BACKGROUND:Respiratory syncytial virus (RSV) can cause substantial morbidity and mortality in adults aged 50-59 years at increased risk of severe RSV disease due to specific underlying conditions (i.e. '50-59 years at-increased-risk [AIR] population'), and in older adults aged ≥60 years (i.e. '≥60 years population'). RESEARCH DESIGN AND METHODS:A static multi-cohort Markov model estimated cost-effectiveness of adjuvanted RSVPreF3 vaccination versus no vaccination among the 50-59 years AIR and ≥60 years populations in Japan, over a five-year time horizon from a healthcare payer perspective. Japan-specific RSV epidemiology and healthcare resource utilization parameters were used; vaccine efficacy was derived from the phase 3 AReSVi-006 trial (NCT04886596). RESULTS:Adjuvanted RSVPreF3 vaccination was cost-effective: in the 50-59 years AIR population, 49,280 RSV cases were prevented and 4333 quality-adjusted life years (QALYs) gained, at an incremental cost-effectiveness ratio (ICER) of Japanese yen (JPY) 2,770,558/QALY; in the ≥60 years population, 2,111,080 RSV cases were prevented and 205,543 QALYs gained, at an ICER of JPY 2,613,241/QALY. Vaccination was more cost-effective when including productivity losses from RSV-ARI. Scenario and sensitivity analyses results were robust. CONCLUSIONS:RSV vaccination may provide substantial health benefits and be a cost-effective intervention to reduce RSV burden in adults in Japan.

Importance:Postoperative fungal endophthalmitis following cataract surgery is rare, but 6 cases of fungal endophthalmitis associated with Sarocladium kiliense (formerly Acremonium kiliense) have occurred in a short term. All of these cases developed after conventional cataract surgery. Objective:To report the findings of an outbreak of postoperative fungal endophthalmitis after use of trypan blue solution during cataract surgery. Design, Setting, and Participants:This is a retrospective case series of 6 patients with postoperative fungal endophthalmitis who were referred to a single hospital from 2 clinics in Japan and underwent vitrectomy in 2025. The clinical findings and culture results were evaluated, and samples of the trypan blue solution were cultured. Exposure:Postoperative fungal endophthalmitis following cataract surgery. Main Outcomes and Measures:The treatment and recovery of patients from postoperative fungal endophthalmitis were evaluated based on the clinical and microbiological findings. Results:The age of the 6 patients ranged from 41 to 84 years (mean [SD], 72.7 [14.5] years), and 5 of the 6 patients (83%) were female. The mean (SD) interval from the initial surgery to examination at the hospital was 16 (6.8) days. The mean (SD) preoperative best-corrected visual acuity was 1.77 (0.93) logMAR units (Snellen equivalent, 20/120). Vitrectomy was performed on all eyes, and the vitreous opacities were most prominent in the anterior vitreous. After anterior chamber irrigation around the intraocular lens, vitrectomy with intravitreal antibiotic injection was performed. S kiliense was identified in the aqueous humor of 5 eyes and in the vitreous of 5 eyes. Five eyes were treated with intravitreal voriconazole, and topical voriconazole was administered to all eyes. Systemic treatment with intravenous liposomal amphotericin B or oral voriconazole was also used. Two eyes required reoperations for further removal of the vitreous opacities, including the extraction of the intraocular lens in 1 eye. The vitreous opacities and inflammation improved in all eyes. The infection was controlled in all cases, with a mean (SD) postoperative visual acuity of 0.26 (0.49) logMAR units (Snellen equivalent, 20/30). The same organism was also detected in the trypan blue solution. Conclusions and Relevance:Postoperative endophthalmitis was associated with the presence of S kiliense from the off-label use of contaminated trypan blue solution during cataract surgery.

This study aimed to evaluate the feasibility and mid-term outcomes of in situ aortic reconstruction using xenopericardial roll grafts for thoracic and thoracoabdominal native aortic and prosthetic graft infection. This retrospective single-centre study included consecutive patients who underwent xenopericardial roll graft replacement, including branched graft reconstruction and/or tissue filling, between 2010 and 2024. A multidisciplinary treatment strategy was adopted. This study included 21 patients who underwent 22 procedures (median age, 67 years; interquartile range, 63.75–73.75). On a procedure basis, the indications were infectious aortic aneurysm in 4 procedures and prosthetic graft infection in 18 procedures. Replacement sites included the ascending aorta (n = 4), aortic arch (n = 11), descending aorta (n = 6), and thoracoabdominal aorta (n = 1). Tissue filling was performed in 12 procedures. The 30-day and operative mortality rates were 13.6

Respiratory syncytial virus (RSV) is a leading cause of respiratory infections (RI) in older adults, but RSV awareness remains low among older adults and their carers in the Asia-Pacific (APAC) region. With the recent approval of RSV vaccines for older adults, insights into RSV-related knowledge, attitudes, perceptions and practices (KAP) could inform targeted disease prevention strategies and policies. This study assessed RSV-related KAP in older adults aged ≥50 years, their carers and physicians in APAC.Table 1.Sociodemographic characteristics of older adults ≥50 YOA, carers of older adults ≥50 YOA and physiciansCells marked with '–' represent data that were either not reported for or not applicable to a given cohort. [a] High-risk older adults included individuals with comorbidities such as respiratory conditions (e.g., chronic obstructive pulmonary disease, asthma), type I/II diabetes mellitus, cardiovascular disease/congestive heart failure, chronic kidney disease and liver disease. [b] Formal carers included professionals who provided nursing care, home care, rehabilitation/wellness or respite care services; informal carers included spouses, children or individuals who volunteered their care. [c] Specialists included pulmonologists/respiratory specialists (n=140), endocrinologists (n=140), cardiologists (n=140), gastroenterologists/hepatologists (n=140), nephrologists (n=140), geriatricians (n=63), infectious disease specialists (n=55) and family/community medicine specialists (n=7). GP: general practitioners; PCP: primary care physicians; SD: standard deviation; YOA: years of age.Figure 1.Key general and RI vaccination drivers among older adults ≥50 YOA and carers of older adults ≥50 YOAPercentage values represent the proportion of respondents for a subgroup within each cohort. Significant covariates (p<0.05) are reported for the differences between subgroups in a cohort: *p<0.05; **p<0.01; ***p<0.001. [a] High-risk older adults included individuals with comorbidities such as respiratory conditions (e.g., chronic obstructive pulmonary disease, asthma), type I/II diabetes mellitus, cardiovascular disease/congestive heart failure, chronic kidney disease and liver disease. [b] Formal carers included professionals who provided nursing care, home care, rehabilitation/wellness or respite care services; informal carers included spouses, children or individuals who volunteered their care. HCP: healthcare practitioner; LT: long-term; RI: respiratory infection; YOA: years of age. A cross-sectional study was conducted in Australia, Hong Kong, Japan, New Zealand, Singapore, South Korea and Taiwan. Qualitative interviews were conducted to refine survey tools, followed by quantitative surveys to explore the KAP focused on general vaccines and RSV prevention.Figure 2.Opportunities for conversations between older adults ≥50 YOA/carers and physicians on RI or RI vaccines in the year prior to the date of the surveyPercentage values represent the proportion of respondents for a subgroup within each cohort. Significant covariates (p<0.05) are reported for the differences between subgroups in a cohort: *p<0.05; **p<0.01; ***p<0.001. [a] High-risk older adults included individuals with comorbidities such as respiratory conditions (e.g., chronic obstructive pulmonary disease, asthma), type I/II diabetes mellitus, cardiovascular disease/congestive heart failure, chronic kidney disease and liver disease. [b] Formal carers included professionals who provided nursing care, home care, rehabilitation/wellness or respite care services; informal carers included spouses, children or individuals who volunteered their care. [c] Specialists included pulmonologists/respiratory specialists (n=140), endocrinologists (n=140), cardiologists (n=140), gastroenterologists/hepatologists (n=140), nephrologists (n=140), geriatricians (n=63), infectious disease specialists (n=55) and family/community medicine specialists (n=7). GP: general practitioners; HCP: healthcare practitioner; PCP: primary care physicians; RI: respiratory infection; YOA: years of age.Figure 3.Reasons discouraging physicians from discussing RI vaccines with older adults ≥50 YOA and older adults ≥50 YOA with chronic medical conditionsPercentage values represent the proportion of respondents for a subgroup within the physician cohort. Significant covariates (p<0.05) are reported for the differences between subgroups in a cohort: *p<0.05; **p<0.01; ***p<0.001. [a] Specialists included pulmonologists/respiratory specialists (n=140), endocrinologists (n=140), cardiologists (n=140), gastroenterologists/hepatologists (n=140), nephrologists (n=140), geriatricians (n=63), infectious disease specialists (n=55) and family/community medicine specialists (n=7). GP: general practitioners; HCP: healthcare practitioner; PCP: primary care physicians; RI: respiratory infection; YOA: years of age. 3,472 older adults (including 1,642 who were high-risk), 700 carers (formal/informal) and 1,525 physicians (specialists/generalists) were enrolled between April–July 2024 (Table 1). Among older adults, key general and RI vaccination drivers included vaccine safety (57.5–70.5% and 61.7–76.8%, respectively), preventing severe illness (57.3–71.3% and 56.4–73.4%) and preventing (re)infection (49.5–65.5% and 54.6–64.8%; Fig. 1A–B). Among carers, key general and RI vaccination drivers included doctor’s recommendation (46.2–49.8% and 51.0–52.5%, respectively), preventing severe illness (43.8–48.4% and 43.8–54.1%), vaccine safety (44.1–44.8% and 52.5–52.9%) and preventing (re)infection (42.9–45.9% and 43.3–47.1%; Fig. 1C–D). In the year prior to the survey, substantial proportions of older adults (46.8–70.3%) and carers (37.6–38.4%) had no opportunities to discuss RI with a doctor, while physicians initiated RI vaccine conversations in 23.5–59.9% of older adults/carers (Fig. 2). More urgent/acute issues (56.7–64.7%) and time constraints (42.1–58.7%) discouraged physicians from discussing RI vaccines with older adults (Fig. 3). This study identified vaccination drivers among older adults/carers (e.g., vaccine safety, efficacy). Limited opportunities for discussing RI vaccines with physicians were barriers to vaccination, highlighting unmet needs in prioritising vaccine conversations and preventive health, particularly for RSV. Funding: GSK Yufan Ho, MSc, GSK: Employed by and hold financial equities in GSK Lutz Beckert, n/a, Asthma and Respiratory Society of New Zealand: Advisor/Consultant|AstraZeneca: Honoraria|GSK: Honoraria Daisuke Kurai, n/a, Alfresa Corporation: Honoraria|Asahi Kasei: Advisor/Consultant|Asahi Kasei: Grant/Research Support|Asahi Kasei: Honoraria|Beckman Coulter: Honoraria|Daiichi Sankyo: Advisor/Consultant|Gilead: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|GSK: Support for attending meetings and/or travel|Janssen: Advisor/Consultant|Janssen: Honoraria|Japanese Association for Infectious Diseases: Committee member involved in preparing the Clinical Practice Guide for RSV Infections for the Japanese Association for Infectious Diseases|KYORIN: Grant/Research Support|KYORIN: Honoraria|Kyowa Kirin: Honoraria|Maruishi Pharmaceutical: Grant/Research Support|MSD: Honoraria|Pfizer: Honoraria|Shionogi & Co.: Grant/Research Support|Shionogi & Co.: Honoraria|SRL, Inc.: Honoraria Ji Yun Noh, M.D.,Ph.D., GSK: Advisor/Consultant|GSK: Grant/Research Support|GSK: Honoraria John Siu Lun Tam, n/a, Asia-Pacific Alliance for the Control of Influenza: Director|The Chinese University of Hong Kong, Faculty of Medicine: Honoraria|The Chinese University of Hong Kong, School of Public Health: Honoraria Grant Waterer, n/a, GSK: Honoraria|Moderna: Honoraria|Pfizer: Honoraria Sumitra Shantakumar, n/a, GSK: Employed by and hold financial equities in GSK Nisa de Souza, n/a, GSK: Employed by GSK at the time of this study Aruni Seneviratna, n/a, GSK: Employed by and hold financial equities in GSK

The emergence and spread of antimicrobial resistant (AMR) have become a major global concern. This nationwide surveillance study, conducted by the Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Clinical Microbiology from 2022 to 2023, examined the antimicrobial susceptibility of respiratory pathogens. A total of 1057 bacterial isolates from 28 medical institutions, predominantly tertiary medical centers, were analyzed. Major pathogens included Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Findings revealed increasing resistance rates, with a notable rise in extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae. Susceptibility to penicillin, cephalosporins, and carbapenems varied, with specific declines observed in several antibiotics relative to prior surveillance data. No metallo-β-lactamase (MBL)-producing P. aeruginosa strains were detected. These findings underscore the need for rigorous antimicrobial stewardship and continuous surveillance to curb the spread of resistant pathogens in Japan.

BACKGROUND:Respiratory syncytial virus (RSV), a common respiratory pathogen, can lead to severe symptoms, especially in older adults (OA). A recently developed RSV prefusion F protein (RSVPreF3 OA) vaccine confers high protection against RSV lower respiratory tract disease (LRTD) over two full RSV seasons. The aim of this study was to assess the potential public health impact of RSVPreF3 OA vaccination in the Japanese OA population. RESEARCH DESIGN AND METHODS:A static Markov model was used to estimate the number of symptomatic RSV cases, hospitalizations and deaths in the Japanese population aged ≥ 60 years over a 3-year time horizon. Japan-specific RSV epidemiology and healthcare resource use parameters were used; vaccine efficacy was derived from a phase 3 randomized study (AReSVi-006, NCT04886596). Vaccination coverage was set to 50%. RESULTS:Without vaccination, >5 million RSV acute respiratory illness (ARI) would occur (2.5 million LRTD and 2.8 million upper respiratory tract infections) leading to ~ 3.5 million outpatient visits, >534,000 hospitalizations and ~ 25,500 RSV-related deaths over 3 years. Vaccination could prevent > 1 million RSV-ARI cases, 728,000 outpatient visits, 143,000 hospitalizations and 6,840 RSV-related deaths. CONCLUSIONS:RSVPreF3 OA vaccination is projected to have a substantial public health impact by reducing RSV-related morbidity and mortality in the OA population.

OBJECTIVES:We conducted this case series to evaluate the feasibility and mid-term outcomes of orthotopic aortic arch reconstruction using xenopericardial grafts to treat native aortic arch/arch graft infection. METHODS:Between 2010 and 2023, adopting a multidisciplinary approach, we treated consecutive patients with aortic arch/arch graft infection by orthotopic branched xenopericardial roll graft replacement and tissue filling. The end points of the study were the graft reinfection and graft-related complications such as pseudoaneurysm formation, thromboembolism, graft stenosis, graft calcification and death. RESULTS:The subjects were 11 patients (8 men and 3 women) with a median age of 66 [51-79, (interquartile range) 59.0, 70.5] years. Of the 11 patients, 7 underwent preoperative mediastinal irrigation/negative-pressure wound treatment. The 30-day mortality was 0% (0/11 patients), and 1 patient died in the hospital after 8 months. Aorta-related death occurred in 18.2% (2/11 patients), with both cases developing local recurrence of fungal infection. The remaining 9 patients (81.8%) remained free of reinfection. The estimated 1-, 3-, 5- and 7-year risk-adjusted survival rates were 91 ± 9%, 81 ± 12%, 58 ± 16% and 58 ± 16%, respectively. The estimated 1-, 3-, 5- and 7-year cumulative aorta-related mortality rates were 9 ± 9%, 19 ± 12%, 19 ± 12% and 19 ± 12%, respectively. Graft-related complications included branch kinking in 1 patient and graft rupture in 1 patient. There were no cases of graft-related thromboembolism or graft calcification. The median follow-up period was 45 [8-101, (interquartile range) 36.5, 70.9] months. The longest follow-up period until date of the currently surviving patients is 101 months. CONCLUSIONS:Although the xenopericardium appeared to be vulnerable to fungal infection, based on the favourable results obtained, we consider that branched xenopericardial roll graft replacement using a multidisciplinary, staged approach may serve as a useful treatment option for aortic arch/arch graft infection.

ObjectivesOlder adults (OA) are at risk of morbidity and mortality from respiratory syncytial virus (RSV), a major cause of seasonal acute respiratory illness. The first RSV vaccine for OA (RSVPreF3 OA) was recently launched in Japan. With the already large and growing OA population in Japan, and limited RSV treatments, prevention is key. The aim of this study was to assess the cost-effectiveness of introducing RSVPreF3 OA for Japanese adults aged >= 60 years.MethodsA static multicohort Markov model was adapted to assess the cost-effectiveness of a single dose of RSVPreF3 OA versus no vaccination over a three-year time horizon. Deterministic and probabilistic sensitivity analyses were conducted to assess parameter uncertainty.ResultsRSVPreF3 OA vaccination prevented 1,008,499 cases and 6,840 deaths, with 109,119 quality-adjusted life-years (QALYs) gained. The incremental cost-effectiveness ratio was Japanese yen (JPY) 4,180,084/QALY gained from a payer perspective and JPY 4,041,917/QALY gained from a societal perspective (with productivity loss from RSV disease), thus vaccination was considered cost-effective. Base case results were robust to changes in sensitivity and scenario analyses.ConclusionsRSVPreF3 OA vaccination for adults >= 60 years can provide substantial health benefits and is a cost-effective intervention to reduce the RSV burden in Japan.

The burden of respiratory syncytial virus (RSV), which causes acute respiratory illness, is well recognized among the pediatric population but also imposes a significant risk to the elderly (age ≥ 60) and those with underlying comorbidities. The study aimed to review the most recent data on epidemiology and burden (clinical and economic) of RSV in the elderly/high-risk populations in China, Japan, South Korea, Taiwan, and Australia. A targeted review was conducted of English, Japanese, Korean, and Chinese language articles published from 1 January 2010 to 7 October 2020 relevant for the purpose. A total of 881 studies were identified, and 41 were included. The median proportion of elderly patients with RSV in all adult patients with acute respiratory infection (ARI) or community acquired pneumonia was 79.78

Listeria monocytogenes is an important pathogen in older patients and immunosuppressed patients, often causing bacteremia. Complications resulting from infections other than COVID-19 must also be considered during COVID-19 treatment.

The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were beta-lactamase-producing ampicillin resistant and beta-lactamase-negative ampicillin resistant, respectively. Extended-spectrum beta-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-beta-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents.

The number of patients with SARS-CoV-2 infection continues to increase, and it has become a global pandemic. Although there is an urgent need to establish an effective treatment, the medication available for dialysis patients has been limited. An antibody cocktail containing two SARS-CoV-2-neutrarizing antibodies, REGN-COV2 has been granted special approval for COVID-19 in Japan, since July 2021, and this intravenous preparation can be used for dialysis patients. At our hospital, we had 22 hemodialysis patients with COVID-19, and five of them were treated with REGN-COV2. On admission, four of the five patients had moderate disease (pneumonia but O2 inhalation) and one patient had mild disease (not having pneumonia). The mean duration of hospitalization treated with REGN-COV2 was 10.2 ± 2.86 days (mean ± SD), which was less than half, compared to patients untreated of similar severity on admission (22.12 ± 15.5). The time to fever resolution was average 7 days, and no cases progressed to severe illness or death. Among these patients, no obvious adverse reactions were shown. Although more studies with a larger number of patients could be needed for a rigorous evaluation of the effect, our result suggests that REGN-COV2 may be safe and having the possibilities in preventing severe disease in hemodialysis patients. Given the difficulty in securing inpatient beds tend to be in short supply, the strategy combined with neutralizing antibody could be beneficial for end-stage kidney disease (ESKD) patients with hemodialysis who are at high risk of severe disease.

AllergyVolume 77, Issue 10 p. 3137-3141 LETTEROpen Access Soluble ST2 enhances IL-33–induced neutrophilic and pro-type 2 inflammation in the lungs Masato Watanabe, Corresponding Author Masato Watanabe masatowa1973@gmail.com orcid.org/0000-0001-9988-5221 Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, Japan Correspondence Masato Watanabe, Department of Respiratory Medicine, Kyorin University School of Medicine, 6-20-2 Sinkawa, Mitaka-city, Tokyo 181-8612, Japan. Email: masatowa1973@gmail.comSearch for more papers by this authorKeitaro Nakamoto, Keitaro Nakamoto Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorToshiya Inui, Toshiya Inui Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorMitsuru Sada, Mitsuru Sada Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorKazuyuki Chibana, Kazuyuki Chibana Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Tochigi, JapanSearch for more papers by this authorChika Miyaoka, Chika Miyaoka Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorYuki Yoshida, Yuki Yoshida Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorJumpei Aso, Jumpei Aso Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorHiroki Nunokawa, Hiroki Nunokawa Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorKojiro Honda, Kojiro Honda Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorMasuo Nakamura, Masuo Nakamura Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorMasaki Tamura, Masaki Tamura Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorAya Hirata, Aya Hirata Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorMiku Oda, Miku Oda Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorSaori Takata, Saori Takata Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorTakeshi Saraya, Takeshi Saraya Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorDaisuke Kurai, Daisuke Kurai Department of General Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorHaruyuki Ishii, Haruyuki Ishii Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorHajime Takizawa, Hajime Takizawa Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this author Masato Watanabe, Corresponding Author Masato Watanabe masatowa1973@gmail.com orcid.org/0000-0001-9988-5221 Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, Japan Correspondence Masato Watanabe, Department of Respiratory Medicine, Kyorin University School of Medicine, 6-20-2 Sinkawa, Mitaka-city, Tokyo 181-8612, Japan. Email: masatowa1973@gmail.comSearch for more papers by this authorKeitaro Nakamoto, Keitaro Nakamoto Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorToshiya Inui, Toshiya Inui Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorMitsuru Sada, Mitsuru Sada Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorKazuyuki Chibana, Kazuyuki Chibana Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Tochigi, JapanSearch for more papers by this authorChika Miyaoka, Chika Miyaoka Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorYuki Yoshida, Yuki Yoshida Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorJumpei Aso, Jumpei Aso Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorHiroki Nunokawa, Hiroki Nunokawa Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorKojiro Honda, Kojiro Honda Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorMasuo Nakamura, Masuo Nakamura Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorMasaki Tamura, Masaki Tamura Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorAya Hirata, Aya Hirata Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorMiku Oda, Miku Oda Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorSaori Takata, Saori Takata Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorTakeshi Saraya, Takeshi Saraya Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorDaisuke Kurai, Daisuke Kurai Department of General Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorHaruyuki Ishii, Haruyuki Ishii Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this authorHajime Takizawa, Hajime Takizawa Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, JapanSearch for more papers by this author First published: 05 June 2022 https://doi.org/10.1111/all.15401AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat To the Editor, Soluble suppression of tumorigenicity 2 (sST2) is a decoy receptor for interleukin 33 (IL-33). We previously reported that high serum levels of sST2 predict unfavorable outcomes in patients with pneumonia1 or asthma,2 although its function in the lungs remains poorly understood. We hypothesized that sST2 modifies IL-33–induced neutrophilic inflammation in the lungs. We measured levels of sST2, IL-33, and pro-neutrophilic or pro-Th17 chemokines in the sputum of patients with asthma, chronic obstructive pulmonary disease (COPD), or asthma–COPD overlap (ACO), and administered a recombinant soluble form of ST2 (ST2-Fc) and/or IL-33 to mice. Both sST2 and IL-33 were high in patients with ACO, whereas only sST2 was high in patients with asthma and only IL-33 was high in patients with COPD (Figure 1A,B; Table S1). There was no correlation between sST2 and IL-33 levels (Figure 1C). IL-33 levels were positively correlated with chemokine (CXC motif) ligand 8 (CXCL8) and chemokine (CC motif) ligand 20 (CCL20) but were not correlated with CXCL1 levels (Figure 1D). We expected sST2 to negatively regulate IL-33–induced pro-neutrophilic inflammation, but this was not the case (Figure 1E). Conversely, elevated levels of both sST2 and IL-33 (characteristic of ACO patients) were associated with elevation of CXCL1 (as reported previously3) and CCL20 levels (Figure 1F). Cell counts were not conducted at the time of collection, so they could not be analyzed. These results do not support the hypothesis that sST2 works as a decoy receptor for IL-33 in human airways. FIGURE 1Open in figure viewerPowerPoint Levels of sST2, IL-33, and chemokines in the airways of patients with asthma, COPD, or ACO. (A, B) Levels of sST2 (A) or IL-33 (B) in sputum from patients with COPD, ACO, or asthma. Data are expressed as median and interquartile range. (C–E) Scatter plots of sST2 and IL-33 (C), IL-33 and chemokine (D), and sST2 and chemokine (E) levels in sputum from the same patients. (F) Levels of CXCL8, CCL20, and CXCL1 in sputum from the same patients. p-values were calculated using Spearman's rank correlations. ACO, asthma–COPD overlap; COPD, chronic obstructive pulmonary disease Based on the clinical data, we suspected that sST2 may be a carrier protein. To test this idea, we administered mice with mouse (m) IL-33 and/or mST2-Fc at 2.5 and 25 μg protein, respectively (molar ratio, 1:2.8), because the concentration of sST2 in the sputum of patients with ACO was approximately 10 times that of IL-33 (medians of 927 and 74.8 pg/m, respectively; Table S1). Surprisingly, mST2-Fc augmented the mIL-33–induced influx of neutrophils and dendritic cells into the alveolar spaces, as well as bronchial inflammation and secretion of CXCL1, matrix metalloproteinase 9 (MMP9), dsDNA, and CCL17 into the airspaces (Figure 2A–C). Also, mIL-33 promoted an influx of eosinophils (Figure 2A) and secretion of IL-5 (data not shown) into the airspaces, but ST2-Fc did not augment this process. Furthermore, we detected ST2-Fc–IL-33 complexes and enhanced recovery of mIL-33 and mST2-Fc in BAL fluid (Figure 2D). Finally, we confirmed that ST2-Fc–IL-33 complex formation did occur between mST2-Fc and mIL-33 in vitro (Figure 2E). Therefore, mST2-Fc augments mIL-33–induced airway neutrophilia and pro-type 2 inflammation via complex formation. FIGURE 2Open in figure viewerPowerPoint Soluble form of ST2 augments IL-33–induced inflammation in mouse lungs. Recombinant mIL-33 (2.5 μg), mST2-Fc (25 μg), both mIL-33 and mST2-Fc (2.5 and 25 μg, respectively), or PBS (50 μl) were administrated to female BALB/c mice via intratracheal spray. Differential cell counts (A), HE stains of lung tissue (B), secretion of CXCL1, MMP9 (with gelatin zymography of MMP9, upper panel), dsDNA, and CCL17 (C), and recovery of mST2-Fc–mIL-33 complexes, IL-33, and ST2 (D) in BAL fluid were assessed 24 h after administration. (E) Presence of mST2-Fc–mIL-33 complexes in a solution of mST2-Fc (4 μg) and mIL-33 (0.4 μg) in PBS (50 μl) after incubation for 1 h at 37°C. The complex (mIL-33 bound to mST2-Fc) was isolated via immunoprecipitation using protein A beads and detected via immunoblot assay. A mixture that was not immunoprecipitated (containing free mIL-33, free mST2-Fc, and mST2-Fc–mIL-33 complexes) was also assessed (input). Data are pooled from three experiments (n = 6, each group) and are expressed as mean ± SEM. ****p < .0001, ***p < .001, **p < .01, *p < .05. p-values were calculated using one-way ANOVA and post hoc Holm–Sidak tests (A, C, and D). BAL, bronchoalveolar lavage; PBS, Phosphate-buffered saline We thus demonstrated that ST2-Fc enhances IL-33 activity in vivo. Similar forms of augmentation, caused by several types of cytokines and their corresponding anti-cytokine monoclonal antibodies, have been reported. For instance, anti-IL-4 and anti-granulocyte-colony stimulating factor (G-CSF) monoclonal antibodies enhance IL-4 and G-CSF, respectively, in mice, via the formation of immune complexes in the circulation system.4 These findings support our discovery that ST2-Fc augments IL-33 activity. Cell-surface IL-33 receptors are composed of cell-surface ST2 (ST2L) and IL-1RAcP, and a fusion protein of ST2 and IL-1RAcP, IL-33trap, binds to IL-33 thirty times more strongly than sST2.5 These findings support our claim that sST2 carries IL-33 to cell-surface IL-33 receptors. Together, ST2-Fc and IL-33 induced greater neutrophilic inflammation with the release of dsDNA than IL-33 alone. Asthmatics with high levels of neutrophil-derived extracellular DNA in their sputum experience more asthma exacerbation and poorer lung function than those without.6 Thus, sST2–IL-33 complexes may contribute to the pathogenesis of neutrophilic asthma. In conclusion, sST2 may augment IL-33 activity via the formation of sST2–IL-33 complexes. FUNDING INFORMATION M. Watanabe reports grants from Grant-in-Aid for Scientific Research, grants from Environmental Restoration and Conservation Agency, grants and personal fees from Novartis, grants from GSK, grants from Pfizer, personal fees from Kyorin Pharmaceutical, personal fees from AstraZeneca, during the conduct of the study; personal fees from ThermoFisher, personal fees from Abbott, outside the submitted work. K. Nakamoto, C. Miyaoka, Y. Yoshida, J. Aso, H. Nunokawa, K. Honda, M. Nakamura, M. Tamura, A. Hirata, M. Oda, T. Saraya, and H. Ishii report grants from Grant-in-Aid for Scientific Research, grants from Environmental Restoration and Conservation Agency, grants and personal fees from Novartis, grants from GSK, grants from Pfizer, personal fees from Kyorin Pharmaceutical, personal fees from AstraZeneca, during the conduct of the study. K. Chibana reports personal fees from GSK, personal fees from Kyorin Pharmaceutical, personal fees from Torii, personal fees from Taiho, personal fees from Novartis, personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, during the conduct of the study. S. Takata reports grants from Grant-in-Aid for Scientific Research, grants from Environmental Restoration and Conservation Agency, grants and personal fees from Novartis, grants from GSK, grants from Pfizer, personal fees from Kyorin Pharmaceutical, personal fees from AstraZeneca, during the conduct of the study; personal fees from Lilly, personal fees from Chugai Pharmaceutical, outside the submitted work. D. Kurai reports grants from Grant-in-Aid for Scientific Research, grants from Environmental Restoration and Conservation Agency, grants and personal fees from Novartis, grants from GSK, grants from Pfizer, personal fees from Kyorin Pharmaceutical, personal fees from AstraZeneca, during the conduct of the study; grants from Grant-in-Aid for Scientific Research, personal fees from Janssen pharmaceutical, personal fees from MSD, personal fees from Meiji seika pharma, personal fees from Pfizer, personal fees from GSK, personal fees from Kyorin Pharmaceutical, personal fees from Sumitomo Dainippon Pharma, personal fees from Astellas Pharma, outside the submitted work. H. Takizawa reports grants from Grant-in-Aid for Scientific Research, grants from Environmental Restoration and Conservation Agency, grants from Novartis, grants from GSK, grants from Pfizer, grants from Kyorin Pharmaceutical, grants from AstraZeneca, during the conduct of the study. T. Inui and M. Sada have nothing to disclose. ACKNOWLEDGEMENTS This research was supported in part by the Environmental Restoration and Conservation Agency, the Grants-In-Aid for Scientific Research (KAKENHI; No. 15K09189 and 19KK0404), the GSK Japan Research Grant, Novartis Research Grants, and grants from Pfizer. We would like to thank all our colleagues who contributed to this study. We would also like to thank Uni-edit (https://uni-edit.net/) for editing and proofreading this manuscript. CONFLICT OF INTEREST None of the authors have any conflicts of interest to declare. CONSENT FOR PUBLICATION Not applicable. Supporting Information Filename Description all15401-sup-0001-AppendixS1.docxWord 2007 document , 125.3 KB Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Watanabe M, Takizawa H, Tamura M, et al. Soluble ST2 as a prognostic marker in community-acquired pneumonia. J Infect. 2015; 70(5): 474- 482. CrossrefPubMedGoogle Scholar 2Watanabe M, Nakamoto K, Inui T, et al. Serum sST2 levels predict severe exacerbation of asthma. Respir Res. 2018; 19(1): 169. CrossrefPubMedGoogle Scholar 3Inui T, Watanabe M, Nakamoto K, et al. Bronchial epithelial cells produce CXCL1 in response to LPS and TNFalpha: a potential role in the pathogenesis of COPD. Exp Lung Res. 2018; 44(7): 323- 331. CrossrefCASPubMedGoogle Scholar 4Woytschak J, Keller N, Krieg C, et al. Type 2 Interleukin-4 receptor signaling in neutrophils antagonizes their expansion and migration during infection and inflammation. Immunity. 2016; 45(1): 172- 184. CrossrefCASPubMedWeb of Science®Google Scholar 5Holgado A, Braun H, Van Nuffel E, et al. IL-33trap is a novel IL-33-neutralizing biologic that inhibits allergic airway inflammation. J Allergy Clin Immunol. 2019; 144(1): 204- 215. CrossrefCASPubMedWeb of Science®Google Scholar 6Lachowicz-Scroggins ME, Dunican EM, Charbit AR, et al. Extracellular DNA, neutrophil extracellular traps, and inflammasome activation in severe asthma. Am J Respir Crit Care Med. 2019; 199(9): 1076- 1085. CrossrefCASPubMedWeb of Science®Google Scholar Volume77, Issue10October 2022Pages 3137-3141 FiguresReferencesRelatedInformation

There are currently no antiviral agents for human metapneumovirus (HMPV), respiratory syncytial virus (RSV), mumps virus (MuV), or measles virus (MeV). Favipiravir has been developed as an anti-influenza agent, and this agent may be effective against these viruses in vitro. However, the molecular mechanisms through which the agent affects virus replication remain to be fully elucidated. Thus, to clarify the detailed molecular interactions between favipiravir and the RNA-dependent RNA polymerase (RdRp) of HMPV, RSV, MuV, MeV, and influenza virus, we performed in silico studies using authentic bioinformatics technologies. As a result, we found that the active form of favipiravir (favipiravir ribofuranosyl-5′-triphosphate [F-RTP]) can bind to the RdRp active sites of HMPV, RSV, MuV, and MeV. The aspartic acid residue of RdRp active sites was involved in the interaction. Moreover, F-RTP was incorporated into the growing viral RNA chain in the presence of nucleotide triphosphate and magnesium ions. The results suggested that favipiravir shows two distinct mechanisms in various viruses: RdRp active site inhibition and/or genome replication inhibition.

DNA gyrase plays important roles in genome replication in various bacteria, including Pseudomonasaeruginosa. The gyrA gene encodes the gyrase subunit A protein (GyrA). Mutations in GyrA are associated with resistance to quinolone-based antibiotics. We performed a detailed molecular evolutionary analyses of the gyrA gene and associated resistance to the quinolone drug, ciprofloxacin, using bioinformatics techniques. We produced an evolutionary phylogenetic tree using the Bayesian Markov Chain Monte Carlo (MCMC) method. This tree indicated that a common ancestor of the gene was present over 760 years ago, and the offspring formed multiple clusters. Quinolone drug-resistance-associated amino-acid substitutions in GyrA, including T83I and D87N, emerged after the drug was used clinically. These substitutions appeared to be positive selection sites. The molecular affinity between ciprofloxacin and the GyrA protein containing T83I and/or D87N decreased significantly compared to that between the drug and GyrA protein, with no substitutions. The rate of evolution of the gene before quinolone drugs were first used in the clinic, in 1962, was significantly lower than that after the drug was used. These results suggest that the gyrA gene evolved to permit the bacterium to overcome quinolone treatment.

1 Department of Respiratory Medicine, Kyorin University School of Medicine, Japan, 2 Departme... B Background and Aims b : Under pandemic condition of coronavirus disease 2019, N95 filtering facepiece respirators (N95 respirators) are lacking in many countries. P4-22: The effect and safety of ultraviolet germicidal irradiation on reusing N95 filtering facepiece respirators at weekly intervals Considering this background, the Centers for Disease Control and Prevention suggested reusing N95 respirators and referred the decontamination method by using ultraviolet irradiation (UVGI). [Extracted from the article] Copyright of Respirology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all Abstracts.)

Background and Aims: The release of membrane vesicles can mediate intercellular communication. Exosomes contain nucleic acids including messenger RNA and small non-cording microRNA (miRNA). Lung fibroblasts are both targets and sources of inflammatory mediators. In this study, we examined whether miR-146a containing exosomes could modulate cyclooxygenase 2 (COX-2) gene expression in human lung fibroblasts. Methods: Human fetal lung (HFL) cells, 1 x 10 cells per plate, were cultured in Dulbecco’s modified Eagle’s Medium (DMEM) with 10% fetal calf serum for 2 days. Culture media were then changed to DMEM without serum for 2 hours following which serum-free DMEM supplemented with and without IL-1β/TNF-α (1 ng/ml) was added. Media were harvested and cell debris was removed by centrifugation at 3000g; EVs were precipitated at 130000g. Size distribution of the particles was then evaluated by NanoSight LM10. Microarray and Realtime Polymerase Chain Reaction (RT-PCR) for COX-2 mRNA and miR-146a were performed with the purified exosomes. Results: We confirmed that HFL-1 cells produced particles in the range of exosomes; 30-100 nm. After 72 hours, the number of exosomes released by IL-1β/TNF-α stimulated cells was increased significantly. Using microarray analysis, 81 miRNAs were found to be differentially expressed including miR-146a after IL-1β/TNF-α stimulation. The differential expression of miR-146a was confirmed by RT-PCR. MiR-146a inhibitor blocked the role of miR-146a to suppress COX-2 mRNA expression in IL-1β/TNF-α treated condition significantly. Prostaglandin E2 levels determined by ELISA were consistent with these results. Conclusions: Exosomal miR-146a derived from human lung fibroblasts can modulate COX-2 gene expression.