Diverse pro-inflammatory ability of mutated spike protein derived from variant strains of SARS-CoV-2.

The severity of COVID-19 has been reported to differ among SARS-CoV-2 mutant variants. The overactivation of macrophages is involved in severe COVID-19, yet the effects of SARS-CoV-2 mutations on macrophages remain poorly understood. To clarify the effects, we examined whether mutations of spike proteins (S-proteins) affect macrophage activation. CD14+ monocyte-derived macrophages were stimulated with the recombinant S-protein of the wild-type, Delta, and Omicron strains or live viral particles of individual strains. Regarding IL-6 and TNF-α, Delta or Omicron S-protein had stronger or weaker pro­inflammatory ability, respectively, than the wild-type. Similar trends were observed between S-proteins and viral particles. S-protein mutations could be related to the diversity in macrophage activation and severity rates in COVID-19 caused by various SARS-CoV-2 strains.

Prognostic significance of chronic kidney disease and impaired renal function in Japanese patients with COVID-19.

BACKGROUND: Renal impairment is a predictor of coronavirus disease (COVID-19) severity. No studies have compared COVID-19 outcomes in patients with chronic kidney disease (CKD) and patients with impaired renal function without a prior diagnosis of CKD. This study aimed to identify the impact of pre-existing impaired renal function without CKD on COVID-19 outcomes. METHODS: This retrospective study included 3,637 patients with COVID-19 classified into three groups by CKD history and estimated glomerular filtration rate (eGFR) on referral: Group 1 (n = 2,460), normal renal function without a CKD history; Group 2 (n = 905), impaired renal function without a CKD history; and Group 3 (n = 272), history of CKD. We compared the clinical characteristics of these groups and assessed the effect of CKD and impaired renal function on critical outcomes (requirement for respiratory support with high-flow oxygen devices, invasive mechanical ventilation, or extracorporeal membrane oxygen, and death during hospitalization) using multivariable logistic regression. RESULTS: The prevalence of comorbidities (hypertension, diabetes, and cardiovascular disease) and incidence of inflammatory responses (white blood counts, and C-reactive protein, procalcitonin, and D-dimer levels) and complications (bacterial infection and heart failure) were higher in Groups 2 and 3 than that in Group 1. The incidence of critical outcomes was 10.8%, 17.7%, and 26.8% in Groups 1, 2, and 3, respectively. The mortality rate and the rate of requiring IMV support was lowest in Group 1 and highest in Group 3. Compared with Group 1, the risk of critical outcomes was higher in Group 2 (adjusted odds ratio [aOR]: 1.32, 95% confidence interval [CI]: 1.03-1.70, P = 0.030) and Group 3 (aOR: 1.94, 95% CI: 1.36-2.78, P < 0.001). Additionally, the eGFR was significantly associated with critical outcomes in Groups 2 (odds ratio [OR]: 2.89, 95% CI: 1.64-4.98, P < 0.001) and 3 (OR: 1.87, 95% CI: 1.08-3.23, P = 0.025) only. CONCLUSIONS: Clinicians should consider pre-existing CKD and impaired renal function at the time of COVID-19 diagnosis for the management of COVID-19.

Lymphoproliferative disorder risk after methotrexate treatment for rheumatoid arthritis.

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a troublesome problem in patients receiving MTX for rheumatoid arthritis (RA). However, its incidence, prognosis, and risk factors remain unclear. In this retrospective study, we evaluated the actual incidence, prognostic impact, and risk factors of MTX-LPD. Of the 986 patients with RA treated with MTX, 90 patients experienced 95 new malignancies (NMs), with LPD as the most frequent in 26 patients. The cumulative LPD incidences were 1.3% and 4.7% at 5 and 10 years after MTX initiation, respectively. Among the 24 patients who discontinued MTX after developing LPD, 15 showed sustained regression, without difference in overall survival between patients with LPD and without NM. Inflammatory markers and absolute lymphocyte counts were not useful for early LPD development detection, but most of the patients with LPD had persistently elevated erythrocyte sedimentation ratios. Regarding concomitant drugs, tacrolimus increased the risk only if patients were not receiving biological disease-modifying antirheumatic drugs (bDMARDs). bDMARDs did not increase the risk for any of the drugs or the number of classes used. The number of LPD cases was lower in patients with IL-6A even after a long period after MTX, although with no statistically significant difference. Thus, approximately 1 in 20 patients with RA developed MTX-LPD over the 10 years of MTX treatment, but it did not affect the survival of patients with RA. Tacrolimus increased the risk of developing LPD for certain patients and should be used with caution.

Clinical utilization of artificial intelligence-based COVID-19 pneumonia quantification using chest computed tomography - a multicenter retrospective cohort study in Japan.

BACKGROUND: Computed tomography (CT) imaging and artificial intelligence (AI)-based analyses have aided in the diagnosis and prediction of the severity of COVID-19. However, the potential of AI-based CT quantification of pneumonia in assessing patients with COVID-19 has not yet been fully explored. This study aimed to investigate the potential of AI-based CT quantification of COVID-19 pneumonia to predict the critical outcomes and clinical characteristics of patients with residual lung lesions. METHODS: This retrospective cohort study included 1,200 hospitalized patients with COVID-19 from four hospitals. The incidence of critical outcomes (requiring the support of high-flow oxygen or invasive mechanical ventilation or death) and complications during hospitalization (bacterial infection, renal failure, heart failure, thromboembolism, and liver dysfunction) was compared between the groups of pneumonia with high/low-percentage lung lesions, based on AI-based CT quantification. Additionally, 198 patients underwent CT scans 3 months after admission to analyze prognostic factors for residual lung lesions. RESULTS: The pneumonia group with a high percentage of lung lesions (N = 400) had a higher incidence of critical outcomes and complications during hospitalization than the low percentage group (N = 800). Multivariable analysis demonstrated that AI-based CT quantification of pneumonia was independently associated with critical outcomes (adjusted odds ratio [aOR] 10.5, 95% confidence interval [CI] 5.59-19.7), as well as with oxygen requirement (aOR 6.35, 95% CI 4.60-8.76), IMV requirement (aOR 7.73, 95% CI 2.52-23.7), and mortality rate (aOR 6.46, 95% CI 1.87-22.3). Among patients with follow-up CT scans (N = 198), the multivariable analysis revealed that the pneumonia group with a high percentage of lung lesions on admission (aOR 4.74, 95% CI 2.36-9.52), older age (aOR 2.53, 95% CI 1.16-5.51), female sex (aOR 2.41, 95% CI 1.13-5.11), and medical history of hypertension (aOR 2.22, 95% CI 1.09-4.50) independently predicted persistent residual lung lesions. CONCLUSIONS: AI-based CT quantification of pneumonia provides valuable information beyond qualitative evaluation by physicians, enabling the prediction of critical outcomes and residual lung lesions in patients with COVID-19.

Association between ABO blood group/genotype and COVID-19 in a Japanese population.

An association between coronavirus disease 2019 (COVID-19) and the ABO blood group has been reported. However, such an association has not been studied in the Japanese population on a large scale. Little is known about the association between COVID-19 and ABO genotype. This study investigated the association between COVID-19 and ABO blood group/genotype in a large Japanese population. All Japanese patients diagnosed with COVID-19 were recruited through the Japan COVID-19 Task Force between February 2020 and October 2021. We conducted a retrospective cohort study involving 1790 Japanese COVID-19 patients whose DNA was used for a genome-wide association study. We compared the ABO blood group/genotype in a healthy population (n = 611, control) and COVID-19 patients and then analyzed their associations and clinical outcomes. Blood group A was significantly more prevalent (41.6% vs. 36.8%; P = 0.038), and group O was significantly less prevalent (26.2% vs. 30.8%; P = 0.028) in the COVID-19 group than in the control group. Moreover, genotype OO was significantly less common in the COVID-19 group. Furthermore, blood group AB was identified as an independent risk factor for most severe diseases compared with blood group O [aOR (95% CI) = 1.84 (1.00-3.37)]. In ABO genotype analysis, only genotype AB was an independent risk factor for most severe diseases compared with genotype OO. Blood group O is protective, whereas group A is associated with the risk of infection. Moreover, blood group AB is associated with the risk of the "most" severe disease.

Clinical significance of prediabetes, undiagnosed diabetes and diagnosed diabetes on critical outcomes in COVID-19: Integrative analysis from the Japan COVID-19 task force.

AIM: Diabetes mellitus (DM) is a known risk factor for severe coronavirus disease 2019 (COVID-19), but the clinical impact of undiagnosed diabetes and prediabetes in COVID-19 are unclear particularly in Japan. We clarify the difference in clinical characteristics, including age, sex, body mass index and co-morbidities, laboratory findings and critical outcomes, in a large Japanese COVID-19 cohort without diabetes, with prediabetes, undiagnosed diabetes and diagnosed diabetes, and to identify associated risk factors. MATERIALS AND METHODS: This multicentre, retrospective cohort study used the Japan COVID-19 Task Force database, which included data on 2430 hospitalized COVID-19 patients from over 70 hospitals from February 2020 to October 2021. The prevalence of prediabetes, undiagnosed diabetes and diagnosed diabetes were estimated based on HbA1c levels or a clinical diabetes history. Critical outcomes were defined as the use of high-flow oxygen, invasive positive-pressure ventilation or extracorporeal membrane oxygenation, or death during hospitalization. RESULTS: Prediabetes, undiagnosed diabetes and diagnosed diabetes were observed in 40.9%, 10.0% and 23.0%, respectively. Similar to diagnosed diabetes, prediabetes and undiagnosed diabetes were risk factors for critical COVID-19 outcomes (adjusted odds ratio [aOR] [95% CI]: 2.13 [1.31-3.48] and 4.00 [2.19-7.28], respectively). HbA1c was associated with COVID-19 severity in prediabetes patients (aOR [95% CI]: 11.2 [3.49-36.3]), but not other groups. CONCLUSIONS: We documented the clinical characteristics and outcomes of Japanese COVID-19 patients according to HbA1c levels or diabetes co-morbidity. As well as undiagnosed and diagnosed diabetes, physicians should be aware of prediabetes related to COVID-19 severity.

A phase II randomized trial of metastasis-directed therapy with alpha emitter radium-223 in men with oligometastatic castration-resistant prostate cancer (MEDAL).

BACKGROUND: The significance of metastasis-directed therapy for oligometastatic prostate cancer has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multidisciplinary treatment for castration-resistant prostate cancer (CRPC). When oligometastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases. The progression of oligometastatic CRPC after targeted therapy may be due in part to the presence of micrometastatic lesions that, though undetected on imaging, were present prior to targeted therapy. Thus the systemic treatment of micrometastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect. Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays. Therefore, for oligometastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases. METHODS: This phase II, randomized trial of Metastasis-Directed therapy with ALpha emitter radium-223 in men with oligometastatic CRPC (MEDAL) is designed to assess the utility of radium-223 in combination with metastasis-directed radiotherapy in patients with oligometastatic CRPC confined to bone. In this trial, patients with oligometastatic CRPC with three or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone. The prior use of androgen receptor axis-targeted therapy and prostate-specific antigen doubling time will be used as allocation factors. The primary endpoint will be radiological progression-free survival against progression of bone metastases on WB-DWI. DISCUSSION: This will be the first randomized trial to evaluate the effect of radium-223 in combination with targeted therapy in oligometastatic CRPC patients. The combination of targeted therapy for macroscopic metastases with radiopharmaceuticals targeting micrometastasis is expected to be a promising new therapeutic strategy for patients with oligometastatic CRPC confined to bone. Trial registration Japan Registry of Clinical Trials (jRCT) (jRCTs031200358); Registered on March 1, 2021, https://jrct.niph.go.jp/latest-detail/jRCTs031200358.

Diagnostic significance of secondary bacteremia in patients with COVID-19.

OBJECTIVES: We investigated the occurrence of non-respiratory bacterial and fungal secondary infections, causative organisms, impact on clinical outcomes, and association between the secondary pathogens and mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: This was a retrospective cohort study that included data from inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021). We obtained demographic, epidemiological, and microbiological data throughout the course of hospitalization and analyzed the cases of COVID-19 complicated by non-respiratory bacterial infections. RESULTS: Of the 1914 patients included, non-respiratory bacterial infections with COVID-19 were diagnosed in 81 patients (4.2%). Of these, 59 (3.1%) were secondary infections. Bacteremia was the most frequent bacterial infection, occurring in 33 cases (55.9%), followed by urinary tract infections in 16 cases (27.1%). Staphylococcus epidermidis was the most common causative organism of bacteremia. Patients with COVID-19 with non-respiratory secondary bacterial infections had significantly higher mortality, and a multivariate logistic regression analysis demonstrated that those with bacteremia (aOdds Ratio = 15.3 [5.97-39.1]) were at higher risk of death. Multivariate logistic regression analysis showed that age, male sex, use of steroids to treat COVID-19, and intensive care unit admission increased the risk for nosocomial bacteremia. CONCLUSIONS: Secondary bacteremia is an important complication that may lead to poor prognosis in cases with COVID-19. An appropriate medical management strategy must be established, especially for patients with concomitant predisposing factors.

Impact of respiratory bacterial infections on mortality in Japanese patients with COVID-19: a retrospective cohort study.

BACKGROUND: Although cases of respiratory bacterial infections associated with coronavirus disease 2019 (COVID-19) have often been reported, their impact on the clinical course remains unclear. Herein, we evaluated and analyzed the complication rates of bacterial infections, causative organisms, patient backgrounds, and clinical outcome in Japanese patients with COVID-19. METHODS: We performed a retrospective cohort study that included inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021) and obtained demographic, epidemiological, and microbiological results and the clinical course and analyzed the cases of COVID-19 complicated by respiratory bacterial infections. RESULTS: Of the 1,863 patients with COVID-19 included in the analysis, 140 (7.5%) had respiratory bacterial infections. Community-acquired co-infection at COVID-19 diagnosis was uncommon (55/1,863, 3.0%) and was mainly caused by Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Hospital-acquired bacterial secondary infections, mostly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were diagnosed in 86 patients (4.6%). Severity-associated comorbidities were frequently observed in hospital-acquired secondary infection cases, including hypertension, diabetes, and chronic kidney disease. The study results suggest that the neutrophil-lymphocyte ratio (> 5.28) may be useful in diagnosing complications of respiratory bacterial infections. COVID-19 patients with community-acquired or hospital-acquired secondary infections had significantly increased mortality. CONCLUSIONS: Respiratory bacterial co-infections and secondary infections are uncommon in patients with COVID-19 but may worsen outcomes. Assessment of bacterial complications is important in hospitalized patients with COVID-19, and the study findings are meaningful for the appropriate use of antimicrobial agents and management strategies.

Japan College of Rheumatology guidance for the use of methotrexate in patients with rheumatoid arthritis: Secondary publication.

Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for the treatment of RA in Japan in 1999 at a recommended dose of 6-8 mg/week. The approved maximum dose of MTX has been 16 mg/week since February 2011 when MTX was approved as a first-line drug in the treatment of RA. Recent evidence of MTX-polyglutamate concentration in the red blood cells of Japanese patients with RA justifies the current daily use of MTX in Japan. Additionally, after a nationwide clinical trial, a subcutaneous MTX injection formula (7.5-15 mg/week) was approved for RA treatment in September 2022. Therefore, in March 2023, a subcommittee of the Japan College of Rheumatology updated the guidance (formerly 'guidelines') for the use of MTX in Japanese patients with RA. This article, an abridged English translation summarizing the 2023 update of the Japan College of Rheumatology guidance for the use of MTX and management of patients with RA, will be helpful to both Japanese and global rheumatology communities.

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors.

BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

blaKPC-2-Encoding IncP-6 Plasmids in Citrobacter freundii and Klebsiella variicola Strains from Hospital Sewage in Japan.

Klebsiella pneumoniae carbapenemase (KPC) producers are an emerging threat to global health, and the hospital water environment is considered an important reservoir of these life-threatening bacteria. We characterized plasmids of KPC-2-producing Citrobacter freundii and Klebsiella variicola isolates recovered from hospital sewage in Japan. Antimicrobial susceptibility testing, whole-genome sequencing analysis, bacterial conjugation, and transformation experiments were performed for both KPC-2 producers. The blaKPC-2 gene was located on the Tn3 transposon-related region from an IncP-6 replicon plasmid that could not be transferred via conjugation. Compared to the blaKPC-2-encoding plasmid of the C. freundii isolate, alignment analysis of plasmids with blaKPC-2 showed that the blaKPC-2-encoding plasmid of the K. variicola isolate was a novel IncP-6/IncF-like hybrid plasmid containing a 75,218-bp insertion sequence composed of IncF-like plasmid conjugative transfer proteins. Carbapenem-resistant transformants harboring blaKPC-2 were obtained for both isolates. However, no IncF-like insertion region was found in the K. variicola donor plasmid of the transformant, suggesting that this IncF-like region is not readily functional for plasmid conjugative transfer and is maintained depending on the host cells. The findings on the KPC-2 producers and novel genetic content emphasize the key role of hospital sewage as a potential reservoir of pathogens and its linked dissemination of blaKPC-2 through the hospital water environment. Our results indicate that continuous monitoring for environmental emergence of antimicrobial-resistant bacteria might be needed to control the spread of these infectious bacteria. Moreover, it will help elucidate both the evolution and transmission pathways of these bacteria harboring antimicrobial resistance. IMPORTANCE Antimicrobial resistance is a significant problem for global health, and the hospital environment has been recognized as a reservoir of antimicrobial resistance. Here, we provide insight into the genomic features of blaKPC-2-harboring isolates of Citrobacter freundii and Klebsiella variicola obtained from hospital sewage in Japan. The findings of carbapenem-resistant bacteria containing this novel genetic context emphasize that hospital sewage could act as a potential reservoir of pathogens and cause the subsequent spread of blaKPC-2 via horizontal gene transfer in the hospital water environment. This indicates that serial monitoring for environmental bacteria possessing antimicrobial resistance may help us control the spread of infection and also lead to elucidating the evolution and transmission pathways of these bacteria.

Impact of upper and lower respiratory symptoms on COVID-19 outcomes: a multicenter retrospective cohort study.

BACKGROUND: Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients. METHODS: This was a multicenter, retrospective cohort study; the database from the Japan COVID-19 Task Force was used. A total of 3314 COVID-19 patients were included in the study, and the data on respiratory symptoms were collected. The participants were classified according to their respiratory symptoms (Group 1: no respiratory symptoms, Group 2: only upper respiratory symptoms, Group 3: only lower respiratory symptoms, and Group 4: both upper and lower respiratory symptoms). The impacts of upper and lower respiratory symptoms on the clinical outcomes were compared. The primary outcome was the percentage of patients with poor clinical outcomes, including the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation or death. RESULTS: Of the 3314 COVID-19 patients, 605, 1331, 1229, and 1149 were classified as Group 1, Group 2, Group 3, and Group 4, respectively. In univariate analysis, patients in Group 2 had the best clinical outcomes among all groups (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.11-0.39), while patients in Group 3 had the worst outcomes (OR: 3.27, 95% CI: 2.43-4.40). Group 3 patients had the highest incidence of pneumonia, other complications due to secondary infections, and thrombosis during the clinical course. CONCLUSIONS: Upper and lower respiratory tract symptoms had vastly different impacts on the clinical outcomes of COVID-19.

Rapid and sensitive SARS-CoV-2 detection using a homogeneous fluorescent immunosensor Quenchbody with crowding agents.

Antigen tests for SARS-CoV-2 are widely used by the public during the ongoing COVID-19 pandemic, which demonstrates the societal impact of homogeneous immunosensor-related technologies. In this study, we used the PM Q-probe and Quenchbody technologies to develop a SARS-CoV-2 nucleocapsid protein (N protein) homogeneous immunosensor based on a human anti-N protein antibody. For the first time, we uncovered the crowding agent's role in improving the performance of the double-labeled Quenchbody, and the possible mechanisms behind this improvement are discussed. The 5% polyethylene glycol 6000 significantly improved both the response speed and sensitivity of SARS-CoV-2 Quenchbodies. The calculated limit of detection for recombinant N protein was 191 pM (9 ng mL-1) within 15 min of incubation, which was 9- to 10-fold lower than the assay without adding crowding agent. We also validated the developed immunosensor in a point-of-care test by measuring specimens from COVID-19-positive patients using a compact tube fluorometer. In brief, this work shows the feasibility of Quenchbody homogeneous immunosensors as rapid and cost-efficient tools for the diagnosis and high-throughput analysis of swab samples in large-scale monitoring and epidemiological studies of COVID-19 or other emerging infectious diseases.

Clinical clustering with prognostic implications in Japanese COVID-19 patients: report from Japan COVID-19 Task Force, a nation-wide consortium to investigate COVID-19 host genetics.

BACKGROUND: The clinical course of coronavirus disease (COVID-19) is diverse, and the usefulness of phenotyping in predicting the severity or prognosis of the disease has been demonstrated overseas. This study aimed to investigate clinically meaningful phenotypes in Japanese COVID-19 patients using cluster analysis. METHODS: From April 2020 to May 2021, data from inpatients aged ≥ 18 years diagnosed with COVID-19 and who agreed to participate in the study were collected. A total of 1322 Japanese patients were included. Hierarchical cluster analysis was performed using variables reported to be associated with COVID-19 severity or prognosis, namely, age, sex, obesity, smoking history, hypertension, diabetes mellitus, malignancy, chronic obstructive pulmonary disease, hyperuricemia, cardiovascular disease, chronic liver disease, and chronic kidney disease. RESULTS: Participants were divided into four clusters: Cluster 1, young healthy (n = 266, 20.1%); Cluster 2, middle-aged (n = 245, 18.5%); Cluster 3, middle-aged obese (n = 435, 32.9%); and Cluster 4, elderly (n = 376, 28.4%). In Clusters 3 and 4, sore throat, dysosmia, and dysgeusia tended to be less frequent, while shortness of breath was more frequent. Serum lactate dehydrogenase, ferritin, KL-6, D-dimer, and C-reactive protein levels tended to be higher in Clusters 3 and 4. Although Cluster 3 had a similar age as Cluster 2, it tended to have poorer outcomes. Both Clusters 3 and 4 tended to exhibit higher rates of oxygen supplementation, intensive care unit admission, and mechanical ventilation, but the mortality rate tended to be lower in Cluster 3. CONCLUSIONS: We have successfully performed the first phenotyping of COVID-19 patients in Japan, which is clinically useful in predicting important outcomes, despite the simplicity of the cluster analysis method that does not use complex variables.

Characteristics of hospitalized patients with COVID-19 during the first to fifth waves of infection: a report from the Japan COVID-19 Task Force.

BACKGROUND: We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. METHODS: We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. RESULTS: Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p < 0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p < 0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. CONCLUSIONS: We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.

Three-day regimen of oseltamivir for post-exposure prophylaxis of influenza in hospital wards: a study protocol for a prospective, multi-center, single-arm trial.

BACKGROUND: In a previous retrospective observational study, a 3-day regimen of oseltamivir as post-exposure prophylaxis (PEP) for preventing transmission of influenza in wards was shown to be comparable to 7- to 10-day regimens provided index cases were immediately separated from close contacts. In order to confirm the efficacy of a 3-day regimen, we started to conduct a prospective, multi-center, single-arm trial. METHODS: This study is a prospective, multi-center, single-arm study designed by the Sectional Meeting of Clinical Study, Japan Infection Prevention and Control Conference for National and Public University Hospitals. Index patients with influenza are prescribed a neuraminidase inhibitor and are discharged immediately or transferred to isolation rooms. The close contacts are given oseltamivir as 75 mg capsules once daily for adults or 2 mg/kg (maximum of 75 mg) once daily for children for 3 days as PEP. All close contacts are monitored for development of influenza for 7 days after starting PEP. DISCUSSION: A 3-day regimen of oseltamivir as PEP has advantages over 7- to 10-day regimens in terms of costs, medication adherence and adverse effects. Trial registration The Institutional Review Board of Hokkaido University Hospital for Clinical Research, 015-0518, registered on November 11, 2016. UMIN Clinical Trials Registry, UMIN000024458, disclosed on October 31, 2016. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000027881 . Japan Registry of Clinical Trials, jRCTs011180015, disclosed on March 14, 2019. https://jrct.niph.go.jp/latest-detail/jRCTs011180015.

Study protocol: a multicenter, uncontrolled, open-label study of palivizumab in neonates, infants, and preschool children at high risk of severe respiratory syncytial virus infection.

BACKGROUND: The prophylactic use of anti-respiratory syncytial virus (RSV) antibody (palivizumab) for severe RSV infection is not approved in Japan in specified groups of infants with neuromuscular diseases or other rare diseases associated with reduced ventilation competence or difficulty in expectoration, which increase the risk of exacerbation of severe RSV infection. The objective of this study is to investigate the efficacy, safety, and pharmacokinetics of palivizumab in pediatric patients with those rare diseases for which palivizumab is not indicated at present. METHODS/DESIGN: This study is a multicenter, uncontrolled, open-label study planned to be carried out between July 1, 2019 and June 30, 2022 at 7 medical institutions in Japan. The study population will be recruited from among neonates, infants, or children aged 24 months or younger with a condition falling under any of the following 5 disease groups: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. The planned sample size is 18 subjects, including at least 3 subjects per disease group. Throughout the RSV season, at least 4 continuous doses of palivizumab will be administered intramuscularly at 15 mg/kg at intervals of 30 days. The efficacy and safety of palivizumab will be comprehensively evaluated based on the incidence of RSV-related hospitalization, and serum palivizumab concentration, serum anti-palivizumab antibody concentration, and the occurrence of adverse events/reactions after the start of palivizumab treatment. DISCUSSION: This study will evaluate the efficacy and safety of palivizumab in pediatric patients with rare diseases which place them at high risk of severe RSV infection, but which fall outside the current indications for palivizumab prophylaxis. The generated data will have implications for the regulatory approval of prophylactic palivizumab treatment in this patient group. TRIAL REGISTRATION: This study has been prospectively registered in Japic Clinical Trials Information, which is managed and administered by the Japan Pharmaceutical Information Center (registration number: JapicCTI-194946 , registration date: September 10, 2019).

Evaluation of polymerase chain reaction-based open reading frame typing method for the clonality investigation of Clostridioides difficile isolates.

Here, we assessed the utility of a polymerase chain reaction-based open reading frame typing assay for investigating the clonality of Clostridioides difficile isolates. This assay has a higher discriminatory power than multi-locus sequence typing for molecular epidemiological analysis of C. difficile isolates and can provide additional information about toxin genotypes.

Molecular epidemiologic and clinical analysis of Helicobacter cinaedi bacteremia in Japan.

BACKGROUND: Helicobacter cinaedi is an important pathogen that causes bloodstream infections. Owing to the challenges in its culture and identification, its clinical and bacterial characteristics remain unknown. Our study aimed to investigate the molecular epidemiology and antimicrobial susceptibility of H cinaedi. MATERIALS AND METHODS: From 2003 to 2016, we analyzed 16 non-repetitive H cinaedi strains, isolated from blood, at the medical hospital of Tokyo Medical and Dental University. Multilocus sequence typing was performed to analyze the genetic relationship across the different isolates. The minimum inhibitory concentrations (MIC) of antibiotics were determined by the agar dilution method. RESULTS: The median age of subjects in this study was 61 years (range, 18-84 years). The most common risk factors included the use of steroids (75.0%) and immunosuppressant drugs (37.5%). In addition, the most common symptoms of H cinaedi bacteremia included colitis (37.5%) and cellulitis (31.3%). The infection recurred in three of seven cases (42.8%) that underwent antibiotic therapy for <10 days. The strains were classified into five sequence types (ST), of which, ST 10 (43.8%) and ST 4 (31.3%) were predominant. The MIC90 values of amoxicillin, gentamycin, imipenem, ciprofloxacin, and clarithromycin were 4, 0.5, 0.25, 64, and 128 mg/L, respectively. CONCLUSIONS: Since there is no recommended guideline yet for the choice or duration of antibiotic therapy and antimicrobial break points, our results suggested, for the first time, that prolonged antibiotic therapy, except with ciprofloxacin and clarithromycin, would be required to ensure resolution of symptoms and prevention of recurrence.