谷口 俊文

Abstract Numerous SARS-CoV-2 variant strains with altered characteristics have emerged since the onset of the COVID-19 pandemic. Remdesivir (RDV), a ribonucleotide analogue inhibitor of viral RNA polymerase, has become a valuable therapeutic agent. However, immunosuppressed hosts may respond inadequately to RDV and develop chronic persistent infections. A patient with respiratory failure caused by interstitial pneumonia, who had undergone transplantation of the left lung, developed COVID-19 caused by Omicron BA.5 strain with persistent chronic viral shedding, showing viral fusogenicity. Genome-wide sequencing analyses revealed the occurrence of several viral mutations after RDV treatment, followed by dynamic changes in the viral populations. The C799F mutation in nsp12 was found to play a pivotal role in conferring RDV resistance, preventing RDV-triphosphate from entering the active site of RNA-dependent RNA polymerase. The occurrence of diverse mutations is a characteristic of SARS-CoV-2, which mutates frequently. Herein, we describe the clinical case of an immunosuppressed host in whom inadequate treatment resulted in highly diverse SARS-CoV-2 mutations that threatened the patient’s health due to the development of drug-resistant variants.

We report the case of an 84-year-old man with a history of IgG4-related sclerosing cholangitis who was diagnosed with advanced esophageal cancer and underwent radiation and chemotherapy. An implantable central venous access port was placed for chemotherapy and total parenteral nutrition. The patient presented with a fever and received antimicrobial therapy for acute cholangitis but remained febrile, and subsequently, yeast was detected in the aerobic bottle of blood culture obtained from the central venous line. The yeast was identified as Wickerhamomyces anomalus. Liposomal amphotericin B was administered, and the central line access port was removed. After confirmation of negative blood cultures and 14 days post treatment, he underwent reinsertion of the central line access port. Due to persistent pain at the insertion site, fluconazole was added for an additional 14 days, and the patient was discharged and transferred to another hospital. Wickerhamomyces anomalus is a rare fungal infection with other synonyms including Pichia anomala, Hansenula anomala, and Candida pelliculosa. A literature review of 53 case reports of Wickerhamomyces anomalus, Pichia anomala, Hansenula anomala, and Candida pelliculosa was conducted, with a total of 211 cases reviewed. Fungemia was reported in 94% of cases, with central venous catheterization, parental feeding, low birth weight, and immunocompromised status identified as major risk factors. The majority of cases were pediatric, particularly neonatal, and there were reports of nosocomial infections causing outbreaks, with some cases involving the eye such as endophthalmitis or keratitis.

Abstract Background Integrase strand transfer inhibitors (INSTIs) are recommended as first-line ART for people living with HIV (PLWH) in most guidelines. The INSTI-resistance-associated mutation E157Q, a highly prevalent (2%–5%) polymorphism of the HIV-1 (human immunodeficiency virus type 1) integrase gene, has limited data on optimal first-line ART regimens. We assessed the virological outcomes of various first-line ART regimens in PLWH with E157Q in real-world settings. Methods A multicentre retrospective observational study was conducted on PLWH who underwent integrase genotypic drug-resistance testing before ART initiation between 2008 and 2019 and were found to have E157Q. Viral suppression (<50 copies/mL) rate at 24 and 48 weeks, time to viral suppression and time to viral rebound (≥100 copies/mL) were compared among the first-line ART regimens. Results E157Q was detected in 167 (4.1%) of 4043 ART-naïve PLWH. Among them, 144 had available clinical data after ART initiation with a median follow-up of 1888 days. Forty-five started protease inhibitors + 2 NRTIs (PI group), 33 started first-generation INSTI (raltegravir or elvitegravir/cobicistat) + 2 NRTIs (INSTI-1 group), 58 started once-daily second-generation INSTI (dolutegravir or bictegravir) + 2 NRTIs (INSTI-2 group) and eight started other regimens. In the multivariate analysis, the INSTI-2 group showed similar or favourable outcomes compared with the PI group for viral suppression rates, time to viral suppression and time to viral rebound. Two cases in the INSTI-1 group experienced virological failure. Conclusions The general guideline recommendation of second-generation INSTI-based first-line ART for most PLWH is also applicable to PLWH harbouring E157Q.

INTRODUCTION: Late diagnosis of the human immunodeficiency virus (HIV) is a major concern epidemiologically, socially and for national healthcare systems. Although the association of certain demographics with late HIV diagnosis has been reported in several studies, the association of other factors, including clinical and phylogenetic factors, remains unclear. In the present study, we conducted a nationwide analysis to explore the association of demographics, clinical factors, HIV-1 subtypes/circulating recombinant form (CRFs) and genetic clustering with late HIV diagnosis in Japan, where new infections mainly occur among young men who have sex with men (MSM) in urban areas. METHODS: Anonymized data on demographics, clinical factors and HIV genetic sequences from 39.8% of people newly diagnosed with HIV in Japan were collected by the Japanese Drug Resistance HIV-1 Surveillance Network from 2003 to 2019. Factors associated with late HIV diagnosis (defined as HIV diagnosis with a CD4 count <350 cells/μl) were identified using logistic regression. Clusters were identified by HIV-TRACE with a genetic distance threshold of 1.5%. RESULTS: Of the 9422 people newly diagnosed with HIV enrolled in the surveillance network between 2003 and 2019, 7752 individuals with available CD4 count at diagnosis were included. Late HIV diagnosis was observed in 5522 (71.2%) participants. The overall median CD4 count at diagnosis was 221 (IQR: 62-373) cells/μl. Variables independently associated with late HIV diagnosis included age (adjusted odds ratio [aOR] 2.21, 95% CI 1.88-2.59, ≥45 vs. ≤29 years), heterosexual transmission (aOR 1.34, 95% CI 1.11-1.62, vs. MSM), living outside of Tokyo (aOR 1.18, 95% CI 1.05-1.32), hepatitis C virus (HCV) co-infection (aOR 1.42, 95% CI 1.01-1.98) and not belonging to a cluster (aOR 1.30, 95% CI 1.12-1.51). CRF07_BC (aOR 0.34, 95% CI 0.18-0.65, vs. subtype B) was negatively associated with late HIV diagnosis. CONCLUSIONS: In addition to demographic factors, HCV co-infection, HIV-1 subtypes/CRFs and not belonging to a cluster were independently associated with late HIV diagnosis in Japan. These results imply the need for public health programmes aimed at the general population, including but not limited to key populations, to encourage HIV testing.

BACKGROUND: While global efforts have been made to prevent transmission of HIV, the epidemic persists. Men who have sex with men (MSM) are at high risk of infection. Despite evidence of its cost-effectiveness in other jurisdictions, pre-exposure prophylaxis (PrEP) for MSM is neither approved nor reimbursed in Japan. METHOD: The cost-effectiveness analysis compared the use of once daily PrEP versus no PrEP among MSM over a 30-year time horizon from a national healthcare perspective. Epidemiological estimates for each of the 47 prefectures informed the model. Costs included HIV/AIDS treatment, HIV and testing for sexually transmitted infections, monitoring tests and consults, and hospitalization costs. Analyses included health and cost outcomes, as well as the incremental cost-effectiveness ratio (ICER) reported as the cost per quality-adjusted life year (QALY) for all of Japan and each prefecture. Sensitivity analyses were performed. FINDINGS: The estimated proportion of HIV infections prevented with the use of PrEP ranged from 48% to 69% across Japan, over the time horizon. Cost savings due to lower monitoring costs and general medical costs were observed. Assuming 100% coverage, for Japan overall, daily use of PrEP costs less and was more effective; daily use of PrEP was cost-effective at a willingness to pay threshold of \5,000,000 per QALY in 32 of the 47 prefectures. Sensitivity analyses found that the ICER was most sensitive to the cost of PrEP. INTERPRETATION: Compared to no PrEP use, once daily PrEP is a cost-effective strategy in Japanese MSM, reducing the clinical and economic burden associated with HIV.

BACKGROUND: Tracking SARS-CoV-2 variants of concern (VOC) by genomic sequencing is time-consuming. The rapid screening of VOCs is necessary for clinical laboratories. In this study, we developed a rapid screening method based on multiplex RT-PCR by extended S-gene target failure (eSGTF), a false negative result caused by S-gene mutations. METHODS: Three S-gene target (SGT) regions (SGT1, codons 65-72; SGT2, codons 152-159; and SGT3, codons 370-377) and an N-gene region (for internal control) were detected in single-tube. Four types of VOC (Alpha, Delta, Omicron BA.1, and Omicron BA.2) are classified by positive/negative patterns of 3 S-gene regions (eSGTF pattern). RESULTS: The eSGTF patterns of VOCs were as follows (SGT1, SGT2, SGT3; P, positive; N, negative): Alpha, NPP; Delta, PNP; Omicron BA.1, NPN pattern; and Omicron BA.2, PPN. As compared with the S-gene sequencing, eSGTF patterns were identical to the specific VOCs (concordance rate = 96.7%, N = 206/213). Seven samples with discordant results had a minor mutation in the probe binding region. The epidemics of VOCs estimated by eSGTF patterns were similar to those in Japan. CONCLUSIONS: Multiplex RT-PCR and eSGTF patterns enable high-throughput screening of VOCs. It will be useful for the rapid determination of VOCs in clinical laboratories.

Symptoms of adverse reactions to vaccines evolve over time, but traditional studies have focused only on the frequency and intensity of symptoms. Here, we attempt to extract the dynamic changes in vaccine adverse reaction symptoms as a small number of interpretable components by using non-negative tensor factorization. We recruited healthcare workers who received two doses of the BNT162b2 mRNA COVID-19 vaccine at Chiba University Hospital and collected information on adverse reactions using a smartphone/web-based platform. We analyzed the adverse-reaction data after each dose obtained for 1,516 participants who received two doses of vaccine. The non-negative tensor factorization revealed four time-evolving components that represent typical temporal patterns of adverse reactions for both doses. These components were differently associated with background factors and post-vaccine antibody titers. These results demonstrate that complex adverse reactions against vaccines can be explained by a limited number of time-evolving components identified by tensor factorization.

INTRODUCTION: Vaccine effectiveness against SARS-CoV-2 infections decreases due to waning immunity, and booster vaccination was therefore introduced. We estimated the anti-spike antibody (AS-ab) recovery by booster vaccination and analyzed the risk factors for SARS-CoV-2 infections. METHODS: The subjects were health care workers (HCWs) in a Chiba University Hospital vaccination cohort. They had received two doses of vaccine (BNT162b2) and a booster vaccine (BNT162b2). We retrospectively analyzed AS-ab titers and watched out for SARS-CoV-2 infection for 90 days following booster vaccination. RESULTS: AS-ab titer eight months after two-dose vaccinations had decreased to as low as 587 U/mL (median, IQR (interquartile range) 360-896). AS-ab titer had then increased to 22471 U/mL (15761-32622) three weeks after booster vaccination. There were no significant differences among age groups. A total of 1708 HCWs were analyzed for SARS-CoV-2 infection, and 48 of them proved positive. SARS-CoV-2 infections in the booster-vaccinated and non-booster groups were 1.8% and 4.0%, respectively, and were not significant. However, when restricted to those 20-29 years old, SARS-CoV-2 infections in the booster-vaccinated and non-booster groups were 2.9% and 13.6%, respectively (p = 0.04). After multivariate logistic regression, COVID-19 wards (adjusted odds ratio (aOR):2.9, 95% confidence interval (CI) 1.5-5.6) and those aged 20-49 years (aOR:9.7, 95%CI 1.3-71.2) were risk factors for SARS-CoV-2 infection. CONCLUSIONS: Booster vaccination induced the recovery of AS-ab titers. Risk factors for SARS-CoV-2 infection were HCWs of COVID-19 wards and those aged 20-49 years. Increased vaccination coverage, together with implementing infection control, remains the primary means of preventing HCWs from SARS-CoV-2 infection.

BACKGROUND Although sotrovimab reduces the risk of hospitalization or death due to COVID-19, there have been few reports of its use in clinical practice. Particularly, information on the effectiveness of sotrovimab against the omicron variant of the virus is limited. We present 10 cases of COVID-19 treated with sotrovimab at our unit between December 2021 and February 2022. CASE REPORT The age of the patients ranged from 32 to 81 years (median: 40 years). The comorbidities included lung cancer, cardiovascular disease, chronic kidney disease requiring hemodialysis, and AIDS. Two of the patients were also organ recipients. Oxygen saturation (SpO2) was above 97% in all patients. None of the patients presented with pneumonia on admission. However, blood test results showed that all patients had risk factors for severe COVID-19 outcomes. The interval from symptom onset to sotrovimab administration and resolution ranged from 2 to 5 days (median: 2 days) and 2 to 15 days (median: 5 days), respectively. Only 1 patient developed pneumonia and was treated with remdesivir after sotrovimab administration. However, this patient did not require oxygen therapy. Although no moderate to severe adverse events were observed, a mild adverse event was observed in 1 patient. CONCLUSIONS Sotrovimab could be safe and effective in preventing progression of COVID-19 in patients with a variety of underlying diseases and who are at high risk of severe disease outcomes.

BACKGROUND: Coronavirus disease (COVID-19) has induced an urgent need to train medical students not only in infection prevention control but also in the treatment of infectious diseases, including COVID-19. This study evaluates the impact of simulated clinical practice with peer role-plays and a lecture on clinical education for COVID-19. METHODS: The sample for the study included 82 fourth- and fifth-year medical students undergoing clinical clerkship in respiratory medicine. They answered questionnaires and participated in semi-structured focus group interviews (FGIs) regarding the advantages of simulated clinical practice with peer role-plays and lectures on clinical education for COVID-19. RESULTS: A total of 75 students participated in the COVID-19 education program between January and November 2021. The responses to the questionnaire revealed that the satisfaction level of students with COVID-19 education was high. No significant change was found among students concerning fear of COVID-19 before and after the program. The degree of burden of handling information on COVID-19 reduced significantly, while the degree with respect to the use of personal protective equipment (PPE), including appropriate wearing and removing of PPE, and care of patients with confirmed COVID-19 while taking steps to prevent infection, exhibited a decreasing trend. Nine FGIs were conducted (n = 74). The advantages of simulated clinical practice were segregated into five categories (infection prevention control, educational methods, burden on healthcare providers, self-reflection, and fear of COVID-19); and that of the lecture were segregated into four categories (information literacy, knowledge of COVID-19, educational methods, and self-reflection). CONCLUSIONS: Simulated clinical practice with peer role-plays and the lecture pertaining to COVID-19 can prove to be efficient and safe methods for learning about COVID-19 infection and prevention control for medical students. They can reduce the burden of COVID-19 patients' care. Moreover, they can also provide an opportunity for self-reflection, realize the burden of medical care, and acquire relevant information.

INTRODUCTION: Genomic surveillance of the SARS-CoV-2 virus is important to assess transmissibility, disease severity, and vaccine effectiveness. The SARS-CoV-2 genome consists of approximately 30 kb single-stranded RNA that is too large to analyze the whole genome by Sanger sequencing. Thus, in this study, we performed Sanger sequencing following long-range RT-PCR of the entire SARS-CoV-2 S-gene and analyzed the mutational dynamics. METHODS: The 4 kb region, including the S-gene, was amplified by two-step long-range RT-PCR. Then, the entire S-gene sequence was determined by Sanger sequencing. The amino acid mutations were identified as compared with the reference SARS-CoV-2 genome. RESULTS: The S:D614G mutation was found in all samples. The R.1 variants were detected after January 2021. Alpha variants started to emerge in April 2021. Delta variants replaced Alpha in July 2021. Then, Omicron variants were detected after December 2021. These mutational dynamics in samples collected in the Chiba University Hospital were similar to those in Japan. CONCLUSION: The emergence of variants of concern (VOC) has been reported by the entire S-gene analysis. As the VOCs have unique mutational patterns of the S-gene region, analysis of the entire S-gene will be useful for molecular surveillance of the SARS-CoV-2 in clinical laboratories.

INTRODUCTION: The usefulness of smartphone-based application software as a way to manage adverse events (AEs) after vaccination is well known. The purpose of this study is to clarify the usefulness and precautions of employing a smartphone application for collecting AEs after the administration of Comirnaty®️. METHODS: Healthcare workers (HCWs) who were vaccinated with Comirnaty®️ were asked to register for the application software and to report AEs for 14 days after vaccination. AEs were self-reported according to severity. The software was set to output an alert in case of fever. RESULTS: The number of HCWs who received the first dose was 2,551, and 2,406 (94.3%) reported their vaccinations. 2,547 received the second dose, and 2,347 (92.1%) reported their vaccinations. With the first dose, the reporting rate stayed above 83.3% until the final day. On the other hand, that of the second dose decreased rapidly after 6 days. The most frequent symptom was "pain at injection site" (more than 70%). Severe AEs were 6.6% after the second dose, with 0.6% visiting a clinic. Many AEs peaked on the day after administration and disappeared within 1 week. There were few reports of fever. CONCLUSION: Smartphone applications can be used to collect information on AEs after vaccination. Application settings and dissemination are necessary to maintain the reporting rate of HCWs.

Legionella pneumophila (L. pneumophila) is responsible for most Legionnaire's disease cases diagnosed worldwide. The species includes 16 serogroups, but most Legionnaire's disease cases (85.7% in Europe, 87.0% in Japan) are caused by L. pneumophila serogroup 1. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) can be used to identify the L. pneumophila serogroup. In this study, we compared three sample preparation methods that are compatible with MALDI-TOF MS: the direct colony transfer method (DCTM), on-target extraction method (OTEM), and in-tube extraction method (ITEM). The aim was to improve the low identification rates for L. pneumophila, and establish and validate a simple, rapid and robust MALDI-TOF MS-based method for routine use in microbiological laboratories for assignment of L. pneumophila isolates to serogroups and identification of reliable peak biomarkers. Using ITEM, 100.0% (29/29) of hot spring water samples and clinical isolates were correctly identified at the species level. Augmented reference spectra correctly identified all 29 strains at the species level and 29 isolates at the serogroup level, displaying sensitivity, specificity and accuracy of 100.0% for serogroup assignment. MALDI-TOF MS is a relatively inexpensive method for assignment of L. pneumophila serogroups that can serve as a first-line tool for rapid prospective typing.

OBJECTIVES: This study aimed to determine antibody responses in healthcare workers who receive the BNT162b2 mRNA COVID-19 vaccine and identify factors that predict the response. METHODS: We recruited healthcare workers receiving the BNT162b2 mRNA COVID-19 vaccine at the Chiba University Hospital COVID-19 Vaccine Center. Blood samples were obtained before the 1st dose and after the 2nd dose vaccination, and serum antibody titers were determined using Elecsys® Anti-SARS-CoV-2S, an electrochemiluminescence immunoassay. We established a model to identify the baseline factors predicting post-vaccine antibody titers using univariate and multivariate linear regression analyses. RESULTS: Two thousand fifteen individuals (median age 37-year-old, 64.3% female) were enrolled in this study, of which 10 had a history of COVID-19. Before vaccination, 21 participants (1.1%) had a detectable antibody titer (≥0.4 U/mL) with a median titer of 35.9 U/mL (interquartile range [IQR] 7.8 - 65.7). After vaccination, serum anti-SARS-CoV-2S antibodies (≥0.4 U/mL) were detected in all 1774 participants who received the 2nd dose with a median titer of 2060.0 U/mL (IQR 1250.0 - 2650.0). Immunosuppressive medication (p < 0.001), age (p < 0.001), time from 2nd dose to sample collection (p < 0.001), glucocorticoids (p = 0.020), and drinking alcohol (p = 0.037) were identified as factors predicting lower antibody titers after vaccination, whereas previous COVID-19 (p < 0.001), female (p < 0.001), time between 2 doses (p < 0.001), and medication for allergy (p = 0.024) were identified as factors predicting higher serum antibody titers. CONCLUSIONS: Our data demonstrate that healthcare workers universally have good antibody responses to the BNT162b2 mRNA COVID-19 vaccine. The predictive factors identified in our study may help optimize the vaccination strategy.

Some coronavirus disease 2019 (COVID-19) patients develop rapidly progressive acute respiratory distress syndrome and require veno-venous extracorporeal membrane oxygenation (V-V ECMO). A previous study recommended the transfer of ECMO patients to ECMO centers. However, because of the pandemic, a limited number of ECMO centers are available for patient transfer. The safe long-distance interhospital transport of these patients is a concern. To minimize transportation time, helicopter use is a suitable choice. We report the first case of a COVID-19 patient on V-V ECMO, transferred to our ECMO center by helicopter. A 45-year-old man with rheumatoid arthritis history, treated with immunosuppressants, presented with fever and sore throat. He was diagnosed with COVID-19 following a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test result and was subsequently prescribed favipiravir. However, his respiratory failure progressively worsened. On day 10 of hospitalization at the previous hospital, he was intubated, and we received a request for ECMO transport on the next day. The ECMO team, who wore personal protective equipment (N95 respirators, gloves, gowns, and face shields), initiated V-V ECMO in the referring hospital and safely transported the patient by helicopter. The flight time was 7 min. He was admitted to the intensive care unit of our hospital and received tocilizumab. He was discharged on hospital day 31 with no significant sequelae. In this case report, we discuss important factors for the safe and appropriate interhospital transportation of COVID-19 patients on ECMO as well as staff and patient safety during helicopter transportation.

OBJECTIVE: Japan is an aging society, and pneumonia is the leading cause of death, but the suitability of antibiotics for treating community-acquired pneumonia (CAP) in Japan is not clear. The purpose of this study was to investigate antibacterial drugs for treating CAP according to age. MATERIALS AND METHODS: Using the Japanese national database from 2011 to 2014, we analyzed the usage of antibiotics for CAP according to age. RESULTS: The numbers of claim information were 9,386, and 70% of the patients were aged ≥ 75 years. Sulbactam/ampicillin (SBT/ABPC) or ceftriaxone (CTRX) was used in 60%, but broad-spectrum antibiotics, combination therapy, and anti-mycoplasma antibiotics were used in 15 - 28% of all age groups. The 30-day survival rate did not differ between SBT/ABPC or CTRX vs. others. There was no difference in 30-day mortality and risk in any group between the ages of 15 and 64 years. On the other hand, the use of anti-mycoplasma antibiotics reduced the 30-day mortality by 0.50 times (p < 0.01), and the use of two or more antibiotics increased the 30-day mortality by 1.45 times (p = 0.02) at age ≥ 65 years. CONCLUSION: Approximately half of the antibiotics used for CAP requiring hospitalization consisted of CTRX or SBT/ABPC as recommended by the Japanese Respiratory Society (JRS) guidelines. On the other hand, the usage of broad-spectrum antibiotics and combination therapy were relatively frequent at all ages, although their use does not always contribute to survival. Our data provide basic information for analyzing the outcome of pneumonia treatment in terms of an antimicrobial resistance action plan in Japan.

INTRODUCTION: Human immunodeficiency virus (HIV) infected individuals are at increased risk of developing active tuberculosis (TB). TB incidence remains higher than in non-HIV subjects after antiretroviral therapy (ART) initiation. This study was conducted to estimate the prevalence of positive IGRA, reflecting latent tuberculosis infection and/or a history of active TB, in HIV-infected individuals after ART initiation in Japan. METHODS: Two IGRAs (Interferon (IFN)-γ release assays), QuantiFERON®-TB Gold Plus (QFT-Plus) and T-Spot®.TB (TSPOT), were used. We also analyzed the TB associated risk factors for the IGRAs results and the role of CD4+ T-cells, CD8+ T-cells and NK cells for producing IFN-γ. We also analyzed the risk factors for positive IGRA responses and the role of CD4+ T-cells, CD8+ T-cells and NK cells for producing IFN-γ. RESULTS: One hundred eight-four subjects were prospectively enrolled. Median age was 49 years. The positivity rates of QFT-Plus and TSPOT were 7.6% [95%CI 4.6-12.4] and 2.7% [95%CI 1.2-6.2], respectively, with significant difference. TB-associated risk factors and NK cells ≥300/μL were selected as independently significant factors by multivariate logistic regression. The NK cell count revealed significant linear regression with IFN-γ production responding to TB-specific antigens. CONCLUSIONS: The prevalence of positive IGRAs was 2.7%-7.6%. QFT-Plus would be practical for a higher positivity rate and reflect TB risk factors. The innate immune system, referring to IFN-γ production, plays an important role in the immune response to TB-specific antigens even after initiating ART.

A 55-year-old Japanese man was hospitalized with the novel coronavirus disease 2019 (COVID-19). On the 14th day after the start of favipiravir administration, the patient developed a fever with a temperature of 38.1°C. His pulse rate also became elevated to 128 bpm, so relative bradycardia was not suspected. Since he was in good overall health and no concomitant symptoms and signs were apparent, we considered it to be drug fever due to favipiravir. After the completion of favipiravir treatment, the patient's temperature normalized within 24 hours. We herein report this case of drug fever caused by favipiravir.

INTRODUCTION: Community-acquired pneumonia (CAP) is one of the most common causes of pediatric infection requiring hospitalization. Antimicrobial resistance due to the inappropriate use poses a threat worldwide. Our objective is to analyze and optimize the trends of antibiotics used for pediatric inpatients with CAP in a claims database provided by the Ministry of Health, Labour and Welfare. METHODS: Our database randomly sampled 10% of the hospitalized patients every October from 2011 to 2014. Patients aged <15 years in whom antibiotic therapy was initiated within two days of admission were listed. Subsequently, we investigated the antibiotics administered on the first day of prescription. RESULTS: A total of 4,831 antibiotics were prescribed for 3,909 patients. Many patients aged ≤ five years were treated with β-lactams alone whereas many patients aged ≥ six years were treated with a single antibiotic, such as a macrolide, tetracycline, and quinolone, which covers atypical bacteria. Combination therapy was primarily used in children aged ≥ six years (nearly 30%); the main combination was a β-lactam and non-β-lactam covering atypical bacteria. Ampicillin-sulbactam was the most frequently prescribed β-lactam in children of all ages other than infants. Ampicillin, however, was most often prescribed in infants, but its usage rate was low at other ages. CONCLUSIONS: Antibiotics were appropriately prescribed and were similar to that recommended in the 2011 guidelines for pediatric inpatients with CAP. However, combination therapy was frequently prescribed in children aged ≥ six years. According to the revised guidelines in 2017, ampicillin should be used more frequently for patients hospitalized with CAP.

OBJECTIVE: On 7 April 2020, the Japanese government declared a state of emergency in response to the novel coronavirus outbreak. To estimate the impact of the declaration on regional cities with low numbers of COVID-19 cases, large-scale surveillance to capture the current epidemiological situation of COVID-19 was urgently conducted in this study. DESIGN: Cohort study. SETTING: Social networking service (SNS)-based online survey conducted in five prefectures of Japan: Tottori, Kagawa, Shimane, Tokushima and Okayama. PARTICIPANTS: 127 121 participants from the five prefectures surveyed between 24 March and 5 May 2020. INTERVENTIONS: An SNS-based healthcare system named COOPERA (COvid-19: Operation for Personalized Empowerment to Render smart prevention And care seeking) was launched. It asks questions regarding postcode, personal information, preventive actions, and current and past symptoms related to COVID-19. PRIMARY AND SECONDARY OUTCOME MEASURES: Empirical Bayes estimates of age-sex-standardised incidence rate (EBSIR) of symptoms and the spatial correlation between the number of those who reported having symptoms and the number of COVID-19 cases were examined to identify the geographical distribution of symptoms in the five prefectures. RESULTS: 97.8% of participants had no subjective symptoms. We identified several geographical clusters of fever with significant spatial correlation (r=0.67) with the number of confirmed COVID-19 cases, especially in the urban centres of prefectural capital cities. CONCLUSIONS: Given that there are still several high-risk areas measured by EBSIR, careful discussion on which areas should be reopened at the end of the state of emergency is urgently required using real-time SNS system to monitor the nationwide epidemic.

AIM: Sarcopenia is defined as a condition that combines decreased skeletal muscle mass with weakness or decreased physical function. It is well known that in older adults, the presence of sarcopenia is a risk of frailty, falls and physical dysfunction. Patients with Werner syndrome are characterized by visceral fat accumulation and thin limbs, but the prevalence of sarcopenia in patients with Werner syndrome has not been investigated. METHODS: A literature search was conducted using Werner syndrome and skeletal muscle as keywords. We also analyzed data from our 7 Werner syndrome patients. RESULTS: A literature search on the relationship between Werner syndrome and skeletal muscle yielded only one article reported from Japan. According to this paper, a decrease in skeletal muscle mass (appendicular skeletal muscle index) was observed in all 9 Werner syndromes investigated. On the other hand, in our 7 Werner syndrome patients, their appendicular skeletal muscle indexes were below the standard value except for one male patient who had continued resistance exercise. CONCLUSION: The decrease in skeletal muscle mass frequently occurs in patients with Werner syndrome. However, resistance exercise may prevent the appearance of sarcopenia and requires early intervention in patients with Werner syndrome. Geriatr Gerontol Int 2021; 21: 139-141.

AIMS: To evaluate the characteristics of diabetes associated with Werner syndrome. METHODS: A literature search was done with search term "Werner syndrome" and "Diabetes". RESULTS AND CONCLUSIONS: Prevalence of diabetes is extremely high in Werner syndrome. Diabetes associated with Werner syndrome is classified as "accompanied with other diseases and conditions and the one occurring mainly in association with other genetic syndromes." This type of diabetes is marked by accumulated visceral fat and high insulin resistance, despite low body mass index. Thiazolidine derivatives and metformin are effective for glycemic control. New antidiabetic drugs, such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, could be potentially beneficial for patients with Werner syndrome. Furthermore, the establishment of diet therapy as well as exercise therapy is warranted. Geriatr Gerontol Int 2021; 21: 142-145.

AIM: To provide guidelines on the diagnosis, treatment, and prevention of skin ulcers in Werner syndrome. METHODS: This article was based on literature from 1996, when WRN was identified as a gene responsible for Werner syndrome, and we evaluated several authentic clinical cases of genetically diagnosed patients. There were 63 patients with Werner syndrome in the Japanese reports retrieved from Medical Online between January 1996 and December 2017. There were 56 patients with Werner syndrome in English reports written by Japanese authors and retrieved from PubMed during the same period. RESULTS: Records on skin ulcers were found in 27 (43%) out of 63 patients and 22 (40%) out of 56 patients from the Japanese and English reports, respectively. The reported ulcers were often located at the distal one-third of the lower legs. There were 8 patients with callosities in the foot in the Japanese reports and 9 patients in the English reports. A skin ulcer in Werner syndrome is generally intractable. Weight-bearing ulcers or callosity should be critically assessed in surgical procedures because they have effects on patient pain and gait. By adopting a recently advanced technique to facilitate wound healing, the cases of ulcers that were difficult to treat and those requiring major operations can be closed with minimally invasive surgery. CONCLUSIONS: Skin ulcers in Werner syndrome are refractory, and they lead to reduced quality of life of patients. A callosity in Werner syndrome is an important therapeutic target for the prevention of ulcers. Geriatr Gerontol Int 2021; 21: 153-159.

For the purpose of examining the characteristics of dyslipidemia and fatty liver in patients with Werner syndrome in Japan in recent years, we searched all case reports of Japanese Werner syndrome reported on Medical Online and PubMed since 1996, and collected and examined the data and clinical features described in these reports. In addition, as there are few descriptions of treatment methods in these reports from Medical Online and PubMed, we analyzed 12 cases for which detailed data on treatment methods are available at Chiba University. Geriatr Gerontol Int 2021; 21: 133-138.

AIM: To clarify the diagnostic value of the calcification in the Achilles tendon for Werner syndrome. METHODS: Calcification of the Achilles tendon in the plain radiograph was investigated in 92 patients with Werner syndrome provided from the nationwide secondary survey in 2010. And the same investigation was performed for 2151 feet in 1853 patients without Werner syndrome, who underwent foot and ankle surgeries at the department of orthopaedic surgery in Nara Medical University from 2004 to 2015. RESULT AND CONCLUSION: Achilles tendon calcification was observed in 70 (76.1%) out of 92 patients with Werner syndrome, whereas that was observed only in 19 feet (0.88%) without Werner syndrome, accompanied by 1 to 4 calcified masses with a maximum diameter ranging from 9.7mm to 63.2mm. The frequency of Achilles tendon calcification in patients with Werner syndrome is far higher than that of patients without Werner syndrome. Achilles tendon calcification could be included in the diagnostic criteria for Werner syndrome. Geriatr Gerontol Int 2021; 21: 163-165.

Skin ulcers in Werner's syndrome often arise from hyperkeratotic lesions and trauma to pressure points such as the plantar region, and are more difficult to treat than wound healing in healthy individuals. Multiple factors contribute to the intractable skin ulcers in Werner's syndrome, including skin thinning, sclerosis, fatty tissue loss, impaired blood flow, calcification, and excessive pressure due to osteoarticular deformity. Treatment includes topical application of a keratolytic agent for keratosis around the ulcer. Treatment of ulcers is the same as for normal ulcers, and if the ulcer is associated with infection and necrotic tissue, surgical debridement with a scalpel or scissors should be performed as much as possible after washing with saline or mildly warm water or with an antibacterial agent. Topical medications that promote softening and debridement of the necrotic tissue are used with careful control of moisture in the wound. Topical agents that promote granulation should be used in wounds where necrotic tissue has been removed without infection. Dressings to maintain a moist environment in the wound may also be useful. If the wound does not improve with conservative treatment, surgical treatment should be considered. Geriatr Gerontol Int ••; ••: ••-•• Geriatr Gerontol Int 2020; ••: ••-••.

INTRODUCTION: Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Although most patients with COVID-19 develop asymptomatic or mild disease, some patients develop severe disease. The effectiveness of various therapeutic agents, including antiviral drugs, steroids, and anti-inflammatories for COVID-19, have been being confirmed. The effect of administering steroids in early disease is unclear. This study therefore aimed to evaluate the effectiveness and risk of exacerbation of steroids administered preceding antiviral drugs in patients with COVID-19 pneumonia. METHODS: This retrospective, single-center, observational study included consecutive patients with COVID-19 between March 2020 and March 2021. Patients were divided into a steroids-first group and antiviral-drugs-first group. Mortality, duration of hospitalization, incidence rate and duration of intensive care unit (ICU) admission, intubation, and extracorporeal membrane oxygenation (ECMO) induction of the two groups were compared. RESULTS: A total of 258 patients were admitted during the study period. After excluding patients who received symptomatic treatment only, who were taking immunosuppressive drugs, or who were administered antiviral drugs only, 68 patients were included in the analysis, 16 in the steroids-first group and 52 in the antiviral-drugs-first group. The rate of intubation, ICU admission and ECMO induction were significantly higher in the steroids-first group than in the antiviral-drugs-first group (81.3% vs. 33.3, p<0.001, 75.0% vs. 29.4%, p = 0.001, and 31.3% vs. 7.8%, p = 0.017, respectively). Furthermore, patients who received steroids within ten days after starting antiviral drugs had significantly lower rates of ICU admission, intubation, and ECMO induction. (81.3% vs. 42.9% p = 0.011, 75.0% vs. 37.1% p = 0.012, and 31.3% vs. 8.6% p = 0.039, respectively). CONCLUSIONS: Administering steroids prior to antiviral drugs soon after symptom onset can aggravate disease severity. When administration of steroids is considered soon after symptom onset, it may be safer to initiate antiviral drugs first.