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Several commercial nucleic acid amplification tests (NAAT) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed. We used six kits available in Japan in 13 NAAT-positive specimens with crossing point values >36 and 7 NAAT-negative specimens from patients with coronavirus disease (COVID-19); their results were compared. Specimens positive in ≥2 assays were considered true positive and examined for concordance with specimen results. The SARS-CoV-2 Detection Kit -Multi- (Toyobo M) (Toyobo, Osaka, Japan) using extracted RNA had the highest concordance (κ 1.00). This was followed by the cobas® SARS-CoV-2 (Cobas) (Roche, Basel, Switzerland) (κ 0.79). There was a weak correlation between number of negative results for each kit and days between onset and testing (Spearman rank correlation: ρ= 0.44; p

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be detected in the stool samples of patients with coronavirus disease 2019 (COVID-19), and this virus can be transmitted via the oral-fecal route. However, there are only few reports on the viral load in the stool samples. In this pilot study, we aimed to evaluate the clinical characteristics and viral load of SARS-CoV-2 in the stool samples of 13 patients with confirmed COVID-19 using pepper mild mottle virus as a control, which has been proposed as a potential marker of human feces contamination in the environmental water bodies. SARS-CoV-2 RNA was detected in the stool samples of four patients (31%), and among them, three exhibited symptoms of diarrhea. One patient who suffered from long-term diarrhea (22 days) exhibited highest level of viral RNA in the stool sample (8.28 log10 copies/g). However, we could not harvest SARS-CoV-2 from the stool sample of any patient, even after culturing with VeroE6/TMPRESS2 cells for four weeks. Our results suggest that SARS-CoV-2 RNA can be detected in the stool samples of patients with COVID-19 suffering from diarrhea. However, further studies elucidating the relationship between SARS-CoV-2 viral load in the stool samples and symptoms of diarrhea in large cohorts and upon adjusting other causative factors and virus infectivity are still warranted.

Introduction In response to global outbreaks of infectious diseases, the need for support from organizations such as the World Health Organization Global Outbreak Alert and Response Network (GOARN) is increasing. Identifying the obstacles and support needs for applicants could increase GOARN deployments from Japan. Methods This cross-sectional study involved a web-based, self-administered questionnaire survey targeting Japanese participants in the GOARN Tier 1.5 training workshop, held in Tokyo in December 2019. Results All 47 Japanese participants in the workshop responded to the survey. Most responders were male and in their 30s and 40s. Participants specialized in case management (42.6%), infection prevention and control (25.6%), epidemiology and surveillance (19.1%). Only two participants (4.6%) had experienced a GOARN deployment. Their motivations for joining the GOARN training workshop were “Desire to be part of an international emerging infectious disease response team” (44.6%), “Interest in making an international contribution” (19.1%), and “Interest in working for the Japanese government in the field of international infectious diseases” (14.9%). Obstacles to GOARN deployments were “Making time for deployments” (45.7%) and “Lack of required professional skills and knowledge” (40.4%). The support needs for GOARN deployments constituted “Periodic simulation training” (51.1%), “Financial support during deployments” (44.7%), and “Technical support for deployments” (40.4%). Conclusions Our study revealed the obstacles and support needs of Japanese candidates for GOARN deployment. Making time and upskilling for GOARN deployment were the main obstacles. More practical training (like GOARN Tier 2.0) with other supports are needed. The national framework is desirable to realize these supports.

Here, we report a case of allogeneic islet transplantation in Japan. A 48-year-old man received intraportal islet transplantation (5,945 islet equivalent/kg), and stabilization of blood glucose levels and suppression of hypoglycemia were achieved. In this case, we used our original assessment method to detect the responses of the recipient's T cells to islet autoantigens over time to monitor cellular autoimmunity. Other markers could not predict graft dysfunction in advance, but our method detected the activation of islet antigen-specific CD8+ T cell responses before the deterioration of pancreatic beta cell function, indicating the possibility of the non-invasive detection of pancreatic beta cell damage due to recurrent autoimmunity.

Introduction The automated quantitative antigen test (QAT), which detects severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is suitable for mass screening. However, its diagnostic capability differentiated by time from onset and potential contribution to infectivity assessment have not been fully investigated. Methods A retrospective, observational study using nasopharyngeal swab specimens from coronavirus disease (COVID-19) inpatients was conducted using LumipulseⓇ SARS-CoV-2 antigen test. Diagnostic accuracy was examined for the early (up to 10 days after onset) and late (over 10 days after onset) stages. Time-course QAT changes and reverse‐transcription quantitative polymerase chain reaction tests results were displayed as locally estimated scatterplot smoothing curve, and receiver operating characteristic curve (ROC) analysis was used to determine the appropriate cutoff value for differentiating the early and late stages. Results We obtained 100 specimens from 68 COVID-19 patients, including 51 early-stage and 49 late-stage specimens. QAT sensitivity and specificity were 0.82 (0.72–0.90) and 0.95 (0.75–0.99) for all periods, 0.93 (0.82–0.98) and 1.00 (0.39–1.00) for the early stage, and 0.66 (0.48–0.82) and 0.93 (0.69–0.99) for the late stage, respectively. The ROC analysis indicated an ideal cutoff value of 6.93 pg/mL for distinguishing early-from late-stage specimens. The sensitivity, specificity, positive predictive value, and negative predictive value for predicting the late stage were 0.76 (0.61–0.87), 0.76 (0.63–0.87), 0.76 (0.61–0.87), and 0.76 (0.63–0.87). Conclusions QAT has favorable diagnostic accuracy in the early COVID-19 stages. In addition, an appropriate cutoff point can potentially facilitate rapid identification of noncontagious patients.

To deal with the risk of emerging diseases with many unknowns, close and timely collaboration and communication between science experts and policymakers are crucial to developing and implementing an effective science-based intervention strategy. The Expert Meeting, an ad hoc medical advisory body, was established in February 2020 to advise Japan's COVID-19 Response Headquarters. The group played an important role in the policymaking process, promoting timely situation awareness and developing science-based proposals on interventions that were promptly reflected in government actions. However, this expert group may have been overly proactive in taking on the government's role in crisis management. For the next stage of managing the coronavirus disease pandemic and future pandemics, the respective roles of the government and its advisory bodies need to be clearly defined. Leadership and strategic risk communication by the government are key.

Introduction Many articles have reported that the coronavirus disease 2019 (COVID-19) causes coagulation abnormalities and pulmonary thrombosis, contributing to a poorer prognosis. The study aimed to evaluate whether pre-admission anticoagulation and antiplatelet therapy prevented severe COVID-19 illness or not. Materials and methods We conducted a study to determine whether taking antiplatelet or anticoagulation agents before admission affected the severity on admission using a large nationwide cohort of hospitalized COVID-19 patients in Japan. We analyzed a large nationwide cohort of hospitalized COVID-19 patients in Japan from February 9 to July 31, 2020. Results and conclusion A total of 4265 patients from 342 facilities in Japan were included. Their use was associated with a slight reduction in the disease severity on admission in a propensity score-matched analysis which controlled for underlying diseases. However, this difference was not statistically significant.

Coagulase-negative staphylococci (CoNS) are the most frequent contaminating bacteria; therefore, we aimed to investigate an indicator of CoNS to predict the increase in blood culture contamination rate (ConR). We performed a retrospective study of selected patients, who underwent blood culture testing. Contamination was defined as the presence of either one of two or more sets of skin-resident bacteria, except for cases with a low likelihood of contamination based on clinical aspects. We calculated the monthly ConR [(total number of contaminated cases per month)/(total number of blood culture sets collected per month) × 100] and analysed the ConR prediction ability using the following four indicators: the number of CoNS-positive sets of blood cultures, cases with at least one CoNS-positive blood culture set, cases with only one CoNS-positive blood culture set, and cases of contamination by CoNS. Cases with CoNS-positive blood cultures correlated with ConR (r = 0.85). Although the area under the receiver operating characteristic curve for the number of cases with ConR ≥ 2.5 differed significantly from that of the number of cases contaminated by CoNS, the negative predictive value was high, reaching up to 95.5% (95% confidential interval 87.3–99.1). The number of CoNS-positive cases could help predict an increase in ConR ≥ 2.5.

We investigated possible sources of newly infected patients with coronavirus disease (COVID-19) after the fourth wave in order to explore unknown sources. Retrospective chart review on all the confirmed patients with COVID-19 admitted to the National Center for Global Health and Medicine (NCGM) in Tokyo, Japan was conducted from May 22 through June 29, 2021. Among the 22 participants, 14 (64%) had a history of known high-risk infection behaviors. Of those, 12 reported that their activities involved eating and drinking. In addition, there were 24 high-risk situations, of those, 21 (88%) were related to indoor dining, and masks were not worn in 22 situations (92%). New source of infection has not been identified. In situations with a high known risk of infection, many cases were related to eating and drinking, and insufficient use of masks was evident. Raising risk awareness on infection prevention and control of COVID-19 is urgently needed.

Background: Antimicrobial resistance (AMR) is a global health problem. However, quantitative evaluation of its disease burden is challenging. This study aimed to estimate the disease burden of bloodstream infections (BSIs) caused by major antimicrobial-resistant bacteria in Japan between 2015 and 2018 in terms of disability-adjusted life-years (DALYs). Methods: DALYs of BSIs caused by nine major antimicrobial-resistant bacteria in Japan were estimated using comprehensive national surveillance data of all routine bacteriological test results from more than 1400 hospitals between 2015 and 2018. The methodology of Cassini et al. was modified to enable comparison of the present results with those in other countries. Results: It was estimated that 137.9 [95% uncertainty interval (UI) 130.7-145.2] DALYs per 100,000 population were attributable to BSIs caused by nine antimicrobial-resistant bacteria in 2018. Methicillinresistant Staphylococcus aureus (MRSA), fluoroquinolone-resistant Escherichia coli (FQREC) and third generation cephalosporin-resistant E. coli (3GREC) accounted for 87.2% overall. The burden did not decrease during the study period and was highest in people aged >65 years. Conclusion: The results revealed, for the first time, the disease burden of BSIs caused by nine major antimicrobial-resistant bacteria in Japan. The estimated disease burden associated with AMR in Japan is substantial and has not begun to decrease. Notably, the burden from FQREC and 3GREC has increased steadily, and that from MRSA is larger in Japan than in the European Union/European Economic Area, whereas the burden from other bacteria is comparatively small. These results are expected to provide useful information for healthcare policy makers for prioritizing interventions for AMR. (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

Background In order to tackle the COVID-19 pandemic, a COVID-19 convalescent plasma (CCP) procurement program was initiated in Japan in April 2020. The program was a collaboration between a government-managed national hospital, an infectious disease research institute, and a blood banking organization. Each party assumed different responsibilities: recruitment, SARS-CoV-2 antibody profiling, and plasmapheresis; conduction of screening tests; and SARS-CoV-2 blood testing, respectively. Methods We adopted a two-point screening approach before the collected CCP was labeled as a CCP product for investigational use, for which we mainly tested anti-SARS-CoV-2 antibody eligibility and blood product eligibility. Anti-SARS-CoV-2 spike protein titer was measured using ELISA, and the IC50 value was denoted as the neutralizing activity. Blood donor eligibility was extended beyond the normal blood donation guidelines to include a broader range of participants. After both eligibility criteria were confirmed, participants were asked to revisit the hospital for blood donation, which is a unique aspect of the Japanese CCP program, as most donations are taking place in normal blood donation venues in other countries. Some donors were re-scheduled for repeat plasma donations. As public interest in anti-SARS-CoV-2 antibodies increased, test results were given to the participants. Results As of September 17, 2020, our collection of CCP products was sufficient to treat more than 100 patients. As a result, projects for administration and distribution are also being conducted. Conclusions We successfully implemented a CCP procurement scheme with the goal to expand to other parts of the country to improve treatment options for COVID-19. This article is protected by copyright. All rights reserved.

Pseudomonas aeruginosa resistance is a major issue worldwide. Drug resistance is related to inappropriate antibiotic use. Because antipseudomonal agents have a wide spectrum, they must be used appropriately. The purpose of this study was to clarify the trends in antipseudomonal agent use in Japan based on sales data from 2006 to 2015. The total antipseudomonal agent use was increased significantly (r = 0.10, Pfor trend = 0.00040). The proportion of fluoroquinolones use was the highest throughout the year, accounting for 88.6-91.4%. The use of piperacillin/tazobactam significantly increased. The increased use of these drugs may be due to the launch of higher doses and additional indications. On the other hand, for antipseudomonal agents, parenteral carbapenems use was 2.7-3.7%, but it has remained unchanged over the years. In Japan, permit and notification systems have been introduced to prevent the inappropriate use of parenteral carbapenems in medical institutions. It was speculated that these efforts suppressed the inappropriate use of parenteral carbapenems. This study clarified the trend of antipseudomonal agent use in Japan from 2006 to 2015. It is important to continue monitoring antipseudomonal agents use to conduct appropriate antimicrobial resistance measures.

INTRODUCTION: Among patients with coronavirus disease 2019 (COVID-19), the factors that affect anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody production remain unclear. This study aimed to identify such factors among patients convalescing from COVID-19. METHODS: This study comprised patients who had been diagnosed with COVID-19 between January 1 and June 30, 2020 and gave consent for anti-SARS-CoV-2 spike protein antibody measurement using enzyme-linked immunosorbent assay during their acute and/or convalescent phases. Factors related to elevated antibody titers and the relationship between the days from disease onset and the development of antibody titers were assessed. RESULTS: A total of 84 participants enrolled in the study. Nineteen participants had antibody titers measured during the convalescent phase only, and 65 participants had antibody titers measured during the acute and convalescent phases. The antibody titers peaked in weeks 5 and 6. The stepwise multivariate log-normal analysis revealed that male sex (P = 0.04), diabetes mellitus (P = 0.03), and high C-reactive protein levels during the disease course (P

We report a case of varicella zoster virus (VZV) meningitis following BNT162b2 mRNA COVID-19 vaccination in an immunocompetent patient. A final diagnosis was made based on identification of VSV via positive polymerase chain reaction of cerebrospinal fluid along with characteristic symptoms such as fever, headache, and stiff neck. This phenomenon has been reported elsewhere; this is the 13th such case reported worldwide and the 7th case in immunocompetent patients, indicating the need for careful monitoring after COVID-19 vaccines.

The aim of this study is to investigate myocardial damage in recovering coronavirus disease 2019 (COVID-19) patients with high-sensitivity troponin levels (hsTnT) and echocardiography. In this single-center cohort study, 215 COVID-19 recovered patients were recruited from all over Japan between April and September 2020. Demographic characteristics, hsTnT levels, and echocardiography data were collected for 209 patients, after excluding those without serum samples or good-quality echocardiographic images. The mean (± standard deviation) age was 44 (± 12) years (range: 36-55 years), and 50.7% of the patients were males. The median time interval (interquartile range) from COVID-19 onset to post-recovery examination was 56 days (34-96 days). Seventy-four recovered patients (35.4%) had hsTnT less than detection sensitivity (< 3 pg/mL) and 135 recovered patients (64.6%) had hsTnT ≥ 3 pg/mL. Ejection fraction was more than 50% in all cases. Left ventricular global longitudinal strain (LVGLS) and right ventricular free-wall longitudinal strain (RVFWLS) were reduced in 62 (29.7%) and 8 patients (3.8%), respectively. They were significantly associated with elevated hsTnT levels. In cases with hsTnT above 5 pg/mL, the LVGLS was greatly reduced to 19.0 ± 2.2% (p < 0.001). Multivariate linear regression analysis showed that elevated hsTnT level was an independent predictor of reduced LVGLS (standardized β = -0.34; p < 0.001). In recovered COVID-19 patients, even a slight increase in hsTnT above detection sensitivity was associated with decreased LVGLS. hsTnT and echocardiography may be useful tools to detect myocardial injury in recovered COVID-19 patients.

We assessed the consistency of seropositive results of three rapid immunoassays (Kits A, B, and C) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared to highly accurate serological tests (Abbott and Roche) among healthcare workers in a hospital in Tokyo. The seroprevalence of SARS-CoV-2 immunoglobulin G was 0.41%, 2.36%, and 0.08% using Kits A, B, and C, respectively. Of the 51 samples that were seropositive on any rapid test, all were seronegative on both the Abbott and the Roche assays. Given that the seroprevalence of SARS-CoV-2 immunoglobulin G varied widely according to the choice of rapid test and the rapid test results were inconsistent with the results of highly accurate tests, the diagnostic accuracy of rapid serological tests for SARS-CoV-2 should be assessed before introducing these tests for point-of-care testing or surveillance.

The objective of this study was to investigate the association between adherence to healthy lifestyles (as measured by the healthy lifestyle index [HLI]) and depressive symptoms among staff members at a large national medical institution in Tokyo, Japan, during the coronavirus disease 2019 (COVID-19) pandemic. The study sample consisted of 1228 staff members aged between 21 and 73 years who participated in a cross-sectional survey conducted in July 2020. We constructed the HLI by assigning 1 point to each healthy lifestyle factor: normal body mass index, sufficient physical activity, non-smoking status, non-to-moderate alcohol consumption, and sufficient sleep duration. The multivariate adjusted odds ratios (95% confidence interval) for depressive symptoms were 1.00 (reference), 0.71 (0.46-1.11), 0.66 (0.43-1.01), and 0.56 (0.33-0.94) for participants with HLI scores of 0 to 2, 3, 4, and 5, respectively (P for trend = 0.032). The present study suggests the role of healthy lifestyles in mental health among hospital staff working during the pandemic.

Real-time reverse transcription polymerase chain reaction (RT-PCR) tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are occasionally repeated when clinicians suspect false-negative results, but the conditions under which repeated RT-PCR testing is warranted remain unclear. We evaluated the practice of repeat RT-PCR testing for SARS-CoV-2 in 45 patients who were retested after an initial negative PCR test. Of these, the diagnosis of coronavirus disease (COVID-19) was confirmed in four patients with typical chest computed tomography (CT) findings and in one patient without typical CT findings in whom the test result was strongly suspected to be false-positive. We recommend repeat RT-PCR testing only for patients with typical CT findings of COVID-19.

Highlights • The rapid antigen test (RAT) and RT-qPCR positive concordance rate is low in COVID-19. • In the early stages of disease, positive and negative concordance rates are acceptable. • Factors related to disagreement between RAT and RT-qPCR results were investigated. • The predictive ability of RAT for disease transmissibility was examined. • RAT and RT-qPCR results were highly consistent; results can infer transmissibility., Objectives Rapid antigen testing (RAT) for coronavirus disease 2019 (COVID-19) has lower sensitivity but high accuracy during the early stage when compared to reverse transcription quantitative polymerase chain reaction (RT-qPCR). The aim of this study was to investigate the concordance between RAT and RT-qPCR results, and their prediction of disease transmission. Methods This single-center retrospective observational study of inpatients with COVID-19 was conducted from March 6 to June 14, 2020. Nasopharyngeal swabs were used to perform RAT and RT-qPCR. The primary endpoint was concordance between RAT and RT-qPCR results. The secondary endpoints were the factors causing disagreement in the results and the estimated transmissibility in RT-qPCR-positive patients with mild symptoms. Results Overall, 229 samples in viral transport medium (VTM) were obtained from 105 patients. The positive and negative concordance rates for VTM were 41% vs 99% (κ = 0.37) and 72% vs 100% (κ = 0.50) for samples collected on disease days 2–9. An increased body temperature (odds ratio 0.54) and absence of drugs with potential antiviral effect (odds ratio 0.48) yielded conflicting results. RAT was associated with the ability to end isolation (OR 0.11, 95% confidence interval 0.20–0.61). Conclusions RAT and RT-qPCR results were highly consistent for samples collected at the appropriate time and could be useful for inferring the possibility of transmissibility.

Introduction Influenza remains a clinically heavy burden worldwide. The objective of this study was to clarify clinical manifestations of severely ill patients infected with influenza. Methods The clinical data for patients who were severely ill with influenza, and required hospitalization were gathered and analyzed between November 2014 and August 2019 (5 influenza seasons) using an internet-surveillance system. Results A total of 924 patients were enrolled and analyzed. The median age was 78 years (IQR, 67–84), and the patients in the 2015–2016 season were significantly younger than those in other seasons. Pneumonia was the most common disease indicated as a cause for hospitalization, followed by a poor general condition and exacerbation of underlying respiratory diseases. Antiviral drugs were administered in 97.0% of the patients with peramivir being the most-frequently use antiviral. In-hospital death was recorded for 44 patients (4.8%). Multivariate analysis indicated that nursing home resident (OR: 6.554) and obesity (OR: 24.343) were independent predictors of in-hospital mortality. Conclusions Complications of influenza infection remain a heavy burden especially among the elderly. Continuous nationwide surveillance will be required to grasp the actual situation of influenza epidemics. (UMIN000015989).

Predicting the need for hospitalisation of patients with coronavirus disease 2019 (COVID-19) is important for preventing healthcare disruptions. This observational study aimed to use the COVID-19 Registry Japan (COVIREGI-JP) to develop a simple scoring system to predict respiratory failure due to COVID-19 using only underlying diseases and symptoms. A total of 6873 patients with COVID-19 admitted to Japanese medical institutions between 1 June 2020 and 2 December 2020 were included and divided into derivation and validation cohorts according to the date of admission. We used multivariable logistic regression analysis to create a simple risk score model, with respiratory failure as the outcome for young (18–39 years), middle-aged (40–64 years) and older (≥65 years) groups, using sex, age, body mass index, medical history and symptoms. The models selected for each age group were quite different. Areas under the receiver operating characteristic curves for the simple risk score model were 0.87, 0.79 and 0.80 for young, middle-aged and elderly derivation cohorts, and 0.81, 0.80 and 0.67 in the validation cohorts. Calibration of the model was good. The simple scoring system may be useful in the appropriate allocation of medical resources during the COVID-19 pandemic.

The aim of this study was to describe the clinical and radiological findings of COVID-19 patients with “silent hypoxia,” who had no dyspnea on admission even though their oximetry saturation was less than 94%. This retrospective cohort study included all COVID-19 patients (n = 270) at a large tertiary care hospital between January 31 and August 31, 2020. Clinical and radiological characteristics of patients who met our criteria of “silent hypoxia”, which included those who reported no dyspnea even though oximetry saturation was

The Ministry of Health, Labour and Welfare has published the Manual of Antimicrobial Stewardship (1st edition) in June 2017 to improve the prescribing practice of antimicrobials for immunocompetent adult and pediatric (both school-aged and older children) patients. Due to the increasing demand for further promoting outpatient antimicrobial stewardship, we conducted a literature and national guideline review to identify the area of need. The results of our review revealed a high antimicrobial prescription rate in the Japanese pediatric population. Furthermore, although the Japanese clinical guidelines/guidance covered the fields of almost all infectious diseases, no system exists to estimate the incidence and treatment patterns of important infectious diseases such as asymptomatic bacteriuria, skin and soft tissue infections, and dental practices in Japan. Therefore, addressing the issues of both establishing surveillance systems and the implementation of guidelines/guidance can be the next step to promote further outpatient antimicrobial stewardship.

Introduction Traveler's diarrhea (TD) is the most common illness among people traveling from resource-rich regions to resource-limited regions, although the precise microbial etiology is unclear in many cases. Methods Stool specimens were prospectively collected from 106 consecutive patients with TD and 16 healthy controls without TD, and were tested using both the FilmArray gastrointestinal panel (BioFire Diagnostics) and conventional stool cultures. Results The 106 patients had traveled to Southeast Asia (55 cases), South Asia (22 cases), Africa (11 cases), and East Asia (7 cases). Among the 106 specimens, 95 specimens (89.6%) were positive for pathogens during the FilmArray testing. The FilmArray testing also identified multiple pathogens in 75.8% of the specimens from positive cases. Conventional stool cultures only detected pathogens in 23.6% of the specimens. Conclusion The FilmArray gastrointestinal panel significantly improved the detection of enteropathogens and allowed for a rapid assessment of the TD's etiology. In addition, conventional stool cultures are likely to underestimate co-infections with multiple infectious pathogens.

In 2020, the COVID-19 pandemic has had unprecedented impacts on various aspects of the world. Each academic society has published a guide and/or guidelines on how to cope with COVID-19 separately. As the one and only nationwide association of academic societies that represent medical science in Japan, JMSF has decided to publish the expert opinion to help patients and care providers find specifically what they want. This expert opinion is a summary of recommendations by many academic societies and will be updated when necessary. Patients that each academic society targets differ even though they suffer from the same COVID-19, and recommendations can be different in a context-dependent manner. Readers are supposed to be flexible and adjustable when they use this expert opinion.

Microbiological diagnosis of coronavirus disease 2019 (COVID-19) is mainly performed through nucleic acid amplification test (NAAT) and antigen test. Although NAAT is the standard diagnostic test, its use is limited by insufficient laboratory resources and long turnaround time. Point-of-care NAAT tests have been introduced to address these shortcomings, but their varied sensitivity and resource constraints remain a concern. Antigen tests require fewer resources but have low sensitivity. Nevertheless, low-sensitivity tests may be useful depending on the situation. In contrast, in some clinical phases of COVID-19, high-sensitivity tests may provide false-negative results. Therefore, the right testing strategy is needed for an accurate diagnosis. In this review, the characteristics and clinical applications of microbiological tests available in Japan (NAAT, antigen test, and antibody test) are discussed. The clinical diagnosis of COVID-19 is slightly complicated, and cases in which the infection spreads from asymptomatic infected individuals are many; hence, laboratory diagnosis is essential to prevent further transmission.

Introduction A large number of antibiotics are used for the treatment of uncomplicated cystitis owing to its high morbidity. As the administration of antibiotics for uncomplicated cystitis may be considered an example of inappropriate use, outpatient antimicrobial stewardship for this condition is important. We evaluated the current pharmacoepidemiology trends for the treatment of uncomplicated cystitis in Japan to predict stewardship strategies. Methods This descriptive observational study analyzed data from an anonymized claims database of employees and their family members covered by the employer’s health insurance. We identified female outpatients diagnosed with acute cystitis (ICD-10 code N300) aged ≥15 years and extracted oral antibiotic prescription records between 2013 and 2016. We excluded prescriptions for >7 days. Results The most prescribed antibiotic category was fluoroquinolones (52.67%), followed by cephalosporins and penems (40.63%). Third-generation cephalosporins accounted for 90.91% of cephalosporin and penem prescriptions. The most common duration of antibiotic prescription was 5 days, except for first-generation cephalosporins, penem (7 days) and sulfamethoxazole and trimethoprim (3 days). Conclusion Fluoroquinolones and third-generation cephalosporins were prescribed to most uncomplicated cystitis cases in Japan. Although the lack of alternatives to quinolones and beta-lactams in Japan is an obstacle for antimicrobial stewardship for uncomplicated cystitis, promoting accurate diagnoses and establishing alternatives available in the Japanese market are important. Shortening the treatment duration is also an important strategy. Further research is needed on local antimicrobial resistance patterns to determine a fixed treatment strategy for uncomplicated cystitis.

Objective To evaluate the efficacy and safety of direct hemoperfusion using a polymyxin B‐immobilized polystyrene column (PMX‐DHP) in severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐positive pneumonia patients. Methods This study was a case series conducted at a designated infectious diseases hospital. Twelve SARS‐CoV‐2‐positive patients with partial pressure of arterial oxygen/percentage of inspired oxygen (P/F) ratio

Patterns of the use of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents in Japan might be influenced by the launch of new anti-MRSA agents, the publication of relevant guidelines, and the increase in the number of generic medicines. However, as anti-MRSA agents are included in multiple anatomical therapeutic chemical classifications, such as glycopeptides and aminoglycosides, the trends of the use of individual anti-MRSA agents remain unclear. Here, we aimed to clarify the trends of anti-MRSA agent use in Japan from 2006 to 2015 based on sales data. Total anti-MRSA agent use was found to have significantly increased from 2006 to 2015 (Pfor trend = 0.027, r = 0.00022). Individual trends for vancomycin (VCM), daptomycin, and linezolid (LZD) use showed significant increases, while those for arbekacin (ABK) and teicoplanin (TEIC) showed decreases. In addition, oral LZD use significantly increased, while there was no significant change in intravenous LZD use. The ratio of oral LZD use to total LZD use increased from 25.5% in 2006 to 39.9% in 2015. Meanwhile, TEIC and ABK use decreased, while VCM use increased, following the launch of generic medicines. These results might reflect the status of guideline compliance, the launch of new anti-MRSA agents, and the decline in the sales promotion of the original medicines. It is extremely important to investigate trends for the use of not only different antibiotic groups but also individual antibiotics to develop and implement antimicrobial resistance countermeasures.

S. pseudintermedius, recently identified as a novel Staphylococcus, causes a rare zoonotic infection that can be transmitted from dogs to humans. A 41-year-old man with atopic dermatitis receiving central parenteral nutrition through a totally implantable venous access port (TIVAP) after surgery for pseudomyxoma peritonei visited our outpatient clinic with a 2-day history of fever. The four strains isolated from the blood cultures from the TIVAP, dog's mouth, dog's nose, and dog's skin were all identified as S. pseudintermedius by partial heat shock protein (hsp60) gene sequencing. Initially, antibiotic-lock therapy with vancomycin (5 mg/mL in normal saline) through the catheter was administered concurrently with intravenous therapy. However, 52 days after the first discharge, he came back with a recurrent TIVAP infection with S. pseudintermedius bacteremia. He was successfully treated with intravenous antibiotic therapy after port removal and had no recurrence for 6 months without contact with the dog. The isolated strains were resistant to fluoroquinolone, which was consistent with trends in veterinary medicine in Japan. This case report raises awareness on S. pseudintermedius infections transmitted from domesticated dogs to patients with any implantable device, and the emerging resistance of S. pseudintermedius to current antibiotics.

We report detection of severe acute respiratory syndrome coronavirus 2 RNA in hemodialysis effluent from a patient in Japan with coronavirus disease and prolonged inflammation. Healthcare workers should observe strict standard and contact precautions and use appropriate personal protective equipment when handling hemodialysis circuitry from patients with diagnosed coronavirus disease.

The aim of this multicenter prospective study was to compare the sensitivity of 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) with that of 67Ga single photon emission computed tomography (SPECT) for the identification of the site of greatest importance for the final diagnosis of the cause of fever of unknown origin (FUO). The study participants consisted of patients with an axillary temperature ≥ 38.0 °C on ≥ 2 occasions within 1 week, with repeated episodes for ≥ 2 weeks prior to providing consent, and whose final diagnosis after undergoing specific examinations, including a chest-to-abdomen CT scan, was uncertain. All the patients underwent FDG-PET/CT imaging first, followed by 67Ga-SPECT imaging within 3 days. The results of the FDG-PET/CT and 67Ga-SPECT examinations were reviewed by the central image interpretation committee (CIIC), which was blinded to all other clinical information. The sensitivities of FDG-PET/CT and 67Ga-SPECT were then evaluated with regard to identifying the site of greatest importance for a final diagnosis of the cause of the fever as decided by the patient’s attending physician. The clinical impacts (four grades) of FDG-PET/CT and 67Ga-SPECT on the final diagnosis were evaluated. A total of 149 subjects were enrolled in this study between October 2014 and September 2017. No adverse events were identified among the enrolled subjects. Twenty-one subjects were excluded from the study because of deviations from the study protocol. Among the 128 remaining subjects, a final diagnosis of the disease leading to the appearance of FUO was made for 92 (71.9%) subjects. The final diagnoses in these 92 cases were classified into four groups: noninfectious inflammatory disease (52 cases); infectious disease (31 cases), malignancy (six cases); and other (three cases). These 92 subjects were eligible for inclusion in the study’s analysis, but one case did not meet the PET/CT image acquisition criteria; thus, PET/CT results were analyzed for 91 cases. According to the patient-based assessments, the sensitivity of FDG-PET/CT (45%, 95% CI 33.1–58.2%) was significantly higher than that for 67Ga-SPECT (25%, 95% CI 15.5–37.5%) (P = 0.0029). The clinical impact of FDG-PET/CT (91%) was also significantly higher than that for 67Ga-SPECT (57%, P

Background There is limited understanding of the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan. Methods This study included 2638 cases enrolled from 227 healthcare facilities that participated in the COVID-19 Registry Japan (COVIREGI-JP). The inclusion criteria for enrollment of a case in COVIREGI-JP are both (1) a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and (2) inpatient treatment at a healthcare facility. Results The median age of hospitalized patients with COVID-19 was 56 years (interquartile range [IQR], 40–71 years). More than half of cases were male (58.9%, 1542/2619). Nearly 60% of the cases had close contact to confirmed or suspected cases of COVID-19. The median duration of symptoms before admission was 7 days (IQR, 4–10 days). The most common comorbidities were hypertension (15%, 396/2638) and diabetes without complications (14.2%, 374/2638). The number of nonsevere cases (68.2%, n = 1798) was twice the number of severe cases (31.8%, n = 840) at admission. The respiratory support during hospitalization includes those who received no oxygen support (61.6%, 1623/2636) followed by those who received supplemental oxygen (29.9%, 788/2636) and invasive mechanical ventilation/extracorporeal membrane oxygenation (8.5%, 225/2636). Overall, 66.9% (1762/2634) of patients were discharged home, while 7.5% (197/2634) died. Conclusions We identified the clinical epidemiological features of COVID-19 in hospitalized patients in Japan. When compared with existing inpatient studies in other countries, these results demonstrated fewer comorbidities and a trend towards lower mortality.

In early 2020, Japan repatriated 566 nationals from China. Universal laboratory testing and 14-day monitoring of returnees detected 12 cases of severe acute respiratory syndrome coronavirus 2 infection; initial screening results were negative for 5. Common outcomes were remaining asymptomatic (n = 4) and pneumonia (n = 6). Overall, screening performed poorly.

Since the initial report of coronavirus disease (COVID-19) from the City of Wuhan, China in December 2019, there have been multiple cases globally. Reported here are 11 cases of COVID-19 at this hospital; all of the patients in question presented with relative bradycardia. The severity of the disease was classified into four grades. Of the patients studied, 3 with mild COVID-19 and 3 with moderate COVID-19 improved spontaneously. Lopinavir/ ritonavir was administered to 3 patients with severe COVID-19 and 2 with critical COVID-19. Both patients with critical COVID-19 required mechanical ventilation and extracorporeal membrane oxygenation. Both patients with critical COVID-19 had a higher fever that persisted for longer than patients with milder COVID-19. The respiratory status of patients with critical COVID-19 worsened rapidly 7 days after the onset of symptoms. Relative bradycardia may be useful in distinguishing between COVID-19 and bacterial community-acquired pneumonia. In patients who have had a fever for > 7 days, the condition might worsen suddenly.

Antimicrobial resistance (AMR) is currently a global health threat. Many countries have issued their own national action plans following the publication of the Global Action Plan on AMR by the World Health Organization. The government of Japan established its own National Action Plan on AMR in 2016; however, Japan's AMR countermeasures are still in the developmental stage. Recently, the AMR Clinical Reference Center (AMR CRC) in Japan estimated the disease burden of AMR in the form of number of deaths attributed to blood-stream infections caused by antimicrobial-resistant organisms. However, a more extensive and precise assessment is needed to understand the disease burden of AMR more clearly and enable us to compare these indicators with those published by other countries. Cassini and colleagues from the World Health Organization estimated the disease burden of AMR in the European Union as disability-adjusted life years (DALYs) in 2018. Their study could be considered an important milestone in terms of its thoroughness. If we hope to estimate the disease burden of AMR in a more precise manner, age-stratified patient data is needed in conjunction with a surveillance report. At present, AMR CRC is attempting to establish such data for examination at the national level - a challenging but worthwhile task.

Background Healthcare-associated infection (HAI) surveillance is useful for improved infection control. To understand the current HAI surveillance systems (HAISS) trend globally, a scoping review was performed. Materials and methods The search strategy included academic literature review, Google search, and questionnaires by the Embassies of Japan (registration number: UMIN000036035). Eighty-two high and 56 upper-middle income countries defined by country income classification for the World Bank were targeted. The following information was reviewed: name of the system, official website, languages used in the official website, foundation year, operating body, survey type (prevalence or incidence), reporting periodicity, mode of participation (mandatory or voluntary), targeted medical facilities, targeted HAIs and definitions, targeted antimicrobial resistant pathogens, and parameters. Online accessibility of the official websites of the SS was assessed through Google search. Results and conclusion Forty-two (30.4%) countries (35 [42.7%] high and 7 [12.5%] upper-middle income countries) had national HAISS. Most systems operated on a voluntary basis, monitored HAI incidence, and used the Center for Disease Control and Prevention definitions. Methicillin-resistant Staphylococcus aureus, surgical site infection, and catheter-related blood stream infection were most commonly monitored. Surveillance for device-associated infections was implemented mainly in intensive care units. Thirty-five countries had at least one official website on their systems, while 7 (20.0%) were identified in the top 30 Google search hits, in English. Approximately half of the academic articles identified through PubMed were from three English-speaking countries. The feasibility and benefits of standardization of the HAI surveillance criteria and efficient feedback methods are future considerations.

Background In 2018, the Japanese medical reimbursement system was revised to introduce a fee for the implementation of an antimicrobial stewardship (AS) fee for pediatric patients. The purpose of this study was to evaluate physicians’ prescription behavior following this revision. Methods We conducted a retrospective observational study from January 1, 2017 to September 30, 2018 of pediatric ( Results The frequency of antibiotic prescription decreased after AS fee implementation, regardless of whether the facility claimed the AS fee, but tended to be lower in facilities that claimed the fee. Additionally, the frequency of antibiotic prescription decreased in all age groups. Despite the reduced frequency of antibiotic prescription, consultation behavior did not change. Conclusions The AS fee system, which compensates physicians for limiting antibiotic prescriptions, helped to reduce unnecessary antibiotic prescription and is thus a potentially effective measure against antimicrobial resistance.

The coronavirus disease 2019 (COVID-19) has spread rapidly across the globe, presenting severe challenges to societies. Gaining a better understanding of patient demographics is essential to develop measures to counteract such spreading. In this context, from a viewpoint of occupational health, we analyzed the publicly available data on patients diagnosed with COVID-19 in Tokyo, which reported the highest number of cases in Japan. A total of 243 cases aged 20 years or older (excluding students) were recorded between January 14 and March 27, 2020. Of 233 cases excluding 10 cases of the first cluster, 162 were men and 176 were of working age (20 to 69 years). Of 203 cases with valid information on employment status, 151 (74%) were workers: 114 employees, 31 self-employed, and 6 medical staff. Of the working patients, the majority were male: 72% in employed and 87% in self-employed. These data suggest the importance of occupational health in controlling the spread of COVID-19. In April 2020, a state of emergency was declared in response to a surge in the number of cases, especially in metropolitan areas. A working schedule associated with lower risks of infection, including telework and flexible working hours, should be rigorously promoted to minimize human-to-human contact. Such policies, along with the implementation of effective measures to protect essential workers from infection, overwork, and stigma, would ensure the smooth running of society amidst the present crisis.

In Japan, there is no national surveillance study of Clostridioides (Clostridium) difficile infection (CDI), and details about the epidemiology and treatment status of CDI are unknown. Additionally, clinical practice guidelines (CPGs) for CDI are published by four different institutions. All CPGs recommend that the antimicrobials, vancomycin (VCM) and metronidazole (MNZ), should be selected according to disease severity. However, the trends for VCM and MNZ use in Japan remain unclear. Therefore, this study was aimed at clarifying the secular trends for VCM and MNZ use based on sales data from 2006 to 2015 and discussing its impact on CDI status and drug costs. This is the first study to clarify the antibiotic use trends for CDI treatment. We found that the total use increased over time (r = 0.0013, Pfor trend < 0.0001). While VCM use significantly decreased (r = -0.0003, Pfor trend = 0.0002), MNZ use increased (r = 0.0017, Pfor trend < 0.0001). These results show that although treatment for CDI was in line with CPGs, CDI incidence might be on an increasing trend. Additionally, despite the increased total use, the total drug costs decreased by 55% ($ 25 million) from 2006 to 2015. It was also surmised that CDI treatment in compliance with CPGs would lead to a reduction in drug costs. Hence, to understand the epidemiology of CDI, it is important to continuously investigate the use of drugs used for CDI therapy.

BackgroundWe aimed to assess the impact of regional heterogeneity on the severity of COVID-19 in Japan.MethodsWe included 27,865 cases registered between January 2020 and February 2021 in the COVID-19 Registry of Japan to examine the relationship between the National Early Warning Score (NEWS) of COVID-19 patients on the day of admission and the prefecture where the patients live. A hierarchical Bayesian model was used to examine the random effect of each prefecture in addition to the patients’ backgrounds. In addition, we compared the results of two models; one model included the number of beds secured for COVID-19 patients in each prefecture as one of the fixed effects, and the other model did not.ResultsThe results indicated that the prefecture had a substantial impact on the severity of COVID-19 on admission. Even when considering the effect of the number of beds separately, the heterogeneity caused by the random effect of each prefecture affected the severity of the case on admission.ConclusionsOur analysis revealed a possible association between regional heterogeneity and increased/decreased risk of severe COVID-19 infection on admission. This heterogeneity was derived not only from the number of beds secured in each prefecture but also from other factors.

We report three cases of tick-associated rash illness (TARI) in Japan that presented with erythema migrans (EM) after a tick bite. Although EM is considered to be a characteristic finding of Lyme disease, EM can occur even if patient is not affected by Lyme disease and if it is bitten by a tick. In Japan, the vector of Lyme disease pathogens are not distributed in most areas, and patients with EM are unlikely to have Lyme disease. We aim to raise TARI awareness among physicians.

BackgroundThe effect of heat-not-burn (HNB) tobacco product use and moderate alcohol drinking on immunogenicity to coronavirus disease (COVID-19) vaccines remain elusive. This study aimed to examine the association of tobacco product use and alcohol consumption with anti-SARS-CoV-2 spike IgG antibody titers after the BNT162b2 vaccine.MethodsParticipants were 3,457 fully vaccinated healthcare workers in the 4 national centers for advanced medical and research in Japan. Smoking status and alcohol consumption were assessed via a questionnaire, and anti-SARS-CoV-2 spike IgG titers were measured by chemiluminescent enzyme immunoassay using serum collected on the median of 64 days after the second vaccination. Multilevel linear regression models were used to estimate the geometric mean titers (GMT) and the ratios of means (RoM) between groups.ResultsOf vaccinated participants, 99.5% (3,440/3,457) were seropositive. Compared with never-smokers (GMT=119), IgG antibody titers were significantly lower among HNB tobacco users (including those who also smoked cigarettes) (GMT=105; RoM=0.88 [95%CI: 0.78–0.99]) and exclusive cigarettes smokers (GMT=96; RoM=0.81 [95%CI: 0.71–0.92]). Compared with non-drinkers of alcohol (GMT=123), alcohol drinkers consuming go/day (GMT=114; RoM=0.93 [95%CI: 0.88–0.98]), 1–1.9 go/day (GMT=105; RoM=0.85 [95%CI: 0.79–0.93]), and ≥2 go/day (GMT=101; RoM=0.82 [95%CI: 0.72–0.94]) had significantly lower antibody titers (P for trendgo/day of alcohol consumption, and then they gradually decreased.ConclusionsResults suggest that in addition to conventional cigarette smoking and heavy alcohol drinking, use of HNB tobacco products and moderate alcohol drinking may be predictors of lower immunological response to COVID-19 vaccine.Key MessagesEpidemiological evidence regarding the association of smoking status and alcohol drinking with COVID-19 vaccine-induced antibody levels is scarce.Users of heat-not-burn (HNB) tobacco products, as well as cigarettes smokers, had lower antibody titers than never-smokers.Not only high-dose but moderate-dose alcohol intake was also associated with decreased vaccine-induced antibody levels.HNB tobacco product use and moderate alcohol drinking may be modifiers of COVID-19 vaccine-induced immunogenicity.

BackgroundLong coronavirus disease (COVID) has been a social concern. Though patient characteristics associated with the development of long COVID are partially known, those associated with its persistence have not been identified. MethodsWe conducted a cross-sectional questionnaire survey of patients after COVID-19 recovery who visited the National Center for Global Health and Medicine between February 2020 and March 2021. Demographic and clinical data and data regarding the presence and duration of long COVID were obtained. We identified factors associated with the development and persistence of long COVID using multivariate logistic and linear regression analysis, respectively. ResultsWe analyzed 457 of 526 responses (response rate, 86.9%). The median age was 47 years, and 378 patients (84.4%) had mild disease in the acute phase. The number of patients with any symptoms after 6 and 12 months after onset or diagnosis were 120 (26.3%) and 40 (8.8%), respectively. Women were at risk for development of fatigue (odds ratio [OR]: 2.03, 95% confidence interval [CI]: 1.31-3.14), dysosmia (OR: 1.91, 95% CI: 1.24-2.93), dysgeusia (OR: 1.56, 95% CI: 1.02-2.39), and hair loss (OR: 3.00, 95% CI: 1.77-5.09) and for persistence of any symptoms (coefficient: 38.0, 95% CI: 13.3-62.8). Younger age and low body mass index were risk factors for developing dysosmia (OR: 0.96, 95% CI: 0.94-0.98 and OR: 0.94, 95% CI: 0.89-0.99, respectively) and dysgeusia (OR: 0.98, 95% CI: 0.96-1.00 and OR: 0.93, 95% CI: 0.88-0.98, respectively). ConclusionWe identified risk factors for the development and persistence of long COVID. Many patients suffer from long-term residual symptoms, even in mild cases.

Background Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2, has been a significant concern worldwide since its outbreak in December 2019. Various treatments are being researched and developed, and there are reports that dexamethasone has reduced the mortality rate and improved the clinical course of critically ill patients with COVID-19. In this study, we examined the clinical efficacy of corticosteroid therapy for patients with COVID-19 in our hospital during the first wave of infections. Methods We retrospectively reviewed the medical records of patients with COVID-19 who were treated with or without corticosteroid therapy at the National Center for Global Health and Medicine in Japan between February and April 2020. The primary outcome was improvement in the patients’ clinical course using a seven-category ordinal scale. We collected data on patient characteristics, treatment, and clinical course, and compared them between two groups: the steroid-using group and the non-steroid-using group. Results Between February and April 2020, 110 patients were diagnosed with COVID-19. Despite poor conditions during admission into the steroid group, there were no statistical differences in clinical course between both groups, as measured using the scale. There were no statistical differences between the two groups in the number of days to fever resolution or negative polymerase chain reaction results. Conclusions There was no difference in the clinical course between both groups. Because of the difference in background, corticosteroids may potentially make the clinical course of severely ill patients similar to that of mildly ill patients.

BackgroundWhile increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infections. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity.MethodsWe described incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2,473 fully vaccinated staff (BNT162b2) for breakthrough infection and selected three matched controls. We measured pre-infection neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the two groups.ResultsNo COVID-19 cases occurred 1–2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2–4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and had returned to work early. There was no measurable difference between cases and controls in pre-infection neutralizing antibody titers against the wild-type, Alpha, and Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type.ConclusionsPre-infection neutralizing antibody titers were not decreased among patients with breakthrough infection under the Delta variant rampage. The result points to the importance of infection control measures in the post-vaccination era, irrespective of immunogenicity profile.

Background Shortages of antimicrobials lead to treatment failures, increase medical costs, and accelerate the development of antimicrobial resistance. We evaluated the effects of the serious cefazolin shortage in 2019 in Japan on the sales, costs, and appropriate use of other antimicrobials. Methods We evaluated monthly defined daily doses/1000 inhabitants/day (DID) values of antimicrobial sales from January 2016 to December 2019 using wholesaler’s sales databases. Using 2016–2018 sales data, we generated a prediction model of DID in 2019 under the assumption that the cefazolin shortage did not occur. We then compared the predicted DID and actual DID. Cefazolin, government-recommended alternatives, and government-not-recommended broad-spectrum alternatives were assessed. Antimicrobial groups according to the AWaRe classification were also assessed to evaluate the effect on appropriate antimicrobial use. In addition, we evaluated changes in costs between 9 months before and after the cefazolin shortage. Results DID values of total antimicrobials increased sharply 1 month before the decrease in cefazolin. Actual DIDs were higher than predicted DIDs for ceftriaxone, flomoxef, clindamycin, cefotiam, piperacillin/tazobactam, and meropenem. Actual DID values were higher than the predicted DID values in the Watch group. The costs of antimicrobials between pre- and post- cefazolin shortage were unchanged. Conclusion The cefazolin shortage brought confusion to the antimicrobial market and led to a setback in the appropriate use of antimicrobials. Early recognition and structures for prompt reactions to antimicrobial shortages are needed. Moreover, development of a system to secure the supply of essential antimicrobials is required.

Background The empirical basis for a quantitative assessment of the disease burden imposed by long-COVID is currently scant. We aimed to inform the disease burden caused by long-COVID in Japan. Methods We conducted a cross sectional self-report questionnaire survey. The questionnaire was mailed to 526 eligible patients, who were recovered from acute COVID-19 in April 2021. Answers were classified into two groups; participants who have no symptom and those who have any ongoing prolonged symptoms that lasted longer than four weeks at the time of the survey. We estimated the average treatment effect (ATE) of ongoing prolonged symptoms on EQ-VAS and EQ-5D-3L questionnaire using inverse probability weighting. In addition to symptom prolongation, we investigated whether other factors (including demography, lifestyle, and acute severity) were associated with low EQ-VAS and EQ-5D-3L values, by multivariable linear regression. Results 349 participants reported no symptoms and 108 reported any symptoms at the time of the survey. The participants who reported any symptoms showed a lower average value on the EQ-VAS (69.9 vs 82.8, respectively) and on the EQ-5D-3L (0.85 vs 0.96, respectively) than those reporting no symptoms considering the ATE of ongoing prolonged symptoms. The ATE of ongoing prolonged symptoms on EQ-VAS was − 12.9 [95% CI − 15.9 to − 9.8], and on the EQ-5D-3L it was − 0.11 [95% CI − 0.13 to − 0.09], implying prolonged symptoms have a negative impact on patients’ EQ-VAS and EQ-5D-3L score. In multivariable linear regression, only having prolonged symptoms was associated with lower scores (− 11.7 [95% CI − 15.0 to − 8.5] for EQ-VAS and − 0.10 [95% CI − 0.13 to − 0.08] for EQ-5D-3L). Conclusions Due to their long duration, long-COVID symptoms represent a substantial disease burden expressed in impact on health-related quality of life.