Disproportionality analysis of amenamevir-induced encephalopathy using the Japanese adverse drug event report database.

INTRODUCTION: Anti-herpesvirus drug-induced encephalopathy can complicate herpes zoster treatment; however, the association between the recently developed anti-herpesvirus drug amenamevir and encephalopathy development remains unknown. Determining the characteristics of amenamevir-induced encephalopathy is essential for potentially improving patient outcomes in the treatment of herpes zoster. The aim of this study is to identify the association between amenamevir treatment and encephalopathy and to determine the risk factors for amenamevir-induced encephalopathy via disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. METHOD: We conducted a retrospective observational study using anonymized data from the JADER database. Encephalopathy was defined according to the Standardized Medical Dictionary for Regulatory Activities Queries specific to "Noninfectious encephalopathy/delirium." Disproportionality analysis was used to calculate the reporting odds ratios (RORs) and 95 % confidence intervals (CIs) to assess associations between amenamevir and encephalopathy. Multivariable logistic regression considered age, gender, chronic kidney disease, and cytochrome P450 3A inhibitor use as potential risk factors. RESULTS: Out of 713,316 patients, 246 were prescribed amenamevir. The median onset of encephalopathy in these patients was 3 days. Disproportionality of encephalopathy was observed in patients treated with amenamevir (ROR, 3.44; 95 % CI, 2.48-4.78). Furthermore, multivariable logistic regression analysis suggested that an age of ≥70 years was associated with amenamevir-induced encephalopathy (ROR, 7.63; 95 % CI, 2.25-25.9). CONCLUSION: These results suggest that amenamevir treatment may be associated with encephalopathy, particularly in patients aged ≥70 years. Healthcare providers should be aware of this potential risk, especially in elderly patients, to prevent severe central nervous system complications.

Multiple Cardiovascular Diseases or Risk Factors Increase the Severity of Coronavirus Disease 2019.

BACKGROUND: This study aimed to determine whether disease severity varied according to whether coronavirus disease 2019 (COVID-19) patients had multiple or single cardiovascular diseases and risk factors (CVDRFs).Methods and Results:COVID-19 patients with single (n=281) or multiple (n=412) CVDRFs were included retrospectively. Multivariable logistic regression showed no significant difference in the risk of in-hospital death between groups, but patients with multiple CVDRFs had a significantly higher risk of acute respiratory distress syndrome (odds ratio: 1.75, 95% confidence interval: 1.09-2.81). CONCLUSIONS: COVID-19 patients with multiple CVDRFs have a higher risk of complications than those with a single CDVRF.

Factors associated with viral clearance periods from patients with COVID-19: A retrospective observational cohort study.

INTRODUCTION: Knowledge is limited on the virologic course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, particularly the time taken for viral clearance and the optimal time to discontinue isolation. This study aims to identify the clinical and demographic factors influencing the time taken for viral clearance in patients with COVID-19 to determine the optimal isolation period. METHODS: This two-center retrospective observational cohort study was conducted between March 1 and June 31, 2020. Patients with COVID-19, which was confirmed by real-time reverse transcription polymerase chain reaction, were included. Data were extracted from medical records. The positive duration, which was defined as the period from the day of symptom onset to the negative conversion day, was assessed using a generalized linear model. RESULTS: We included 63 patients. The mean positive duration was 20 days. The positive duration was significantly shorter for patients younger than 30 years of age and those between 30 and 60 years of age than for patients older than 60 years of age. We observed a more scattered distribution of the positive duration in older patients than in younger patients. CONCLUSIONS: Younger patients who recovered from COVID-19 took less time to clear SARS-CoV-2 than older patients; thus, a classification of the isolation periods based on age could be considered. A uniform viral clearance period for older patients may be difficult to determine because of biases such as underlying medical conditions. Further surveillance measures are recommended to determine the viral clearance time and the optimal isolation period.

Epidemiological trends of imported infectious diseases in Japan: Analysis of imported 2-year infectious disease registry data.

INTRODUCTION: The epidemiology of infectious diseases in Japan remains undefined despite the increasing tourism. GeoSentinel, an epidemiological surveillance system for reporting imported infectious diseases, has only two participating facilities in Japan. Although the number of infectious diseases is reported by the National Institute of Infectious Diseases, there is no detailed clinical information about these cases. Therefore, we established J-RIDA (Japan Registry for Infectious Diseases from Abroad) to clarify the status of imported infectious diseases in Japan and provide detailed information. METHODS: J-RIDA was started as a registry of imported infectious diseases. Case registration began in October 2017. Between October 2017 and September 2019, 15 medical institutions participated in this clinical study. The registry collected information about the patient's age, sex, nationality, chief complaint, consultation date, date of onset, whether visit was made to a travel clinic before travel, blood test results (if samples were collected), travel history, and final diagnosis. RESULTS: Of the 3046 cases included in this study, 46.7% to Southeast Asia, 13.0% to Africa, 13.7% to East Asia, 11.5% to South Asia, 7.5% to Europe, 3.8% to Central and South America, 4.6% to North America, 3.9% to Oceania, and 2.8% to Central and west Asia. More than 85% of chief complaints were fever and general symptoms, gastrointestinal symptoms, respiratory symptoms, or dermatologic problems. The most common diseases were travelers' diarrhea, animal bite, upper respiratory infection, influenza, and dengue fever. CONCLUSIONS: We summarized two-year cases registered in Japan's imported infectious disease registry. These results will significantly contribute to the epidemiology in Japan.

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19.

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.).

Spinal epidural abscess caused by non-typhoidal Salmonella: A case report and literature review.

Non-typhoidal Salmonellae are Gram negative bacilli commonly causing self-limiting gastroenteritis, representing a public health issue particularly in tropical countries. Further, the epidemiology of invasive infection by non-typhoidal Salmonella species is poorly understood. Herein, we presented a case of an unusual Salmonella enterica subsp. enterica serovar Altona epidural abscess that cause osteomyelitis and psoas abscess in a 52-year-old Japanese man. To ensure adequate antibiotics penetration into the epidural space, the patient was treated with antibiotics in doses similar to those administered for meningitis. We also reviewed the literature on patients who developed non-typhoidal Salmonella epidural abscesses, and we found 10 other previously reported cases. Salmonella Enteritidis was the pathogen most commonly identified, similar to gastroenteritis. More surveillance of non-typhoidal Salmonella serovars, especially in cases of severe infection, and investigation of antibiotic penetration rate into the epidural space are warranted to decide the best treatment course.

Absolute Method to Certify Quantum Yields of Photon Upconversion via Triplet-Triplet Annihilation.

For the consistent development of the field of photon upconversion via triplet-triplet annihilation (TTA-UC), it is pivotal to know the true quantum yield of TTA-UC emission. Although TTA-UC quantum yields have been determined by common relative measurements using quantum yield standards, there is still a discrepancy between the reported values even for the benchmark sensitizer-emitter pair of platinum(II) octaethylporphyrin (PtOEP) and 9,10-diphenylanthracene (DPA). Here, to resolve this situation, we show a method to obtain the absolute quantum yield of TTA-UC photoluminescence. The difficulty in obtaining absolute TTA-UC quantum yield by the integrating sphere measurement is to accurately calibrate the contribution of reabsorbed upconverted emission by triplet sensitizers. The reabsorption correction is successfully carried out by comparing sensitizer phosphorescence with and without the integrating sphere. An absolute TTA-UC quantum yield of the PtOEP-DPA pair is obtained as 36%, which shows a good agreement with the relative TTA-UC quantum yield. An absolute TTA-UC quantum yield of another red-to-blue TTA-UC pair, platinum(II) meso-tetraphenyltetrabenzoporphyrin (PtTPBP) and 2,5,8,11-tetra-tert-butylperylene (TTBP), is obtained as 27%. These absolute TTA-UC quantum yields can be used as certified values to check the measurement setup and sample condition for determining relative TTA-UC quantum yields in each laboratory.

Simple and Versatile Platform for Air-Tolerant Photon Upconverting Hydrogels by Biopolymer-Surfactant-Chromophore Co-assembly.

Exploration of triplet-triplet annihilation based photon upconversion (TTA-UC) in aqueous environments faces difficulty such as chromophores insolubility and deactivation of excited triplets by dissolved oxygen molecules. We propose a new strategy of biopolymer-surfactant-chromophore coassembly to overcome these issues. Air-stable TTA-UC with a high upconversion efficiency of 13.5% was achieved in hydrogel coassembled from gelatin, Triton X-100 and upconverting chromophores (triplet sensitizer and emitter). This is comparable to the highest UC efficiency observed to date for air-saturated aqueous UC systems. Moreover, this is the first example of air-stable TTA-UC in the form of hydrogels, widening the applicability of TTA-UC in biological applications. The keys are two-fold. First, gelatin and the surfactant self-assemble in water to give a developed hierarchical structure with hydrophobic domains which accommodate chromophores up to high concentrations. Second, thick hydrogen-bonding networks of gelatin backbone prevent O2 inflow to the hydrophobic interior, as evidenced by long acceptor triplet lifetime of 4.9 ms. Air-stable TTA-UC was also achieved for gelatin with other nonionic surfactants (Tween 80 and Pluronic f127) and Triton X-100 with other gelling biopolymers (sodium alginate and agarose), demonstrating the versatility of current strategy.

Donor-Acceptor-Collector Ternary Crystalline Films for Efficient Solid-State Photon Upconversion.

It is pivotal to achieve efficient triplet-triplet annihilation based photon upconversion (TTA-UC) in the solid-state for enhancing potentials of renewable energy production devices. However, the UC efficiency of solid materials is largely limited by low fluorescence quantum yields that originate from the aggregation of TTA-UC chromophores and also by severe back energy transfer from the acceptor singlet state to the singlet state of the triplet donor in the condensed state. In this work, to overcome these issues, we introduce a highly fluorescent singlet energy collector as the third component of donor-doped acceptor crystalline films, in which dual energy migration, i.e., triplet energy migration for TTA-UC and succeeding singlet energy migration for transferring energy to a collector, takes place. To demonstrate this scheme, a highly fluorescent singlet energy collector was added as the third component of donor-doped acceptor crystalline films. An anthracene-based acceptor containing alkyl chains and a carboxylic moiety is mixed with the triplet donor Pt(II) octaethylporphyrin (PtOEP) and the energy collector 2,5,8,11-tetra- tert-butylperylene (TTBP) in solution, and simple spin-coating of the mixed solution gives acceptor films of nanofibrous crystals homogeneously doped with PtOEP and TTBP. Interestingly, delocalized singlet excitons in acceptor crystals are found to diffuse effectively over the distance of ∼37 nm. Thanks to this high diffusivity, only 0.5 mol % of doped TTBP can harvest most of the singlet excitons, which successfully doubles the solid-state fluorescent quantum yield of acceptor/TTBP blend films to 76%. Furthermore, since the donor PtOEP and the collector TTBP are separately isolated in the nanofibrous acceptor crystals, the singlet back energy transfer from the collector to the donor is effectively avoided. Such efficient singlet energy collection and inhibited back energy transfer processes result in a large increase of UC efficiency up to 9.0%, offering rational design principles toward ultimately efficient solid-state upconverters.

Characteristics of health problems in returned overseas travelers at a tertiary teaching hospital in a suburban area in Japan.

Few studies have analyzed the characteristics of patients who develop physical disorders after overseas travel. We retrospectively reviewed the medical records of 183 patients who visited Nara Medical University Hospital from 2008 to 2016 because of physical problems after traveling abroad. The main travel destinations were Southeast Asia (n = 100), Africa (n = 27), and South Asia (n = 23). The main reasons for the travel were leisure (n = 96), business (n = 51), and volunteer work (n = 19). The most common final diagnosis was gastrointestinal disease (n = 72), followed by febrile disease (n = 59) and respiratory disease (n = 19). There were eight malaria cases, including one patient who was infected after <14 days of overseas travel. Additionally, 61 of 71 cases of travelers' diarrhea and 15 of 21 cases of dengue fever occurred after <14 days travel. 26 cases of vaccine preventable diseases, such as hepatitis A, typhoid fever, and influenza, were observed. Consequently, healthcare providers should notify Japanese overseas travelers that there is a non-negligible health risk inherent to short-term travel, while stressing on the importance of pre-travel medical consultation.

Molecular diagnosis and characterization of a culture-negative mycotic aneurysm due to ST54 Haemophilus influenzae type b with PBP 3 alterations.

Mycotic aneurysm is a rare but life-threatening disease that warrants an integrated therapeutic approach involving surgical intervention and prolonged antibiotic use. However, the causative organisms are often unidentified because antibiotics started empirically render blood and tissue cultures negative. Molecular diagnosis has been reported to be useful in such culture-negative cases. We report a case of a culture-negative mycotic aortic aneurysm due to Haemophilus influenzae, diagnosed by direct 16S rRNA polymerase chain reaction (PCR) and sequencing of the resected aneurysm tissue. PCR for serotype revealed type b, and PCR and sequencing of the ftsI gene revealed alterations in penicillin-binding protein 3, suggesting resistance to ampicillin. Multilocus sequence typing demonstrated that the isolate belonged to sequence type 54.

Molecularly Dispersed Donors in Acceptor Molecular Crystals for Photon Upconversion under Low Excitation Intensity.

For real-world applications of photon upconversion based on the triplet-triplet annihilation (TTA-UC), it is imperative to develop solid-state TTA-UC systems that work effectively under low excitation power comparable to solar irradiance. As an approach in this direction, aromatic crystals showing high triplet diffusivity are expected to serve as a useful platform. However, donor molecules inevitably tend to segregate from the host acceptor crystals, and this inhomogeneity results in the disappointing performance of crystalline state TTA-UC. In this work, a series of cast-film-forming acceptors was developed, which provide both regular acceptor alignment and soft domains of alkyl chains that accommodate donor molecules without segregation. A typical triplet sensitizer, PtII octaethylporphyrin (PtOEP), was dispersed in these acceptor crystals without aggregation. As a result, efficient triplet energy transfer from the donor to the acceptor and diffusion of triplet excitons among regularly aligned anthracene chromophores occurred. It resulted in TTA-UC emission at low excitation intensities, comparable to solar irradiance.

Chronic invasive sinus and intracerebral aspergillosis controlled by combination therapy with micafungin and a daily dose of 400 mg itraconazole oral solution.

Chronic invasive aspergillosis of the sinus is frequently fatal in the absence of early surgical and chemotherapeutic intervention because of its invasion of vascular tissue. We attempted to control a case of inoperable invasive aspergillosis of the sinus with micafungin and itraconazole oral solution. We prescribed a daily oral dose of 400 mg of itraconazole, which is twice the usual dose, and monitored the serum concentration of the drug. Finally, we were able to control the spread of the lesion. This case indicates that combination therapy with micafungin and a daily dose of 400 mg itraconazole oral solution is an alternative treatment strategy for inoperable invasive aspergillosis of the sinus.

[A Case of Disseminated Cutaneous Mycobacterium chelonae Infection Successfully Improved with Thermal Therapy].

A 54-year-old female with dermatomyositis treated with cyclosporine and methylprednisolone presented with multiple subcutaneous nodules on her upper and lower extremities on December 2011. The number of lesions gradually increased. She had a history of surgical intervention such as debridement, skin graft of right lower leg due to trauma and subsequent bacterial infection on August 2011. Culture from a skin lesion on June 2012 confirmed Mycobacterium chelonae, which was susceptible to clarithromycin (CAM). We started treatment with CAM, imipenem/cilastatin (IPM/CS) and tobramycin (TOB) for 2 weeks. Then CAM monotherapy was continued, however CAM was discontinued because of liver dysfunction. In September 2012 new nodular lesions were observed on the left arm and right leg. We administrated azithromycin, IPM/CS and TOB. Subcutaneous nodules were partially improved, but new lesions appeared on her right leg. A culture of skin lesion yielded M. chelonae, which was highly resistant to CAM and IPM/CS. Based on the sensitivity test, moxifloxacin was used. However, there was no significant improvement in her skin lesions, so we started thermal therapy on day 57 after admission. She showed an excellent response to thermal therapy, and there has been no recurrence.

Continuous ampicillin infusion as an alternative to intermittent infusion for adult inpatients: a case series.

Intravenous ampicillin has been extensively used for various kinds of infections for more than fifty years. This drug is administered intermittently, which can result in missed or delayed drug administration and sleep interruption that can have a negative impact on the quality of life during hospitalization. Continuous infusion may solve these concerns. We reviewed the cases of five patients who were treated with continuous ampicillin infusions in our hospital. The ampicillin serum concentrations were from 11.3 to 32.8 µg/mL, which was above the ampicillin MICs of the causative organisms, ≤0.06 to 4 µg/mL. Although the dosages given of ampicillin varied in each case, the serum concentrations showed a strong correlation with creatinine clearance (r(2) = 0.91). All the patients improved at the time of discharge, or transfer to another hospital, with no significant complications during the continuous infusion. Continuous ampicillin infusion could be a better alternative for frequent intermittent infusion for adult inpatients with infections due to ampicillin-susceptible organisms.

Infective endocarditis and meningitis due to Scedosporium prolificans in a renal transplant recipient.

Scedosporium prolificans is a ubiquitous filamentous fungi that may cause disseminated diseases in neutropenic patients with hematological malignancies. We report a fatal case of renal transplant recipient who developed both infective endocarditis and meningitis due to S. prolificans during treatment with micafungin and itraconazole for chronic necrotizing aspergillosis. Breakthrough Scedosporium infection should be considered among differential diagnosis of invasive fungal diseases in patients with renal transplant recipients receiving antifungal agents.

Financial Burden as a Potential Barrier to Vaccine Completion in Post-hematopoietic Stem Cell Transplant Patients in Japan.

Introduction The administration of routine vaccinations to patients following hematopoietic stem cell transplantation (HSCT) is highly recommended. However, studies examining reasons for not completing vaccination in post-HSCT patients are lacking. Method We reviewed the medical records of patients who sought vaccination following HSCT from January 2012 to December 2018 at the Center for Infectious Diseases, Nara Medical University. Results Information regarding patients' backgrounds, administered vaccines, and reasons for not administering recommended vaccines was collected for the study. Thirty-five patients (22 men and 13 women) with a median time from HSCT to the first visit of 25 months were enrolled. Vaccine coverage was highest for diphtheria, tetanus, and acellular pertussis (DTaP) at 89% (31 patients), followed by 23-valent pneumococcal, measles/rubella/mumps, and Japanese encephalitis at 71% (25 patients), 71% (25 patients), and 63% (22 persons), respectively. However, vaccine coverage for hepatitis B, 13-valent pneumococcal, and Hib was low at 26% (three patients), 11% (four patients), and 40% (14 patients), respectively. The reason for not completing the recommended vaccination series was not provided for most cases; however, the economic barrier was cited for all vaccines. Discussion This study identified several cases in Japan where individuals stopped completing post-HSCT vaccinations due to financial constraints. Larger-scale studies may be necessary in Japan in the future for further investigation.

Regional and temporal genotype profiling of Clostridioides difficile in a multi-institutional study in Japan.

Clostridioides difficile, a cause of healthcare-associated infections, poses a significant global health threat. This multi-institutional retrospective study focuses on epidemic dynamics, emphasizing minor and toxin-negative clinical isolates through high-resolution genotyping. The genotype of the C. difficile clinical isolates during 2005 to 2022 was gathered from 14 hospitals across Japan (N = 982). The total number of unique genotypes was 294. Some genotypes were identified in every hospital (cross-regional genotypes), while others were unique to a specific hospital or those in close geographic proximity (region-specific genotypes). Notably, a hospital located in a sparsely populated prefecture exhibited the highest prevalence of region-specific genotypes. The isolation rate of cross-regional genotypes positively correlated with the human mobility flow. A 6-month interval analysis at a university hospital from 2019 to 2021 revealed a temporal transition of the genotype dominance. The frequent isolation of identical genotypes over a brief timeframe did not always align with the current criteria for defining nosocomial outbreaks. This study highlights the presence of diverse indigenous C. difficile strains in regional environments. The cross-regional strains may have a higher competency to spread in the human community. The longitudinal analysis underscores the need for further investigation into potential nosocomial spread.

[Staphylococcal scalded skin syndrome associated with long-term catherter related infection in an adult].

Staphylococcal scalded skin syndrome (SSSS) is an extensive desquamative erythmatous condition caused by the Staphylococcus aureus exfoliative toxin. Although adult cases of SSSS are rare, the mortality rate is high. We report herein on a case of SSSS due to long-term catheter-related bloodstream infection caused by exfoliative toxin B, which produced methicillin-resistant Staphylococcus aureus. A 64-year-old man was admitted to our hospital with a high fever and generalized exfoliative dermatitis. He had an implanted port vascular access device in his left arm. The port was removed because it was thought to be the focus of infection. A Gram stain of the pus from the incision site revealed Gram positive coccus in clusters, and we administered intravenous vancomycin. MRSA was isolated from blood cultures and the pus, and histiology of a skin biopsy specimen from the exfoliation dermatitis showed epidermal detachment in the uppermost layer, which was consistent with SSSS. Although the patient developed infective endocarditis and septic embolisms, he eventually recovered. PCR of the MRSA was positive for exfoliative toxin B, and we finally diagnosed an adult case of SSSS due to exfoliative toxin B producing MRSA.