC-440. Both carbapenemase producers harboring the blaISAba1-OXA-51-like gene were incorrectly identified as non-CPOs using panels NMIC-440 and NMIC/ID-442. For detecting carbapenemase producers, the overall PPA and negative percent agreement (NPA) between panel NMIC-440 and the comparator methods were 96.7% (58/60) and 71.2% (52/73), respectively, and the PPA and NPA between panels NMIC/ID-441 or NMIC/ID-442 and the comparator methods were 96.7% (58/60) and 74.0% (54/73), respectively. BD Phoenix CPO Detect panels can successfully screen carbapenemase producers, particularly IMP producers, regardless of the, Microbiology spectrum, 11(3), art. no. e0089723; 2023

Background: The lung cancer biopsy specimens obtained by endobronchial ultrasound-guide sheath (EBUS-GS) trans lung biopsy occasionally do not contain cancer cells. It is a problem that there is a possibility that they may not contain cancer cells. Aim of the study: To investigate the proportion of biopsy specimens containing cancer cells in total biopsy specimens. Materials & methods: Patients with lung cancer diagnosed by EBUS-GS were selected. The primary end point was the proportion of specimens containing tumors in the total specimens obtained by EBUS-GS. Results: Twenty-six patients were investigated. The percentage of specimens containing cancer cells in the total specimens was 79.0%. Conclusion: The proportion of biopsy specimens containing cancer cell to all biopsy specimens by EBUS-GS was high, but not 100%., Lung Cancer Management, 11(4), art. no. 0001; 2023

Studies indicated potential harm from empirical broad-spectrum therapy. A recent study of hospitalizations for community-acquired pneumonia suggested that empirical anti-methicillin-resistant Staphylococcus aureus (MRSA) therapy was associated with an increased risk of death and other complications. However, limited evidence supports empirical anti-MRSA therapy for older patients with aspiration pneumonia. In a nationwide Japanese database, patients aged ≥65 years on admission with aspiration pneumonia were analyzed. Patients were divided based on presence of respiratory failure and further sub-categorized based on their condition within 3 days of hospital admission, either receiving a combination of anti-MRSA agents and other antibiotics, or not using MRSA agents. An inverse probability weighting method with estimated propensity scores was used. Out of 81,306 eligible patients, 55,098 had respiratory failure, and 26,208 did not. In the group with and without respiratory failure, 0.93% and 0.42% of the patients, respectively, received anti-MRSA agents. In patients with respiratory failure, in-hospital mortality (31.38% vs. 19.03%, p < 0.001), 30-day mortality, and 90-day mortality were significantly higher, and oxygen administration length was significantly longer in the anti-MRSA agent combination group. Anti-MRSA agent combination use did not improve the outcomes in older patients with aspiration pneumonia and respiratory failure, and should be carefully and comprehensively considered., Microorganisms, 11(8), art. no. 1905; 2023

Factors affecting the start date of the influenza epidemic season and total number of infected persons per 1,000,000 population in 47 prefectures of Japan were evaluated. This retrospective observational study (September 2014–August 2019; N = 472,740–883,804) evaluated data from a Japanese health insurance claims database. Single and multiple regression analyses evaluated the time to start of the epidemic or total infected persons per 1,000,000 population with time to absolute humidity (AH) or number of days with AH (≤ 5.5, ≤ 6.0, ≤ 6.5, and ≤ 7.0), total visitors (first epidemic month or per day), and total population. For the 2014/15, 2015/16, and 2016/17 seasons, a weak-to-moderate positive correlation (R2: 0.042–0.417) was observed between time to start of the epidemic and time to first day with AH below the cutoff values. Except in the 2016/17 season (R2: 0.089), a moderate correlation was reported between time to start of the epidemic and the total population (R2: 0.212–0.401). For all seasons, multiple regression analysis showed negative R2 for time to start of the epidemic and total visitors and population density (positive for time to AH ≤ 7.0). The earlier the climate becomes suitable for virus transmission and the higher the human mobility (more visitors and higher population density), the earlier the epidemic season tends to begin., Scientific reports, 13(1), art. no. 13000; 2023

This study aimed to examine the validity of urinary N-terminal titin fragment/creatinine (urinary N-titin/Cr) reflecting muscle damage biomarker in patients with interstitial lung disease. This retrospective study enrolled patients with interstitial lung disease. We measured urinary N-titin/Cr. Furthermore, we measured the cross-sectional areas of the pectoralis muscles above the aortic arch (PMCSA) and erector spinae muscles of the 12th thoracic vertebra muscles (ESMCSA) to assess muscle mass until 1 year. We examined the correlation between urinary N-titin/Cr and the change in muscle mass. We plotted receiver operating characteristic curves to estimate the cut-off points for urinary N-titin/Cr for distinguishing the greater-than-median and smaller-than-median reduction of muscle mass after 1 year. We enrolled 68 patients with interstitial lung disease. The median urinary N-titin/Cr value was 7.0 pmol/mg/dL. We observed significant negative correlations between urinary N-titin/Cr and changes in the PMCSA after 1 year (p < 0.001) and changes in the ESMCSA after 6 months (p < 0.001) and 1 year (p < 0.001). The cut-off points for urinary N-titin/Cr were 5.2 pmol/mg/dL and 10.4 pmol/mg/dL in the PMCSA and ESMCSA, respectively. In summary, urinary N-titin/Cr may predict muscle loss in the long-term and act as a clinically useful biomarker reflecting muscle damage., Scientific Reports, 13(1), art. no. 9723; 2023

Background: The Asian Working Group for Sarcopenia 2019 (AWGS 2019) is the gold standard diagnostic criteria for sarcopenia in Asian populations. The calf circumference (CalF), the strength, assistance in walking, rising from a chair, climbing stairs, and falls (SARC-F) and the SARC-CalF questionnaires for sarcopenia screening have been used by AWGS 2019. The aim of this study was to assess accuracy of these three sarcopenia screening tools in patients with interstitial lung disease. Methods: In this cross-sectional study, stable patients with interstitial lung disease were enrolled. The SARC-F, SARC-CalF, and CalF, used in patients with interstitial lung disease, were compared to the diagnostic criteria proposed by AWGS 2019. The accuracy of screening tools was compared using sensitivity and specificity. Moreover, areas under the receiver operating characteristic curves (AUC) were computed. Results: Seventy eight patients were analyzed, and sarcopenia was identified in 25 (32.1%) patients with interstitial lung disease by the AWGS 2019 criteria. The sensitivity of the CalF was highest (96%) of the three screening tools, while the specificity was 60%. The sensitivity of SARC-F and SARC-CalF were 24% and 68%, while the specificity were 92% and 66%, respectively. The AUCs of CalF, SARC-F, and SARC-CalF in all patients were 0.78, 0.58, and 0.67, respectively. Conclusions: The CalF is most suitable for screening sarcopenia in patients with interstitial lung disease, while SARC-F and SARC-CalF are not., BMC Pulmonary Medicine, 22, art. no. 45; 2022

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus. It involves multiple organ systems, including the lungs. However, the significance of the lung involvement in SFTS remains unclear. In the present study, we aimed to investigate the relationship between the clinical findings and abnormalities noted in the chest computed tomography (CT) of patients with SFTS. The medical records of 22 confirmed SFTS patients hospitalized in five hospitals in Nagasaki, Japan, between April 2013 and September 2019, were reviewed retrospectively. Interstitial septal thickening and ground-glass opacity (GGO) were the most common findings in 15 (68.1%) and 12 (54.5%) patients, respectively, and lung GGOs were associated with fatalities. The SFTS patients with a GGO pattern were elderly, had a disturbance of the conscious and tachycardia, and had higher c-reactive protein levels at admission (p = 0.009, 0.006, 0.002, and 0.038, respectively). These results suggested that the GGO pattern in patients with SFTS displayed disseminated inflammation in multiple organs and that cardiac stress was linked to higher mortality. Chest CT evaluations may be useful for hospitalized patients with SFTS to predict their severity and as early triage for the need of intensive care., Viruses, 14(2), art. no. 279; 2022

Somatic mutations in epidermal growth factor receptor (EGFR) found in lung adenocarcinomas are used as biomarkers for the treatment with EGFR-tyrosine kinase inhibitors, including gefitinib. The bypass tracks with amplification of AXL is one of the mechanisms underlying the resistance to gefitinib. We, therefore, carried out a candidate gene approach method to identify AXL polymorphisms associated with the effectiveness of gefitinib. EGFR mutations were first dentified by mutantenriched PCR-restriction fragment length polymorphism (RFLP), and then 2 tag single nucleotide olymorphisms (SNPs) of AXL were examined by PCR-RFLP in 62 Japanese patients with advanced lung adenocarcinoma and treated with gefitinib in two general hospitals in Nagasaki. Subsequently, the association of EFGR mutations and the AXL polymorphism with the effectiveness of gefitinib was examined in these patients. We next examined the effect of the AXL polymorphism on the expression and function of this gene. It is worthy of note that EGFR mutations and the AXL polymorphism rs6508974 independently contributed to the effectiveness of gefitinib, and the polymorphism was proved to be a possible biomarker for selecting non-responders and responders to gefitinib treatment even in the absence of EGFR mutations. Furthermore, this SNP increased the transcriptional activity of the AXL transcript variant 3, one of the three AXL transcript variants, which to some extent increased the epithelial-mesenchymal transition in cancer cells. Taken together, AXL is one of the genes that determine the effectiveness of gefitinib and a biomarker for selecting non-responders and responders among lung adenocarcinoma patients with no EGFR mutations, suggesting that rs6508974 in AXL might be a functional SNP in lung denocarcinoma., Acta medica Nagasakiensia, 65(3), pp.111−121; 2022

Allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are important fungal infections caused by Aspergillus species. An overlap of ABPA and CPA has been reported; therefore, it is critical to determine whether the main pathology is ABPA or CPA and whether antifungals are required. In this study, we investigated whether the serum cytokine profile is useful for understanding the pathology and for differentiating between these diseases. We compared the various serum cytokine levels among healthy subjects and patients diagnosed with asthma, ABPA, or CPA at Nagasaki University Hospital between January 2003 and December 2018. In total, 14 healthy subjects, 19 patients with asthma, 11 with ABPA, and 10 with CPA were enrolled. Interleukin (IL) -5 levels were significantly higher in patients with ABPA than in those with CPA, and IL-33 and tumor necrosis factor (TNF) levels were significantly higher in patients with CPA than in those with asthma (p < 0.05, Dunn’s multiple comparison test). The sensitivity and specificity of the IL-10/IL-5 ratio (cutoff index 2.47) for diagnosing CPA were 70% and 100%, respectively. The serum cytokine profile is useful in understanding the pathology of ABPA and CPA, and the IL-10/IL-5 ratio may be a novel supplemental biomarker for indicating the pathology of CPA., Journal of Fungi, 8(5), art. no. 436; 2022

Background: Immune checkpoint inhibitors (ICIs) have achieved important outcomes in cancer treatment. However, current clinical biomarker tests are not suitable for some patients because they require tumor tissues and have poor predictive value for treatment responses. Therefore, the identification of biomarkers that enable screening tests in all patients is necessary. Methods: We performed an immune complexome analysis of non-small cell lung cancer patients treated with nivolumab to comprehensively identify and compare antigens incorporated into immune complexes (IC-antigens) in serum samples from the responders (n = 15) and non-responders (n = 20). Additionally, combinations of IC-antigens characteristic to the responder group were evaluated by logistic regression analysis and receiver operating characteristics curves to examine their predictiveness for ICI treatment responses. Results: The combination of predictive biomarkers detected before treatment was profilin-1, purine nucleoside phosphorylase, alpha-enolase, and nucleoside diphosphate kinase A [p = 0.0043, odds ratio = 2.26, 95% confidence interval (CI) = 1.19–4.28, area under the curve = 0.76]. The combination of predictive biomarkers detected after treatment was peptidyl-prolyl cis-trans isomerase A, ubiquitin-like modifier-activating enzyme 1, complement component C8 beta chain, and apolipoprotein L1 (p = 0.0039, odds ratio = 2.56, 95% CI = 1.25–5.23, area under the curve = 0.77). Conclusion: Combinations of serum IC-antigens may predict the therapeutic effect of nivolumab in non-small cell lung cancer patients., Clinica Chimica Acta, 532, pp. 84-88; 2022

Severe fever with thrombocytopenia syndrome (SFTS) and Japanese spotted fever (JSF; a spotted fever group rickettsiosis) are tick-borne zoonoses that are becoming a significant public health threat in Japan and East Asia. Strategies for treatment and infection control differ between the two; therefore, initial differential diagnosis is important. We aimed to compare the clinical characteristics of SFTS and JSF based on symptomology, physical examination, laboratory data, and radiography findings at admission. This retrospective study included patients with SFTS and JSF treated at five hospitals in Nagasaki Prefecture, western Japan, between 2013 and 2020. Data from 23 patients with SFTS and 38 patients with JSF were examined for differentiating factors and were divided by 7:3 into a training cohort and a validation cohort. Decision tree analysis revealed leukopenia (white blood cell [WBC] < 4000/µL) and altered mental status as the best differentiating factors (AUC 1.000) with 100% sensitivity and 100% specificity. Using only physical examination factors, absence of skin rash and altered mental status resulted in the best differentiating factors with AUC 0.871, 71.4% sensitivity, and 90.0% specificity. When treating patients with suspected tick-borne infection, WBC < 4000/µL, absence of skin rash, and altered mental status are very useful to differentiate SFTS from JSF., Viruses, 14(8), art. no. 1807; 2022

Introduction The COVID-19 pandemic has been a major concern worldwide; however, easily accessible treatment options for patients with mild COVID-19 remain limited. Since the oral intake of Lactococcus lactis strain plasma (LC-Plasma) enhances both the innate and acquired immune systems through the activation of plasmacytoid dendritic cells (pDCs), we hypothesised that the oral intake of LC-Plasma could aid the relief or prevention of symptoms in patients with asymptomatic or mild COVID-19. Methods and analysis This is an exploratory, multicentre, double-blinded, randomised, placebo-controlled trial. This study was initiated in December 2021 and concludes in April 2023. The planned number of enrolled subjects is 100 (50 subjects×2 groups); subject enrolment will be conducted until October 2022. Patients with asymptomatic or mild COVID-19 will be enrolled and randomly assigned in a 1:1 ratio to group A (oral intake of LC-Plasma-containing capsule, 200 mg/day, for 14 days) or group B (oral intake of placebo capsule, for 14 days). The primary endpoint is the change in subjective symptoms measured by the severity score. Secondary endpoints include SARS-CoV-2 viral loads, biomarkers for pDC activation, serum SARS-CoV-2-specific antibodies, serum cytokines, interferon and interferon-inducible antiviral effectors and the proportion of subjects with emergency room visits to medical institutions or who are hospitalised. Ethics and dissemination The study protocol was approved by the Clinical Research Review Board of Nagasaki University, in accordance with the Clinical Trials Act of Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act, and other current legal regulations in Japan. Written informed consent will be obtained from all the participants. The results of this study will be reported in journal publications., BMJ open, 12 (9), art. no. e061172; 2022

Managing mild illness in COVID-19 and predicting progression to severe disease are concerning issues. Here, we investigated the outcomes of Japanese patients with mild COVID-19, and identified triage risk factors for further hospitalization and emergency department (ED) visits at a single tertiary hospital. A triage checklist with 30 factors was used. Patients recommended for isolation were followed up for 10 days for subsequent ED visits or hospital admission. Overall, 338 patients (median age, 44.0; 45% women) visited the clinic 5.0 days (median) after symptom onset. Thirty-six patients were immediately hospitalized following triage; others were isolated. In total, 72 non-hospitalized patients visited the ED during their isolation, and 30 were hospitalized after evaluation for oxygen desaturation. The median ED visit and hospitalization durations after symptom onset were 5.0 and 8.0 days, respectively. The checklist factors associated with hospitalization during isolation were age > 50 years, body mass index > 25 kg/m2, hypertension, tachycardia with pulse rate > 100/min or blood pressure > 135 mmHg at triage, and >3-day delay in hospital visit after symptom onset. No patients died. Altogether, 80% of patients with mild COVID-19 could be safely isolated at home. Age, BMI, underlying hypertension, date after symptom onset, tachycardia, and systolic blood pressure at triage might be related to later hospitalization., Journal of Clinical Medicine, 11(18), art. no. 5444; 2022

Background: Influenza affects approximately a billion people globally, including > 10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model. Methods: Using the JMDC Claims Database, we identified index case (IC) as the first family member diagnosed with influenza during the 2018–19 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model. Results: The median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N = 84 672) and OTV (N = 62 004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th–97.5th percentiles, 1.68–1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs’ age category, virus type, and month of onset revealed similar trends favoring BXM. Conclusions: BXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment., Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 75(6), pp. 927-935; 2022

Introduction: We investigated the performance of the cobas® 6800 system and cobas SARS-CoV-2 & Influenza A/B, a fully automated molecular testing system for influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This enabled an assay in a batch of 96 samples in approximately 3 h. Methods: An assay was performed using the cobas SARS-CoV-2 & Influenza A/B on the cobas 6800 system for samples collected in four facilities between November 2019 and March 2020 in our previous study. The results were compared with those obtained using the reference methods. Results: Of the 127 samples analyzed, the cobas SARS-CoV-2 & Influenza A/B detected influenza A virus in 75 samples, of which 73 were positive using the reference methods. No false negative results were observed. The overall positive and negative percent agreement for influenza A virus detection were 100.0% and 96.3%, respectively. There were no positive results for the influenza B virus or SARS-CoV-2. Conclusion: The cobas 6800 system and cobas SARS-CoV-2 & Influenza A/B showed high accuracy for influenza A virus detection and can be useful for clinical laboratories, especially those that routinely assay many samples., Virology Journal, 19(1), art. no. 188; 2022

Primary ciliary dyskinesia (PCD) is a genetic and congenital disease associated with an abnormal ciliary ultrastructure and function and is estimated to affect 1 in 15,000–20,000 individuals. A PCD diagnosis can be achieved by genotyping. Here, we performed whole-exome analysis for the diagnosis of PCD and described the detailed clinical characteristics of the case. A 39-year-old Japanese woman with sinusitis and bronchiectasis without situs inversus had had upper and lower respiratory symptoms since childhood and had received long-term macrolide therapy without an accurate diagnosis. A moderate deterioration of cilia function was observed by high-speed video microscopy analysis; additionally, the number of cells with moving cilia was fewer than that in patients without PCD. Electron microscopy revealed no apparent structural abnormalities. We performed whole-exome analysis and identified novel biallelic variants of SPEF2 in the homozygous state (c.1860_1861insCT).We confirmed the absence of SPEF2 protein expression in the cilia of the nasal mucosa using fluorescent immunostaining. Accordingly, she was diagnosed as having PCD with the SPEF2 variant. The present case suggests that the deterioration of cilia function is moderate, the number of respiratory cells with moving cilia might be reduced, and the respiratory condition could be severe in patients with PCD with the SPEF2 variant., Journal of Clinical Medicine, 12(1), art. no. 317; 2022

Severe fever with thrombocytopenia syndrome (SFTS) and Japanese spotted fever (JSF; a spotted fever group rickettsiosis) are tick-borne zoonoses that are becoming a significant public health threat in Japan and East Asia. Strategies for treatment and infection control differ between the two; therefore, initial differential diagnosis is important. We aimed to compare the clinical characteristics of SFTS and JSF based on symptomology, physical examination, laboratory data, and radiography findings at admission. This retrospective study included patients with SFTS and JSF treated at five hospitals in Nagasaki Prefecture, western Japan, between 2013 and 2020. Data from 23 patients with SFTS and 38 patients with JSF were examined for differentiating factors and were divided by 7:3 into a training cohort and a validation cohort. Decision tree analysis revealed leukopenia (white blood cell [WBC] < 4000/µL) and altered mental status as the best differentiating factors (AUC 1.000) with 100% sensitivity and 100% specificity. Using only physical examination factors, absence of skin rash and altered mental status resulted in the best differentiating factors with AUC 0.871, 71.4% sensitivity, and 90.0% specificity. When treating patients with suspected tick-borne infection, WBC < 4000/µL, absence of skin rash, and altered mental status are very useful to differentiate SFTS from JSF., Viruses, 14(8), art. no. 1807; 2022

Introduction The COVID-19 pandemic has been a major concern worldwide; however, easily accessible treatment options for patients with mild COVID-19 remain limited. Since the oral intake of Lactococcus lactis strain plasma (LC-Plasma) enhances both the innate and acquired immune systems through the activation of plasmacytoid dendritic cells (pDCs), we hypothesised that the oral intake of LC-Plasma could aid the relief or prevention of symptoms in patients with asymptomatic or mild COVID-19. Methods and analysis This is an exploratory, multicentre, double-blinded, randomised, placebo-controlled trial. This study was initiated in December 2021 and concludes in April 2023. The planned number of enrolled subjects is 100 (50 subjects×2 groups); subject enrolment will be conducted until October 2022. Patients with asymptomatic or mild COVID-19 will be enrolled and randomly assigned in a 1:1 ratio to group A (oral intake of LC-Plasma-containing capsule, 200 mg/day, for 14 days) or group B (oral intake of placebo capsule, for 14 days). The primary endpoint is the change in subjective symptoms measured by the severity score. Secondary endpoints include SARS-CoV-2 viral loads, biomarkers for pDC activation, serum SARS-CoV-2-specific antibodies, serum cytokines, interferon and interferon-inducible antiviral effectors and the proportion of subjects with emergency room visits to medical institutions or who are hospitalised. Ethics and dissemination The study protocol was approved by the Clinical Research Review Board of Nagasaki University, in accordance with the Clinical Trials Act of Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act, and other current legal regulations in Japan. Written informed consent will be obtained from all the participants. The results of this study will be reported in journal publications., BMJ open, 12 (9), art. no. e061172; 2022

Managing mild illness in COVID-19 and predicting progression to severe disease are concerning issues. Here, we investigated the outcomes of Japanese patients with mild COVID-19, and identified triage risk factors for further hospitalization and emergency department (ED) visits at a single tertiary hospital. A triage checklist with 30 factors was used. Patients recommended for isolation were followed up for 10 days for subsequent ED visits or hospital admission. Overall, 338 patients (median age, 44.0; 45% women) visited the clinic 5.0 days (median) after symptom onset. Thirty-six patients were immediately hospitalized following triage; others were isolated. In total, 72 non-hospitalized patients visited the ED during their isolation, and 30 were hospitalized after evaluation for oxygen desaturation. The median ED visit and hospitalization durations after symptom onset were 5.0 and 8.0 days, respectively. The checklist factors associated with hospitalization during isolation were age > 50 years, body mass index > 25 kg/m2, hypertension, tachycardia with pulse rate > 100/min or blood pressure > 135 mmHg at triage, and >3-day delay in hospital visit after symptom onset. No patients died. Altogether, 80% of patients with mild COVID-19 could be safely isolated at home. Age, BMI, underlying hypertension, date after symptom onset, tachycardia, and systolic blood pressure at triage might be related to later hospitalization., Journal of Clinical Medicine, 11(18), art. no. 5444; 2022

Background: Influenza affects approximately a billion people globally, including > 10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model. Methods: Using the JMDC Claims Database, we identified index case (IC) as the first family member diagnosed with influenza during the 2018–19 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model. Results: The median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N = 84 672) and OTV (N = 62 004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th–97.5th percentiles, 1.68–1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs’ age category, virus type, and month of onset revealed similar trends favoring BXM. Conclusions: BXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment., Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 75(6), pp. 927-935; 2022

Introduction: We investigated the performance of the cobas® 6800 system and cobas SARS-CoV-2 & Influenza A/B, a fully automated molecular testing system for influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This enabled an assay in a batch of 96 samples in approximately 3 h. Methods: An assay was performed using the cobas SARS-CoV-2 & Influenza A/B on the cobas 6800 system for samples collected in four facilities between November 2019 and March 2020 in our previous study. The results were compared with those obtained using the reference methods. Results: Of the 127 samples analyzed, the cobas SARS-CoV-2 & Influenza A/B detected influenza A virus in 75 samples, of which 73 were positive using the reference methods. No false negative results were observed. The overall positive and negative percent agreement for influenza A virus detection were 100.0% and 96.3%, respectively. There were no positive results for the influenza B virus or SARS-CoV-2. Conclusion: The cobas 6800 system and cobas SARS-CoV-2 & Influenza A/B showed high accuracy for influenza A virus detection and can be useful for clinical laboratories, especially those that routinely assay many samples., Virology Journal, 19(1), art. no. 188; 2022

Primary ciliary dyskinesia (PCD) is a genetic and congenital disease associated with an abnormal ciliary ultrastructure and function and is estimated to affect 1 in 15,000–20,000 individuals. A PCD diagnosis can be achieved by genotyping. Here, we performed whole-exome analysis for the diagnosis of PCD and described the detailed clinical characteristics of the case. A 39-year-old Japanese woman with sinusitis and bronchiectasis without situs inversus had had upper and lower respiratory symptoms since childhood and had received long-term macrolide therapy without an accurate diagnosis. A moderate deterioration of cilia function was observed by high-speed video microscopy analysis; additionally, the number of cells with moving cilia was fewer than that in patients without PCD. Electron microscopy revealed no apparent structural abnormalities. We performed whole-exome analysis and identified novel biallelic variants of SPEF2 in the homozygous state (c.1860_1861insCT).We confirmed the absence of SPEF2 protein expression in the cilia of the nasal mucosa using fluorescent immunostaining. Accordingly, she was diagnosed as having PCD with the SPEF2 variant. The present case suggests that the deterioration of cilia function is moderate, the number of respiratory cells with moving cilia might be reduced, and the respiratory condition could be severe in patients with PCD with the SPEF2 variant., Journal of Clinical Medicine, 12(1), art. no. 317; 2022

We evaluated a novel transcription-reverse transcription concerted reaction (TRC) assay that can detect influenza A and B within 15 min using nasopharyngeal swab and gargle samples obtained from patients with influenza-like illness, between January and March 2018 and between January and March 2019. Based on the combined RT-PCR and sequencing results, in the nasal swabs, the sensitivity and specificity of TRC for detecting influenza were calculated as 1.000 and 1.000, respectively. In the gargle samples, the sensitivity and specificity of TRC were 0.946 and 1.000, respectively. The TRC assay showed comparable performance to RT-PCR in the detection of influenza viruses., European Journal of Clinical Microbiology & Infectious Diseases, Article in Press.

Introduction: Digital immunoassays (DIAs) and molecular point-of-care (POC) tests for influenza were recently developed. We aimed to evaluate and compare the positive rate with molecular POC tests and DIAs in detecting influenza virus A, B and respiratory syncytial virus (RSV). Methods: A prospective observational study was conducted in 2019–2020. Nasopharyngeal swab samples were collected from adult outpatients with influenza-like illness who visited four hospitals and clinics in Japan. DIAs were performed at each facility. The clinical diagnosis was determined based on the findings of DIAs, history taking, and physical assessment. Molecular POC test and reverse transcription polymerase chain reaction (RT-PCR) were performed later. Results: A total of 182 patients were evaluated. The positive rate for influenza virus with molecular POC test was significantly higher than that with DIAs (51.6% versus 40.7%, p = 0.046). In patients who tested positive for influenza virus with only molecular POC test, the presence of influenza virus was confirmed by RT-PCR. In a comparison between the patients who were positive for influenza virus with only molecular POC test and those with both molecular POC test and DIA, the percentage of patients who sought consultation within 18 h after the onset of symptoms was significantly higher in the molecular POC test only group than in the both methods group (70.0% versus 43.2%, p = 0.044). Conclusions: A molecular POC test could contribute to the accurate diagnosis of influenza in patients with influenza-like illness, especially those who visited a hospital immediately after the onset of symptoms., Journal of Infection and Chemotherapy, Article in Press.

BACKGROUND Although the risk factors for chronic kidney disease progression after deceased donor liver transplantation have been widely reported, there are few reports describing the factors associated with kidney function changes in patients after living donor liver transplantation (LDLT). This study aims to further investigate these kidney function change factors. MATERIAL AND METHODS This retrospective study was performed using the data of patients who underwent LDLT at the Nagasaki University Hospital, Japan from August 2000 to November 2017. Factors contributing to post-transplantation estimated glomerular filtration rate(eGFR) changes were analyzed. RESULTS A total of 191 cases were reviewed. The average age was 53.8 years, and 108 (56.5%) patients were male. Compared to pre-transplantation eGFR levels, eGFR 1 year after LDLT improved in 65 patients (34%) and deteriorated in 126 patients (66%). Multivariate regression analysis revealed that pre-transplant diuretics (P=0.04) and tacrolimus trough value 1 year after transplantation (P=0.04) were significantly associated with elevated eGFR changes. eGFR elevation 1 year after LDLT was more pronounced in patients with a low tacrolimus trough level 1 year after LDLT (P=0.01). Therefore, mycophenolate mofetil was added to tacrolimus in patients with poor renal function before LDLT. CONCLUSIONS Tacrolimus trough level was associated with eGFR changes 1 year after LDLT. The adjusted dose of tacrolimus and combined use of other immunosuppressants may be important to maintain renal function after LDLT., Annals of transplantation, 26, e928858; 2021

Aims: Estimating the monetary value of the convenience of using influenza antivirals approved in Japan from a patient perspective using a conjoint analysis. Methods: An online survey (August 2020) was performed on individuals aged 20–64 years living in Japan who had taken oral or inhalant antivirals for influenza treatment in the 2018/19 or 2019/20 seasons. Efficacy and safety were assumed to be equivalent among the antivirals. The attributes for the conjoint analysis included route (oral or inhalant), duration, frequency of administration, and out-ofpocket expenses. A conditional logit model was applied as a baseline model. The monetary value of each attribute was calculated by comparing the same utility of the linearly interpolated level of the out-of-pocket attribute. Another survey to determine the experiences of the latest antiviral intake was also conducted on the same respondents. Results: Of the respondents, 1,550 were men and 1,587 were women. The monetary value for oral antivirals was estimated to be higher, saving JPY 741 (USD 7.06, as of August 2020), compared with inhalant. Regarding the length and frequency of administration, five days corresponds to an increase of JPY 2,072, compared with one day, and twice a day corresponds to a JPY 574 increase compared to once a day. Conclusions: The results suggest that – among the antivirals approved in Japan – the monetary value of the utility is the highest in the single dose oral antiviral, baloxavir marboxil (baloxavir). Although the drug cost was highest in baloxavir among the brand antivirals, the difference in the value of utility for influenza patient was estimated to be larger than the difference in the drug costs. Limitations: Although individuals with diverse attributes from all over the country were included in the survey, they are not necessarily a representative population of the Japanese society., Journal of Medical Economics, 24(1), pp.244-254; 2021

Percutaneous renal biopsy is an essential tool for diagnosing various renal diseases; however, little is known about whether renal biopsy performed by physicians with short nephrology experience is safe in Japan. This study included 238 patients who underwent percutaneous renal biopsy between April 2017 and September 2020. We retrospectively analyzed the frequency of post-renal biopsy complications (hemoglobin decrease of ≥10%, hypotension, blood transfusion, renal artery embolization, nephrectomy and death) and compared their incidence among physicians with varied experience in nephrology. After renal biopsy, a hemoglobin decrease of ≥10%, hypotension and transfusion occurred in 13.1%, 3.8% and 0.8% of patients, respectively. There were no cases of post-biopsy renal artery embolism, nephrectomy, or death. The composite complication rate was 16.0%. The incidence of post-biopsy complications was similar between physicians with ≥3 years and <3 years of clinical nephrology experience (12.5% vs. 16.8%, p = 0.64). Furthermore, the post-biopsy composite complication rates were similar between physicians with ≥6 months and <6 months of clinical nephrology experience (16.3% vs. 15.6%, p > 0.99). Under attending nephrologist supervision, a physician with short clinical nephrology experience can safely perform renal biopsy., Healthcare, 9(4), art. no. 474; 2021

Clinical Infectious Diseases, 72(11), pp. e859-e867; 2021

Background: The recent increase in cases of azole-resistant Aspergillus fumigatus (ARAf) infections is a major clinical concern owing to its treatment limitations. Patient-derived ARAf occurs after prolonged azole treatment in patients with aspergillosis and involves various cyp51A point mutations or non-cyp51A mutations. The prognosis of patients with chronic pulmonary aspergillosis (CPA) with patient-derived ARAf infection remains unclear. In this study, we reported the case of a patient with ARAf due to HapE mutation, as well as the virulence of the isolate. Case presentation: A 37-year-old male was presented with productive cough and low-grade fever. The patient was diagnosed with CPA based on the chronic course, presence of a fungus ball in the upper left lobe on chest computed tomography (CT), positivity for Aspergillus-precipitating antibody and denial of other diseases. The patient underwent left upper lobe and left S6 segment resection surgery because of repeated haemoptysis during voriconazole (VRC) treatment. The patient was postoperatively treated with VRC for 6 months. Since then, the patient was followed up without antifungal treatment but relapsed 4 years later, and VRC treatment was reinitiated. Although an azole-resistant isolate was isolated after VRC treatment, the patient did not show any disease progression in either respiratory symptoms or radiological findings. The ARAf isolated from this patient showed slow growth, decreased biomass and biofilm formation in vitro, and decreased virulence in the Galleria mellonella infection model compared with its parental strain. These phenotypes could be caused by the HapE splice site mutation. Conclusions: This is the first to report a case demonstrating the clinical manifestation of a CPA patient infected with ARAf with a HapE splice site mutation, which was consistent with the in vitro and in vivo attenuated virulence of the ARAf isolate. These results imply that not all the ARAf infections in immunocomp, BMC Infectious Diseases, 21(1), art. no. 573; 2021

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of unknown aetiology with a poor prognosis. Several clinical trials of nintedanib in patients with IPF have reported its inhibitory effect on reduced lung function, incidence of acute exacerbation of IPF and worsened health-related quality of life. Although nintedanib has a manageable safety and tolerability profile over long-term use, it was discontinued in over 20% of patients because of adverse events such as diarrhoea and liver dysfunction. This might explain why nintedanib use in patients with IPF is not widespread, especially among patients with early-stage IPF. In the present study, we aimed to clarify the efficacy, safety and tolerability of nintedanib in patients with stage I/II IPF, based on the Japanese IPF disease severity staging classification system. Methods and analysis: This is an ongoing, prospective, multicentre observational cohort study of patients with stage I/II IPF who will start receiving nintedanib. Totally, 215 patients at 35 sites in Kyushu and Okinawa, Japan will be enrolled and followed up for 3 years. Nintedanib therapy would be initiated at the discretion of the investigator. The primary endpoint, change in forced vital capacity (FVC) at 156 weeks, will be shown as the mean change in FVC from baseline to week 156 with 95% CIs estimated using the Wald method. The safety endpoint—occurrence of adverse events—will be assessed in each system organ class/preferred term. Ethics and dissemination: The study protocol and informed consent documents were approved by the Institutional Review Board at Nagasaki University Hospital (approval number 19102146) and each participating site. Written informed consent was obtained from all participants. Patient recruitment has begun. The results will be disseminated through scientific peer-reviewed publications and national and international conferences. Trial registration number: UMIN000038192., BMJ open, 11(6), art. no. e047249; 2021