Efficacy of cefiderocol, a novel siderophore cephalosporin, against multi-drug resistant Acinetobacter baumannii clinical isolates in Japan.

Multidrug-resistant Acinetobacter baumannii (MDRAB) is an important pathogen that causes nosocomial infections and is resistant to almost all antibiotics, including carbapenems. Cefiderocol is a novel siderophore cephalosporin that is active against a broad spectrum of Gram-negative bacteria. However, the susceptibility of MDRAB from Japan to cefiderocol has not yet been reported. In this study, we measured the minimum inhibitory concentrations (MICs) of antibiotics, including cefiderocol, against MDRAB clinical isolates collected during a nosocomial outbreak from 2009 to 2010 at Teikyo University Hospital in Japan. We found that all 10 MDRAB clinical isolates tested were susceptible to cefiderocol, with an MIC range of 0.12 to 1 µg/mL, all isolates were resistant to ampicillin-sulbactam, nine of the 10 isolates were susceptible to tigecycline, and all 10 isolates had an intermediate phenotype to colistin. DNA sequencing revealed that all strains harbored an OXA-51-like carbapenemase, one of the major causes of carbapenem resistance in A. baumannii in Japan. In conclusion, this study showed that susceptibility to cefiderocol of MDRAB clinical isolates in Japan was equivalent to that of colistin or tigecycline. Cefiderocol could be a possible choice for the treatment of MDRAB infections.

Virological outcomes of various first-line ART regimens in patients harbouring HIV-1 E157Q integrase polymorphism: a multicentre retrospective study.

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.

Optimizing Excitation Light for Accurate Rapid Bacterial Species Identification with Autofluorescence.

Rapid identification of bacterial species in patient samples is essential for the treatment of infectious diseases and the economics of health care. In this study, we investigated an algorithm to improve the accuracy of bacterial species identification with fluorescence spectroscopy based on autofluorescence from bacteria, and excitation wavelengths suitable for identification. The diagnostic accuracy of each algorithm for ten bacterial species was verified in a machine learning classifier algorithm. The three machine learning algorithms with the highest diagnostic accuracy, extra tree (ET), logistic regression (LR), and multilayer perceptron (MLP), were used to determine the number and wavelength of excitation wavelengths suitable for the diagnosis of bacterial species. The key excitation wavelengths for the diagnosis of bacterial species were 280 nm, 300 nm, 380 nm, and 480 nm, with 280 nm being the most important. The median diagnostic accuracy was equivalent to that of 200 excitation wavelengths when two excitation wavelengths were used for ET and LR, and three excitation wavelengths for MLP. These results demonstrate that there is an optimum wavelength range of excitation wavelengths required for spectroscopic measurement of bacterial autofluorescence for bacterial species identification, and that measurement of only a few wavelengths in this range is sufficient to achieve sufficient accuracy for diagnosis of bacterial species.

Changes in health and sleep quality after anti-retroviral treatment modification in Japanese people living with HIV.

BACKGROUND: Anti-retroviral treatment (ART) modification for treatment simplification is performed in virologically controlled people living with Human Immunodeficiency Virus (PLWH). However, studies on the impact of these stable treatment modifications on health-related quality of life (HRQoL) measured using patient-reported outcomes (PROs) in clinical practice are scarce; this was the focus of this study. METHODS: PLWH who visited Teikyo University Hospital between October 2019 and March 2021, and whose ART was changed to a newly recommended single-tablet regimen for treatment simplification, were included in the study. HRQoL and sleep quality were evaluated using the Short-Form (SF) 8 and Pittsburgh Sleep Quality Index (PSQI) global score, respectively, at two time points: before and after treatment modification. Comorbidities, duration of Human Immunodeficiency Virus diagnosis, ART initiation, ART regimens, and blood test data before and after treatment were assessed. The SF-8 was used to calculate the physical component summary (PCS) and mental component summary (MCS) scores. RESULTS: Forty-nine patients (all male) were included into the study. There was no change in the PCS score before and after ART modification. The MCS score significantly improved from 48.50 ± 6.56 to 50.76 ± 4.37 (p = 0.0159). Thirteen patients' ARTs were changed to dolutegravir/lamivudine. Their HRQoL and sleep quality changes were further analyzed. Their MCS and PSQI scores had improved significantly. Thirty patients' ARTs were changed to bictegravir/tenofovir alafenamide/emtricitabine; however, there were no significant changes in their HRQoL or PSQI score. CONCLUSION: ART modification for treatment simplification based on PROs may improve the HRQoL of PLWH.

Association of demographics, HCV co-infection, HIV-1 subtypes and genetic clustering with late HIV diagnosis: a retrospective analysis from the Japanese Drug Resistance HIV-1 Surveillance Network.

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.

Staphylococcus haemolyticus attenuates the antibacterial effect of teicoplanin via aggregates and biofilms.

OBJECTIVES: This study aimed to determine the inhibitory and bactericidal effects of teicoplanin (TEC) on TEC-susceptible Staphylococcus haemolyticus isolated from a patient with cancer in whom infection persisted despite TEC therapy. We also focused on the biofilm-forming ability of the isolate in vitro. METHODS: S. haemolyticus clinical isolate (strain 1369A) and its control strain, ATCC 29970 were cultured in Luria-Bertani (LB) broth with TEC. The inhibitory and bactericidal effects of TEC on planktonic, adherent, biofilm-dispersed, and biofilm-embedded cells of these strains were analyzed by using a biofilm formation/viability assay kit. The expression of biofilm-related genes was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Biofilm formation was determined by using scanning electron microscopy (SEM). RESULTS: The clinical isolate of S. haemolyticus had enhanced ability to bacterial growth, adherence, aggregation, and biofilm formation, thus the inhibitory and bactericidal effects of TEC on planktonic, adherent, biofilm-dispersed, and biofilm-embedded cells of the isolate were attenuated. Additionally, TEC induced cell aggregation, biofilm formation, and some biofilm-related gene expression of the isolate. CONCLUSION: The clinical isolate of S. haemolyticus is resistant to TEC treatment due to cell aggregation and biofilm formation.

Urine neutrophil gelatinase-associated lipocalin as a biomarker of adult pyelonephritis.

BACKGROUND: Pyelonephritis is a common infection at any age. Urine neutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker of acute renal failure, is related to pyelonephritis in pediatric patients, although the significance of this urine biomarker in adult patients are not clear. We investigated the relationship between urine NGAL of pyelonephritis and non-pyelonephritis. PATIENTS AND METHODS: We prospectively enrolled adult patients who were hospitalized due to pyelonephritis or non-pyelonephritis. Pyelonephritis was diagnosed in patients with fever and bacteriuria, with no any other infection focuses. Non-pyelonephritis was diagnosed in patients who had fever and another infection focus without bacteriuria. Urine samples were collected on days 0, 3 and 7. Urine NGAL levels were measured by ELISA. RESULTS: There were 35 patients in the pyelonephritis group and 19 patients in the non-pyelonephritis group. Urine NGAL level were significantly higher in the pyelonephritis group than the non-pyelonephritis group on day 0 (median 302 ng/mL vs 25 ng/mL, p = 0.006). The area under the receiver operating characteristic curve of NGAL was 0.78 (p = 0.006). Urine NGAL level had a specificity of 66.7% and sensitivity of 87.0% at the cut-off level of 250 ng/mL for diagnosing pyelonephritis. CONCLUSIONS: Urine NGAL level at the diagnosis of infection are elevated in adult patients with pyelonephritis, but not in those with non-pyelonephritis. Urine NGAL might be a supportive biomarker for the diagnosis of pyelonephritis.

Enterococcus casseliflavus Infection: A Review of Clinical Features and Treatment.

Some Enterococcus species, including Enterococcus faecalis and E. faecium, are increasingly becoming a common cause of nosocomial infections, accounting for the majority of human enterococcal infections, while other species, such as E. casseliflavus, have also been shown to be pathogenic to humans due to the increase in immunocompromised patients. These infections vary widely in their mode of transmission, symptoms, and other characteristics. Treatment is difficult in some cases because enterococci are resistant to numerous antimicrobial agents. Enterococcus faecalis and E. faecium are the best-known opportunistic pathogens, but others, including E. casseliflavus, occasionally cause opportunistic infections. This review summarizes the clinical features of E. casseliflavus infections and discusses effective therapeutic strategies. Bacteremia was the most common form of E. casseliflavus infections. Because E. casseliflavus carries the VanC gene, which confers resistance to vancomycin, less resistant drugs such as ampicillin were found more effective in treating the bacteremia. The second most common form of E. casseliflavus infection was trauma-induced endophthalmitis. This was commonly reported in active young to middle-aged patients. Vitreoretinal surgery and local or systemic administration of sensitive antimicrobial agents seem to be key to successful treatment. Other conditions such as infective endocarditis, meningitis, peritonitis, and pyothorax have also been reported as forms of E. casseliflavus infection. This review clarifies the clinical features of E. casseliflavus infection and provides important insights into its treatment.

Evaluation of an immunological assay for the identification of multiple carbapenemase-producing Gram-negative bacteria.

Carbapenemase-producing Gram-negative organisms (CPOs) frequently gain multidrug-resistant phenotypes and thereby limit the therapeutic options available. Colonisation and infection with CPOs are critical risks for mortality in clinical settings, especially in critical care medicine. Carbapenemase genes on plasmids have transferred to many Gram-negative species, and these species have spread, leading to global concern regarding antimicrobial resistance. A molecular rapid diagnostic test (mRDT) for CPOs is urgently required in critical care medicine. Here, we evaluated a rapid lateral flow immunoassay (LFIA) for CPOs isolated from patients at university hospitals, including intensive care units, and compared the results with those obtained using the multiplex polymerase chain reaction (PCR) method. NG-test CARBA 5 detected multiple carbapenemases, KPC, OXA-48, NDM, VIM, and IMP variants expressed in clinical isolates. Quick Chaser IMP detected IMP variants. The LFIAs exhibited 100% sensitivity and specificity relative to clinical isolates on agar plates. By contrast, the multiplex PCR method exhibited a limited ability to detect IMP-7-producing isolates not belonging to the IMP1 group, which resulted in 97% sensitivity and 100% specificity for IMP-producing isolates. Our results demonstrate that the LFIA is a useful mRDT to identify CPOs and has an advantage over the PCR method for both detection time and sensitivity to the IMP groups. LFIA could complement the nucleic acid amplification test used to identify CPOs. In conclusion, we evaluated sensitive and specific LFIAs capable of detecting carbapenemase production in Gram-negative bacteria. We anticipate that LFIAs will become a point-of-care test enabling rapid detection of carbapenemases in hospital settings, particularly in intensive care units.

First case of necrotizing fasciitis and bacteremia caused by Bifidobacteriumbreve.

We report the first case of necrotizing fasciitis and bacteremia caused by Bifidobacterium breve. Some Bifidobacterium breve strains are known as probiotic bacterium. However, it causes bacteremia in infants and immunocompromised patients. Our patient developed necrotizing fasciitis which was thought to have been infected from chronic diabetic foot ulcers. Bifidobacterium breve was isolated from the patient's blood and soft tissue sample. The patient underwent amputation and intravenous antibiotics administration.

Tigecycline Suppresses the Virulence Factors of Multidrug-Resistant Acinetobacter baumannii Allowing Human Neutrophils to Act.

Purpose: To determine the ability of human neutrophils to kill multidrug-resistant Acinetobacter baumannii (MDRAB) in the presence of tigecycline (TGC). Methods: Clinical isolates of MDRAB were cultured with human neutrophils and H2O2 in the presence of TGC. The numbers of viable bacteria, catalase activity, gene expression at the K locus of the MDRAB, reactive oxygen species (ROS) production, and granule exocytosis in human neutrophils were determined. Results: There was a time-dependent increase in the numbers of MDRAB after co-culturing with human neutrophils, whereas there was a significant decrease in the MDRAB numbers when co-cultured with both, human neutrophils and TGC for 6 h. The presence or absence of TGC did not affect total ROS production or the expression of CD11b, CD15, and CD63 on human neutrophils occurred when co-cultured with MDRAB. TGC significantly suppressed catalase activity and gene expression at the K locus of MDRAB, and significantly reduced the thickness of the capsule. Additionally, the bacterial viability of TGC-treated MDRAB cultured with H2O2 was lower than that without H2O2 after 6 h of culture. Conclusion: TGC significantly suppressed the expression of catalase and the capsule in MDRAB without adverse effects on neutrophil function, allowing human neutrophils to kill MDRAB. TGC is an effective antibiotic for treating MDRAB infections.

Association Between the Levels of Serum Free Testosterone and Lifestylerelated Diseases in People Living with HIV.

BACKGROUND: Recently, male hypogonadism was reported to be prevalent in people living with HIV (PLWH), even in cases diagnosed based on the serum free testosterone level (fTST). However, studies on the management of PLWH showing the relationship between male hypogonadism and lifestyle-associated diseases, are sparse. OBJECTIVE: This study evaluated the relationship between serum fTST levels and lifestyle-related diseases in virologically stable PLWH. METHODS: This study was a retrospective cohort single-center study. The study included HIVinfected men on antiretroviral therapy, with available data on serum fTST levels at Teikyo University Hospital between June 2020 and September 2020. Clinical information was collected at the time of fTST measurement. A simple regression analysis was used to identify continuous variables significantly associated with serum fTST levels. Student's t-test and Mann-Whitney U test were also used to identify non-continuous variables that were significantly correlated with serum fTST levels. RESULTS: Sixty male patients were evaluated. The median age was 47 (40-62) years. Low serum fTST levels were significantly associated with old age, low hemoglobin and total cholesterol levels, and high hemoglobin A1c levels. Non-use of INSTI and comorbid hypertension were also significantly associated with low serum fTST levels. CONCLUSION: Hypertension and the serum hemoglobin A1c level as a standard parameter for diabetes was significantly associated with low serum fTST levels in Japanese male PLWH. This study suggested that sex-hormone replacement therapy could be a preferred option for PLWH with low serum fTST levels to manage their long-term complications.

Relationship of sleep disorders with long-term complications and health-related quality of life in people with well-controlled human immunodeficiency virus.

ABSTRACT: Although sleep disorders are common in patients with human immunodeficiency virus (HIV) infection, they have not been adequately evaluated under currently advanced treatments, mainly with integrase strand transfer inhibitors. However, the relationship of sleep disorders with long-term complications and quality of life (QOL) status in patients infected with HIV is still poorly understood. Such associations are important in the management of outpatients with HIV. Hence, this study aimed to evaluate these associations.This cross-sectional observational study assessed the QOL changes of patients with HIV before and after the treatment regimen change. Male patients with well-controlled HIV who attended our hospital and changed HIV medications for reasons other than treatment failure between October 2019 and September 2021 were included. At the time of regimen change, sleep disorder status was assessed according to the Pittsburgh sleep quality index (PSQI), and health-related QOL (HRQOL) was assessed using the medical outcomes study 8-item short form health survey. In addition, we collected information on age, blood tests, and long-term comorbid conditions present during the evaluation. The HIV treatment regimen was also reviewed.Out of 45 male Japanese patients with HIV that were included in this study, 24 (53.3%) and 21 (46.7%) were classified into the sleep disorder group and nonsleep disorder group, respectively, according to their PSQI scores. The sleep disorder group had a significantly lower HRQOL mental component summary (P = .0222) than the nonsleep disorder group. The prevalence rates of hypertension, dyslipidemia, and diabetes mellitus were not significantly different between the 2 groups. In addition, a significant correlation was observed between PSQI scores and the HRQOL status (mental component summary, P = .0450; physical component summary, P = .0350).Sleep disorders remain common in patients with well-controlled HIV infection receiving current treatment. Sleep disorder is significantly associated with a low HRQOL in these patients. Hence, sleep status evaluation is necessary to improve HIV management.

The Clinical Effect of Seasonal Flu Vaccination on Health-Related Quality of Life.

PURPOSE: This study aimed to determine the clinical effect of seasonal flu vaccination in adult outpatients based on the effect on health-related quality of life (HRQOL). PATIENTS AND METHODS: We reviewed the clinical data of adult flu outpatients with mild symptoms who presented to the outpatient clinic of Teikyo University Hospital, Tokyo, Japan, from 2018 to 2020 winter season and were enrolled in the prospective observational study of the clinical efficacy of anti-flu agents (UMIN000034896). We evaluated influenza vaccination status, clinical symptoms, and the status of HRQOL as measured by Short Form-8® (SF-8®) at first visit. The SF-8® survey generated two-component summaries; a physical component summary and a mental component summary. RESULTS: The data of 79 patients were evaluated in this study. Of the 79 patients, 37 were vaccinated for influenza at least three weeks before contracting seasonal influenza. Not every patient needed to be hospitalized for treatment. There were no significant differences in clinical backgrounds between vaccinated patients and non-vaccinated patients. Univariate analysis showed influenza vaccination was significantly associated with higher scores on the physical component summary of HRQOL (p=0.0011). CONCLUSION: Influenza vaccinations would be clinically valuable for adult outpatients with seasonal flu and mild symptoms, because they can significantly inhibit the decrease of HRQOL due to influenza infection.

Effects of colistin and tigecycline on multidrug-resistant Acinetobacter baumannii biofilms: advantages and disadvantages of their combination.

We investigated the antimicrobial effects of colistin (CST) and tigecycline (TGC), either alone or in combination, on biofilm-dispersed and biofilm-embedded multidrug-resistant Acinetobacter baumannii (MDRAB) strains R1 and R2. The bacterial growth of biofilm-dispersed MDRAB was inhibited by CST or TGC. However, the inhibitory effects were attenuated by a combination of CST and low concentrations of TGC. The bactericidal effects of CST, but not TGC, were observed on biofilm-dispersed MDRAB. Notably, the bactericidal effects increased with a combination of CST and high concentrations of TGC, whereas they were attenuated with the combination of CST and low concentrations of TGC. Although biofilm formation by MDRAB decreased with increasing concentrations of CST or TGC, there was no complete disruption of the biofilms. Additionally, the biofilms increased with a combination of 1-2 µg/mL CST and TGC at 2 µg/mL and 2-4 µg/mL for strains R1 and R2, respectively. Biofilm-embedded MDRAB was eradicated with CST, but not TGC. Notably, the eradication effects increased with a combination of CST and high concentrations of TGC, whereas attenuation happened with the combination of CST and low concentrations of TGC. These results provide information on the combined effects of CST and TGC in the treatment of biofilm-associated MDRAB infection.

Osteomyelitis and pyomyositis due to Staphylococcus aureus in an osteomalacic adult with multiple fractures.

Multifocal osteomyelitis and pyomyositis usually arise from hematogenous dissemination, especially in patients with immunodeficiency, trauma, or injection drug abuse. We report the case of a 75-year-old man with multifocal pyomyositis and osteomyelitis, which were due to Staphylococcus aureus and were presumably related to multiple fractures. The patient had no risk factors for these hematogenous infections. He was treated with antibiotic therapy for about 80 days and drainage of the abscesses. Regarding the cause of his multipe fractures, he was found to have hypophosphatemia and eventually diagnosed as osteomalacia. To our best knowledge, this case was the first report on multifocal osteomyelitis and pyomyositis around the fracture sites in an osteomalacic adult. Osteomalacia should be considered as one of the differential diagnoses when osteoarticular infection with multifocal fractures is detected.

Magnetic resonance imaging changes in Asian people living with HIV.

BACKGROUND: Previous studies have reported a significant increase in age-related magnetic resonance imaging (MRI) changes in relatively younger people living with HIV (PLWH). However, there is little data available for brain changes in Asian PLWH. The data to differentiate HIV specific brain change from usual aging change was also sparse. To clarify them, we assessed the presence of leukoaraiosis and brain atrophic changes on MRI in young and middle-aged Japanese PLWH. METHODS: We reviewed data from well-controlled PLWH (age: 20-64 years) and coeval controls. We evaluated the presence of leukoaraiosis, as well as the extent of whole-brain grey matter (GM) atrophy and parahippocampal atrophy on brain MRI and determined between-group differences. Moreover, we evaluated the severity of parahippocampal atrophy based on the voxel-based specific regional analysis system for Alzheimer's disease. RESULTS: We enrolled 40 PLWH and 33 controls (median age: 40.15 and 48.00 years, respectively, [p = .3585]). Leukoaraiosis was significantly more prevalent among the PLWH (20 cases [50%]) than in the controls (9 cases [27.3%]) (univariate: p = .0483, multivariate: p = .0206). The extent of whole-brain GM atrophy was significantly greater in the PLWH than in the controls (univariate: p < .001, multivariate: p = .0012). Contrastingly, there was no significant between-group difference in the extent and severity of parahippocampal atrophy. CONCLUSIONS: Aging changes in the brain were significantly more prevalent in well-controlled Japanese PLWH. However, the process of atrophic brain changes might differ between HIV and one of age-related diseases, Alzheimer's disease.

Clinical Efficacy of Baloxavir Marboxil in the Treatment of Seasonal Influenza in Adult Patients: A Prospective Observational Study.

PURPOSE: Baloxavir marboxil, a recently developed antiviral drug, has been used to treat influenza in some countries including Japan. The aim of this study was to determine the clinical efficacy of the drug, which currently remains unclear. PATIENTS AND METHODS: Overall, 43 adult patients with seasonal influenza who visited the outpatient clinic of Teikyo University Hospital in Tokyo during the winter of 2018-2019 were enrolled. Of them, 14, 13, and 16 were prescribed baloxavir marboxil (40 or 80 mg once), oseltamivir (75 mg twice daily for 5 days), and laninamivir (40 mg once), respectively. A questionnaire was used to collect data about symptoms, and the Medical Outcome Study 8-Items Short Form Health Survey was employed to examine health-related quality-of-life (HRQOL) before and 7 days after admission. The main study endpoints included time to defervescence and the extent of improvement in HRQOL after treatment initiation. The data were analyzed with Welch's t-test and Fisher's exact test using StatFlex version 6. RESULTS: No significant differences in clinical background characteristics were observed among the patients. The mean time to defervescence in the baloxavir group (median [interquartile range]; 1.0 [1.0-2.0] days) was significantly shorter than that in the laninamivir group (2.0 [1.5-3.5] days; p=0.0322). No significant differences in mean time to defervescence, change in HRQOL, and time for resolution of other symptoms were observed between the groups. CONCLUSION: The results suggest that baloxavir marboxil has a better antipyretic effect than oseltamivir and laninamivir. Moreover, baloxavir marboxil might be clinically more valuable than the other two drugs owing to higher medication adherence among patients.

Exposure to low temperatures suppresses the production of B-cell activating factor via TLR3 in BEAS-2B cells.

Acute viral respiratory tract infections (RTIs) are commonly associated with cold weather; however, the mechanism behind this is still unclear. Secretory IgA (sIgA) mainly contributes to the immune response against pathogenic microorganisms in the respiratory tract. Certain pathogen-associated molecular patterns (PAMPs) induce the expression of B-cell activating factor (BAFF) in epithelial cells, macrophages, and dendritic cells. BAFF transforms B cells into plasma cells, which leads to the mass production of immunoglobulins, including IgA, on the mucosal epithelium. However, no studies have described the relationship between cold exposure and BAFF and/or sIgA in RTI. The aim of our study was to determine this relationship in vitro by investigating the effect of low temperature on BAFF production by BEAS-2B cells after the addition of toll-like receptor (TLR) ligands. We showed stimulation of polyinosinic:polycytidylic acid (poly I:C), which led BEAS-2B to produce interferon (IFN)-ß. IFN-ß itself induced BEAS-2B cells to produce BAFF. Janus kinase inhibitor I decreased the amount of BAFF produced in BEAS-2B cells upon stimulation with IFN-ß and poly I:C. Significantly less BAFF was produced post-poly I:C stimulation in low-temperature conditions than in normal-temperature conditions (mean ± SD: 41.2 ± 23.3 [33 °C] vs. 138.3 ± 7.1 pg/mL [37 °C], P = 0.05). However, the low-temperature condition itself was not cytotoxic. The stimulation of poly I:C produced BAFF from BEAS2B cells via IFN-ß production and the JAK/signal transducer and activator of transcription pathway played an important role in BAFF production in BEAS-2B cells. Cold exposure reduced BAFF production by BEAS2B cells after stimulation with the TLR3 ligand. Cold exposure may, therefore, suppress the production of BAFF, resulting in the inhibition of IgA secretion in the bronchial epithelium, which explains the increased frequency of RTIs in cold weather.

Prevalence of and Risk Factors for Low Free Testosterone Levels in Japanese Men with Well-controlled Human Immunodeficiency Virus Infection.

BACKGROUND: The change in the prevalence of hypogonadism with age in men with human immunodeficiency virus (HIV) infection is subject to debate. OBJECTIVE: To address this issue, we diagnosed hypogonadism based on serum levels of free testosterone (fTST) rather than total testosterone which is thought to be an inaccurate indicator. We also determined the relationship between age and fTST levels and identified risk factors for hypogonadism in men with HIV infection. METHODS: We retrospectively reviewed fTST levels and associated clinical factors in 71 wellcontrolled HIV-infected men who were treated at Teikyo University Hospital between April 2015 and March 2016 and who had data available on serum fTST levels, measured >6 months after starting antiretroviral therapy. fTST was measured using radioimmunoassay on blood samples collected in the morning. Risk factors for hypogonadism were identified using Welch's t-test and multiple regression analysis. RESULTS: The men had a mean (± standard deviation) age of 47.4 ± 13.6 years, and mean (± standard deviation) serum fTST level of 13.0 ± 6.1 pg/mL. Fifteen (21.1%) men had hypogonadism based on a fTST <8.5 pg/mL. Serum fTST levels significantly decreased with age (-0.216 pg/mL/year). Older age and low hemoglobin levels were identified as risk factors for hypogonadism. CONCLUSION: The men in the study experienced a more rapid decline in fTST levels with age than men in the general population (-0.161 pg/mL/year). Serum fTST levels in men with HIV infection should be monitored, especially in older men and those with low hemoglobin levels.