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Takahiko Tanimoto,1,2 Yoshihiro Eriguchi,1 Tomonori Sato,1 Akiko Yonekawa,1 Noriko Miyake,1 Koichi Akashi,1 Nobuyuki Shimono3 1Department of Clinical Immunology and Rheumatology / Infectious Disease, Kyushu University Hospital, Fukuoka, Japan; 2Department of Infectious Diseases, Kagoshima Seikyo Hospital, Kagoshima, Japan; 3Center for the Study of Global Infection, Kyushu University Hospital, Fukuoka, JapanCorrespondence: Yoshihiro Eriguchi, Department of Clinical Immunology and Rheumatology / Infectious Disease, Kyushu University Hospital, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan, Tel +81 92-801-1011, Fax +81 92-862-8200, Email eriguchi.yoshihiro.145@m.kyushu-u.ac.jpAbstract: Platypnea-orthodeoxia syndrome (POS) is a rare disorder associated with coronavirus disease 2019 (COVID-19) pneumonia. However, POS may be underdiagnosed. We report the case of a 59-year-old female patient with POS complicated by pulmonary embolism in COVID-19. Imaging revealed ground-glass opacities predominantly in the lower lobes and a pulmonary embolus in the right upper lobe. She was diagnosed with POS due to marked postural discrepancies between supine and upright oxygen saturations and blood oxygenation. Intracardiac shunt, one of the etiologies of POS, was not detected by bubble contrast echocardiography, and postural de-saturation gradually improved with methylprednisolone and edoxaban administration. In our literature review, only 3 of the 16 patients with POS associated with COVID-19 had cardiac shunting, suggesting that moderate to severe COVID-19 causes POS without cardiac shunts. COVID-19-associated vasculopathy and lower lung lesion predominance in COVID-19 pneumonia may cause ventilation-perfusion mismatch due to gravitational shunting of blood into the poorly ventilated lower lungs in the upright position, which may ultimately cause POS. Hypoxemia impedes rehabilitation, whereas early initiation of supine positioning in bed, with knowledge of the pathophysiology of POS, may have a positive effect.Keywords: platypnea, orthodeoxia, COVID-19, ventilation-perfusion mismatch

Yong Chong,1 Shinji Shimoda,1 Noriko Miyake,1 Takatoshi Aoki,2 Yoshikiyo Ito,3 Tomohiko Kamimura,2 Nobuyuki Shimono4 1Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 2Department of Blood and Marrow Transplantation, Hara-Sanshin Hospital, Fukuoka, 3Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, 4Center for the Study of Global Infection, Kyushu University Hospital, Fukuoka, Japan Background: Routine fluoroquinolone prophylaxis in neutropenic patients with hematological malignancies is still controversial, because of antibiotic resistance concerns. The recovery of the fecal microbiota to the initial composition in patients receiving multiple courses of quinolone prophylaxis and repeated chemotherapy has not been evaluated. Methods: We prospectively examined the changes in the fecal bacterial composition before and after levofloxacin prophylaxis. A sequential observation of bacterial resistance in patients receiving multiple prophylactic courses was also conducted. Results: In this trial, 68 cases, including (35 with the first course and 33 with the second and subsequent courses) were registered. The disappearance of quinolone-susceptible (QS) Enterobacteriaceae and dominant emergence of quinolone-resistant (QR) coagulase negative staphylococci (CNS) and QR Enterococci were observed after the first prophylaxis. The detection of QS Enterobacteriaceae was recovered before the second and subsequent courses to a level of the initial composition (28/35 samples, 80.0% before the first course vs 23/33 samples, 69.7% before the second and subsequent courses, P=0.41). In contrast, the detection rate of QR CNS and Enterococci significantly increased at the second and subsequent courses, even before prophylaxis (8/35 samples, 22.9% before the first course vs 20/33 samples, 60.6% before the second and subsequent courses, P=0.003). The incomplete recovery of the initial bacterial composition was associated with a prophylactic interval of within 30 days. Of the patients receiving multiple prophylactic courses, six had QR Escherichia coli, including extended-spectrum β-lactamase (ESBL) producers, at the first course, and four (66.3%) of the six patients had persistent detection of QR E. coli at the second course. Conclusion: In patients receiving multiple courses of prophylactic quinolone, along with a common chemotherapy schedule, newly emergent resistant bacteria could be frequently persistent in their fecal flora. Keywords: febrile neutropenia, prophylaxis, fluoroquinolone, antibiotic resistance, fecal flora, chemotherapy

There is increasing interest in the role of T cell exhaustion and it is well known that the natural history of chronic hepatitis C virus infection ( HCV) is modulated by CD8+ T cell immunobiology. There are many pathways that alter the presence of exhaustive T cells and, in particular, they are functionally impaired by inhibitory receptors, such as programmed death-1 ( PD-1) and T cell immunoglobulin and mucin domain-containing protein 3 ( Tim-3). We obtained spleen, liver and peripheral blood (before and after splenectomy) lymphoid cells from 25 patients with HCV-related cirrhosis undergoing liver transplantation for end-stage disease or splenectomy for portal hypertension. In all samples we performed an extensive phenotypic study of exhaustion markers [ PD-1, Tim-3, interferon ( IFN)-γ) and their ligands ( PD-L1, PD-L2, galectin-9] in CD8+ T cell subpopulations (both total and HCV-specific) and in antigen-presenting cells ( APC; monocytes and dendritic cells). In the spleen, total and HCV-specific CD8+ T cells demonstrated enhanced markers of exhaustion, predominantly in the effector memory subpopulation. Similarly, splenic APC over-expressed inhibitory receptor ligands when compared to peripheral blood. Finally, when peripheral blood CD8+ T cells were compared before and after splenectomy, markers of exhaustion were reduced in splenic CD8+ T cells and APC. Our data in HCV-related cirrhosis suggest that CD8+ T cells in the spleen manifest a significantly higher exhaustion compared to peripheral blood and may thus contribute to the failure to control HCV. Counteracting this process may contribute to inducing an effective immune response to HCV. [ABSTRACT FROM AUTHOR]

Cholesterol embolization (CE) is a potentially serious complication associated with invasive arterial maneuvers, in which standard therapy has not been established. We experienced two cases of CE in patients with severe atherosclerosis whose renal function deteriorated within a few months after invasive arterial maneuvers. CE was confirmed either by renal biopsy (case 1) or skin biopsy (case 2). Oral administration of prednisolone at a daily dose of 30 mg (0.4 mg/kg) was effective to improve their renal function. Our observation suggests that corticosteroid therapy may be beneficial in some patients with CE. [ABSTRACT FROM AUTHOR]

Evaluating SARS-CoV-2 viral loads in nasopharyngeal (NP) and saliva samples, factors affecting viral loads, and the performance of rapid antigen testing (RAT) have not been comprehensively conducted during SARS-CoV-2 Omicron epidemic. This prospective study included outpatients enrolled during Omicron variant period in Japan. Paired NP swab and saliva samples were collected to measure viral loads by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The correlation between viral loads and clinical symptoms was examined. The performance of an immunochromatography-based RAT kit was also assessed. A total of 153 patients tested within 3 days of symptom onset were included. The mean viral load was 5.60 log 10 copies/test and 3.65 log 10 copies/test in NP and saliva samples, respectively, resulting in a significant difference ( P < 0.0001). Fever over 37°C (axillary temperature) and total number of symptoms other than fever were identified as independent factors positively correlated with the viral loads in both NP and saliva samples. RAT sensitivity using NP and saliva samples was 92% and 68%, respectively, using positive RT-qPCR results as the reference. The sensitivity of RAT using NP and saliva samples was significantly higher in patients with fever ≥37°C and/or at least one symptom than in those with fever <37°C and/or no symptoms (97% vs 83% in NP swabs; 80% vs 50% in saliva). Distinct symptoms, including fever ≥37°C, may reflect high Omicron variant viral loads. Rapid antigen testing, not only using nasopharyngeal swabs but also using saliva, would be useful for COVID-19 diagnosis as point-of-care testing, particularly for symptomatic patients., Importance: We examined nasopharyngeal and salivary viral loads using samples collected from outpatients with SARS-CoV-2 infection during the Omicron epidemic in Japan and explored the outpatient factors correlated with viral loads. In addition, we evaluated the performance of an authorized rapid antigen testing (RAT) kit using nasopharyngeal and saliva samples with RT-PCR testing as the reference. Intriguingly, a correlation between fever and other symptoms and SARS-CoV-2 viral loads in nasopharyngeal and saliva samples was observed based on one COVID-19 outpatient visit. RAT sensitivity was influenced by viral loads. Nevertheless, nasopharyngeal RAT is considered useful for SARS-CoV-2 point-of-care diagnosis. In patients with distinct symptoms, including high-grade fever, salivary RAT could be a practical diagnostic tool because of the higher estimated viral loads. After the Omicron epidemic, outpatients with mild COVID-19 have become the main focus of diagnosis and treatment. Our study provides valuable information regarding the point-of-care diagnosis of these patients.

Background: Efforts to promote antimicrobial stewardship aimed at reducing antimicrobial resistance are necessary regardless of hospital scale owing to delays in new antimicrobial development. We aimed to evaluate the effects of pharmacist-driven interventions on broad-spectrum antimicrobial usage and the prognosis of patients with bacteremia in a medium-sized hospital lacking infectious disease physicians and a microbiology laboratory., Methods: This single-center, retrospective, pragmatic, quasi-experimental study was conducted to compare pre- and post-intervention effects at Saiseikai Futsukaichi Hospital. We analyzed the days of therapy (DOT) for carbapenems and days of antibiotic spectrum coverage (DASC) for antimicrobials using an interrupted time series analysis. Cox proportional hazards analysis was performed to assess 30-day mortality using propensity score and inverse probability of treatment weighting in patients with bacteremia., Results: Pharmacist-driven interventions significantly reduced the DOT (incidence rate ratio [IRR]: 0.53, 95 % confidence intervals [CI]: 0.33-0.81, p = 0.003) and DASC (IRR: 0.87, 95 % CI: 0.78-0.97, p = 0.016). The 30-day mortality due to bacteremia did not significantly differ between pre- and post-intervention in all patients (adjusted hazard ratio [HR]: 0.92, 95 % CI: 0.56-1.51, p = 0.74). Conversely, pharmacist-driven interventions significantly reduced the 30-day mortality owing to bacteremia with Pitt bacteremia score (PBS) ≥4 (adjusted HR: 0.52, 95 % CI: 0.28-0.99, p = 0.047)., Conclusions: Pharmacist-driven interventions may represent a valuable approach for optimizing antimicrobial treatment and improving prognosis, especially in patients with PBS ≥4, which will potentially benefit patients in similar healthcare environments facing challenges related to antimicrobial stewardship and patient prognosis., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: The prognosis of immunocompromised individuals with COVID-19 remains a significant concern. Information regarding the clinical and virological characteristics of immunocompromised patients infected with SARS-CoV-2 during the Omicron variant period is limited., Methods: Medical records of patients admitted to our hospital with COVID-19 during the Omicron (BA.1-5) epidemic were retrospectively reviewed. Clinical, virological (nasopharyngeal swabs and blood), and serological data were compared between immunocompromised patients receiving immunosuppressive medications (calcineurin inhibitors, mycophenolate mofetil, or steroids) and control patients not receiving immunosuppressive medications., Results: Twenty-eight immunocompromised patients (25 transplant recipients) and 26 control patients were included. Fourteen of the immunocompromised patients (50%) received monoclonal antibodies. The immunocompromised group included 15 mild/moderate (53.6%), 10 severe (35.7%), and three critical (10.7%) disease severities. The mortality rate due to COVID-19 during hospitalization was 3.6% (1/28) in the immunocompromised group, with no difference between the two groups. Three cases of re-exacerbation after discharge occurred in the immunocompromised group and none in the control group. Linear regression based on nasopharyngeal real-time-PCR cycle threshold (Ct) values according to the time since symptom onset showed markedly slower viral clearance in the immunocompromised group than in the control group (P slope  = 0.078). In the immunocompromised group, patients who received monoclonal antibodies showed faster viral clearance than those who did not receive monoclonal antibodies. The convalescent anti-spike IgG titers were comparable to those in the control group in patients who received monoclonal antibodies and significantly lower than those in the control patients in patients who did not receive monoclonal antibodies (P < 0.001). The prevalence of viremia at onset was significantly higher in the immunocompromised group than in the control group (35.7%, [10/28] vs. 11.5%, [3/26]; P = 0.003). All three patients with critical disease severity in the immunocompromised group exhibited viremia, one of whom died. All three patients with viremia in the control group were critical, of whom two died., Conclusions: Immunocompromised individuals receiving immunosuppressive medications are more likely to show delayed post-infection SARS-CoV-2 viral clearance and the development of viremia, potentially resulting in worsening severity and outcomes, especially in viremic patients, even during the Omicron epidemic., (© 2024. The Author(s).)

Introduction: People living with human immunodeficiency virus (PLWH) have higher mortality rates from COVID-19 than those without HIV. Additionally, the seroconversion rate of antibodies following a second dose of SARS-CoV-2 vaccine is lower in PLWH than non-infected individuals, indicating the need for booster vaccination. Here, we evaluated the humoral and cellular immune responses to booster SARS-CoV-2 vaccination in PLWH., Methods: The dynamics of anti-spike IgG titers and antigen-specific interferon (IFN)-γ levels to SARS-CoV-2 vaccination were assessed over a 6-month period following a third vaccination of 34 PLWH., Results: Antibody titers for humoral immunity were 50 % lower at 24 weeks post-vaccination than those at 12 weeks. However, those at 24 weeks after the booster vaccination were approximately eight times higher than before. Regarding cellular immunity, IFN-γ levels at 24 weeks after the third vaccination were lower than those at 12 weeks, but nearly 90 % of participants maintained a cut-off value of ≥0.15 IU/mL. A comparison between two groups with CD4 + T lymphocytes counts of <500/μL or ≥500/μL exhibited no statistically significant differences in antibody or IFN-γ levels. However, in the group with CD4 + T lymphocyte counts of <500/μL, the rate of IFN-γ above the cut-off value at 24 weeks after the booster vaccination was lower than that of ≥500/μL., Conclusion: An immune response is expected in PLWH given successful antiretroviral therapy with booster SARS-CoV-2 vaccination. However, caution should be exercised for cases with low CD4 + T-lymphocyte counts. (240/250 words)., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: SARS-CoV-2 mRNA vaccination, recognized for high immunogenicity, frequently induces adverse reactions, especially fever. We previously reported a correlation between post-vaccination fever and specific antibody responses to the primary series and first booster. We herein report changes in adverse reactions and the correlation between post-vaccination fever and antibody responses across successive vaccinations, from monovalent to bivalent mRNA vaccines., Methods: This cohort study was conducted at a Japanese hospital to investigate adverse reactions to the monovalent primary, first booster, and BA.4/5 bivalent BNT162b2 vaccinations. Local and systemic reactions were reported through a self-reporting diary after each dose. The spike-specific IgG titers were measured following each vaccination., Results: Across 727 vaccinations in the vaccine series, the bivalent booster induced fewer adverse reactions than earlier doses. Fever ≥ 38.0 °C was significantly less frequent in the bivalent booster (12.3 %) compared to the primary series and monovalent booster (22.0 %, 26.2 %, p < 0.001). Reaction severity was also reduced in the bivalent booster. In the analysis of 70 participants with complete data for all doses, post-vaccination fever ≥ 38.0 °C exhibited the highest relative risk (RR) among all solicited reactions throughout the vaccine series (RR: 5.24 [95 % CI: 2.40-11.42] for monovalent and 6.24 [95 % CI: 2.14-18.15] for bivalent). The frequency of fever ≥ 38.0 °C after all doses was 8.6 % (6/70), with no fever ≥ 39.0 °C across all vaccinations. A high-grade post-vaccination fever was correlated with higher IgG titers, with multivariate analyses confirming this correlation as independent for each dose and unaffected by previous post-vaccination fever., Conclusions: The bivalent mRNA vaccine booster showed fewer and milder adverse reactions than the monovalent doses. Although vaccinees with a history of post-vaccination fever were more likely to experience fever after a subsequent dose, such recurrences were infrequent. A correlation between post-vaccination fever and increased IgG titers was identified for each vaccination, irrespective of post-vaccination fever history., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objectives: To evaluate the long-term impact of immunosuppressive therapeutic agents on antibody response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with autoimmune rheumatic diseases (AIRD) in order to propose a strategy for annual vaccination., Methods: This prospective multicentre cohort study evaluated the humoral response to second and third BNT162b2 and/or mRNA-1273 vaccines in 382 Japanese AIRD patients classified into 12 different medication groups and in 326 healthy controls (HCs). The third vaccination was administered six months after the second vaccination. Antibody titres were measured using the Elecsys Anti-SARS-CoV-2 S assay., Results: The seroconversion rate and antibody titres were lower in AIRD patients than in HCs 3-6 weeks after the second vaccination and 3-6 weeks after the third vaccination. Seroconversion rates were <90% after the third vaccination in patients receiving mycophenolate mofetil and rituximab. Antibody levels after the third vaccination were significantly lower in the groups prescribed TNF inhibitor with or without methotrexate, abatacept and rituximab or cyclophosphamide than those of HCs in a multivariate analysis adjusting for age, sex, and glucocorticoid dosage. The third vaccination induced an adequate humoral response in patients treated with sulfasalazine, bucillamine, methotrexate monotherapy, iguratimod, interleukin-6 inhibitors or calcineurin inhibitors including tacrolimus., Conclusions: Repeated vaccinations in many immunosuppressed patients produced antibody responses similar to those observed in HCs. In contrast, annual vaccination in patients receiving TNF inhibitors, abatacept, mycophenolate mofetil and rituximab may require caution., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Pretravel consultation (PTC) is important for older adults owing to health problems associated with overseas travel. Although older adults in Japan, their PTC characteristics are less known. This study aimed to investigate the epidemiology of clients aged ≥ 60 years based on data from the Japan Pre-travel Consultation Registry (J-PRECOR)., Methods: Clients aged ≥ 60 years who visited J-PRECOR cooperative hospitals from February 1, 2018, to May 31, 2022, were included. The primary endpoint was a comparison of prescriptions for vaccines for hepatitis A, tetanus toxoid, and malaria prophylaxis in travelers to high-risk malaria countries in yellow fever vaccination (YFV)-available facilities with and without YFV., Results: In total, 1000 clients (median age: 67 years) were included. Although 523 clients were immunized with YFV, only 38.6% of the 961 unimmunized clients were vaccinated with the tetanus toxoid-containing vaccine. Malaria chemoprophylaxis was prescribed to 25.7% of clients traveling for ≤55 days. At YFV-capable institutes, 557 clients traveling to yellow fever risk countries took PTC, 474 of whom received YFV and 83 were unvaccinated. Lower age (odds rate 0.85 per 1 year; 95% CI 0.80-0.90) and lower hepatitis A vaccination rate (0.29; 95% CI 0.14-0.63) were significantly associated with YFV., Conclusions: Preventive interventions other than YFV should be offered to older adults., Competing Interests: Declaration of competing interest K.Y. received research grants from Fujirebio, Inc.; Mizuho Medy, Co., Ltd.; VisGene, Co., Ltd.; Canon Medical Systems, Corp.; Sanyo Chemical Industries, Ltd.; and CarbGeM Inc. Outside the submitted work. The authors therefore declare no conflicts of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: SARS-CoV-2 Omicron breakthrough infection (Omicron-BTI) after vaccination has been frequently observed. A more detailed understanding of the humoral immunity against Omicron-BTI is required., Methods: We measured strain-specific live-virus based neutralizing activity, anti-spike IgG, and anti-receptor-binding domain (RBD) IgG titers in individuals with Omicron/BA.1-BTI and directly compared them with controls with diverse combinations of wild-type (WT) mRNA vaccination and infection history., Results: Omicron-BTI individuals showed markedly higher neutralizing titers against all the WT, Delta, and Omicron strains in convalescent sera, compared with unvaccinated Omicron-infection individuals with only Omicron neutralizing activity. Similar tendencies were found in strain-specific anti-spike and anti-RBD IgG titers. The Omicron-specificity (BA.1/WT neutralizing ratio), Omicron-neutralizing efficiency per antibody unit, and anti-Omicron RBD-directivity of anti-spike antibodies in Omicron-BTI individuals were all significantly lower than those in unvaccinated Omicron-infection individuals, but they were equivalent to or higher than those in uninfected vaccinees. The induction of Omicron-specific neutralizing activity after Omicron-BTI was not weakened for eight months from the last vaccination., Conclusions: These findings suggest that cross-reactive vaccine-induced immunity was intensively stimulated following Omicron breakthrough infection, which contributed to Omicron neutralization. Measuring SARS-CoV-2 variant-specific antibody levels as well as neutralizing activity is useful for evaluating humoral immunity after breakthrough infection in the current situation of antigenic gaps between vaccinated and epidemic (Omicron sub-lineages) strains., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Yong Chong reports equipment, drugs, or supplies was provided by Shionogi and Co Ltd. Natsumi Susai, Tomoyo Yoshinaga reports a relationship with Shionogi and Co Ltd that includes: employment.]., (Copyright © 2023. Published by Elsevier Ltd.)

Background: The emergence of omicron variants exhibiting antigenic changes has led to an increase in breakthrough infection among individuals with a wild-type SARS-CoV-2 vaccine booster. The correlation between post-booster spike-specific antibodies and omicron infection risk remains unclear., Methods: This prospective cohort study included SARS-CoV-2-naive healthcare workers with three-dose BNT162b2. Post-booster spike-specific IgG and interferon-γ levels were measured. Breakthrough infection was documented during a 10-month omicron-predominant period. Household and healthcare contacts were followed to identify subsequent infections. The IgG titers were additionally measured at the end of follow-up, and the titers at exposure were estimated from the two-point titers., Results: Of 333 participants, 89 developed infection, of whom 37 (41.6 %) were household contacts. Kaplan-Meier curves indicated that higher IgG titers were significantly correlated with lower cumulative infection incidence (p = 0.029), whereas the interferon-γ levels were not (p = 0.926). Multivariate Cox analysis showed that increasing IgG titers were associated with a reduced hazard ratio (HR) of 0.26 (95% CI, 0.12-0.55). Household exposure posed a greater infection risk than healthcare exposure (HRs, 11.24 [6.88-18.40] vs. 2.82 [1.37-5.44]). The difference in geometric mean IgG titers of infected and uninfected participants was significant among household contacts (20,244 AU/mL vs. 13,842 AU/mL, p = 0.031). Estimation of IgG titers at exposure showed a significantly higher infection incidence in those exposed with titers of <3,000 AU/mL than in those with higher titers (79.2 % vs. 32.3 %, p < 0.001)., Conclusions: Spike-specific antibodies induced by a wild-type SARS-CoV-2 vaccine booster are suggested to be effective in protecting against omicron infection. Household exposure would be a significant source of infection for hospital healthcare workers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Neutralizing potency of humoral immune responses induced by prior infection or vaccination is vital for protecting of individuals and population against severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). However, the emergence of viral variants that can evade neutralization by vaccine- or infection-induced immunity is a significant public health threat and requires continuous monitoring. Here, we have developed a novel scalable chemiluminescence-based assay for assessing SARS-CoV-2-induced cytopathic effect to quantify the neutralizing activity of antisera. The assay leverages the correlation between host cell viability and ATP levels in culture to measure the cytopathic effect on target cells induced by clinically isolated, replication-competent, authentic SARS-CoV-2. With this assay, we demonstrate that the recently arisen Omicron subvariants BQ.1.1 and XBB.1 display a significant decrease in sensitivity to neutralization by antibodies elicited from breakthrough infections with Omicron BA.5 and from receipt of three doses of mRNA vaccines. Thus, this scalable neutralizing assay provides a useful platform to assess the potency of acquired humoral immunity against newly emerging SARS-CoV-2 variants. IMPORTANCE The ongoing global pandemic of SARS-CoV-2 has emphasized the importance of neutralizing immunity in protecting individuals and populations against severe respiratory illness. In light of the emergence of viral variants with the potential to evade immunity, continuous monitoring is imperative. A virus plaque reduction neutralization test (PRNT) is a "gold standard" assay for analyzing neutralizing activity for authentic viruses that form plaques, like influenza virus, dengue virus, and SARS-CoV-2. However, this method is labor intensive and is not efficient for performing large-scale neutralization assays on patient specimens. The assay system established in this study allows for the detection of a patient's neutralizing activity by simply adding an ATP detection reagent, providing a simple evaluation system for neutralizing activity of antisera as an alternative to the plaque reduction method. Our extended analysis of the Omicron subvariants highlights their increasing capability to evade neutralization by both vaccine- and infection-induced humoral immunity., Competing Interests: The authors declare no conflict of interest.

Background: The association between lipoprotein subclasses and carotid intima-media thickness (cIMT) progression has yet to be fully evaluated. We assessed which lipoprotein subclasses were associated with maximum cIMT levels in the general population., Methods: In this study, cholesterol and triglyceride content of 20 lipoprotein subclasses were analyzed using gel permeation high-performance liquid chromatography (GP-HPLC) in 864 Japanese women and men (mean age 57 y, free of chronic liver or kidney diseases and off lipid-lowering, hormone replacement, or adrenocorticosteroid medications). Univariate and multivariate regression analyses and univariate and partial correlation analyses were performed to examine the relationships between lipoprotein subclasses and maximum cIMT levels., Results: After adjusting for age, sex, systolic blood pressure, smoking, diabetes, and anti-hypertensive agents, elevated low-density lipoprotein (LDL)-2 and -3 cholesterol (particle diameter 25.5 nm and 23.0 nm, respectively; medium and small LDL) were associated with higher maximum cIMT levels in both women and men (all p for trend < 0.05). These associations were significant even after participants taking anti-diabetic or anti-hypertensive agents were excluded. No significant associations were found between any triglyceride subclasses and maximum cIMT levels., Conclusions: Smaller LDL particle cholesterol values are the most atherogenic lipoprotein parameter., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Infection control during COVID-19 outbreaks in nursing facilities is a critical public health issue. Antibody responses before and after the fourth (second booster) dose of wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in nursing home residents have not been fully characterized., Methods: This study included 112 individuals: 54 nursing home residents (mean age: 84.4 years; 35 SARS-CoV-2-naive and 19 previously infected) and 58 healthcare workers (mean age: 47.7 years; 25 SARS-CoV-2-naive and 33 previously infected). Antispike and antinucleocapsid antibody responses to messenger RNA vaccination were evaluated using serum samples collected shortly and 5 months after the third dose, and shortly after the fourth dose., Results: The median immunoglobulin G (IgG) level in SARS-CoV-2-naive residents was similar to that in SARS-CoV-2-naive healthcare workers after the fourth dose (24,026.3 vs. 30,328.6 AU/mL, p = .79), whereas after the third dose the IgG level of SARS-CoV-2-naive residents was approximately twofold lower than that in SARS-CoV-2-naive healthcare workers. In residents with previous SARS-CoV-2 infection, timing of infection in relation to vaccination affected the kinetics of antibody responses. Residents infected after the third dose showed the highest IgG levels after the fourth dose among all groups (median: 64,328.8 AU/mL), in contrast to residents infected before initiating vaccination with antibody levels similar to those of SARS-CoV-2-naive residents., Conclusions: Advanced aged nursing home residents, poor responders in the initial SARS-CoV-2 vaccine series, could achieve sufficient antibody responses after the fourth (second booster) vaccination, comparable to those of younger adults., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

The efficacy of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the elderly is partially hindered by immunosenescence, resulting from decreased mtDNA levels. This study evaluated the correlation between mtDNA levels in peripheral leukocytes and immune response to the SARS-CoV-2 vaccine. Two hundred ten participants (median age 79.5 years), including 83 frail residents/inpatients and 70 robust outpatients, were analyzed. Anti-spike IgG antibody (IgG(S)) titers were serially measured from before the first vaccination to after the third vaccination. The mtDNA levels and cell-mediated immunity were measured in 45 elderly and 22 elderly individuals two months after the third vaccination. The robust group had consistently higher IgG(S) titers than the frail group. The mtDNA levels positively correlated with IgG(S) titers, as well as with cell-mediated immunity. These findings suggest that mtDNA levels positively impact vaccine-induced immunity. Further studies into maintaining mtDNA levels may provide insights into immunosenescence in the elderly., Competing Interests: The authors have nothing to declare with regard to conflicts of interest., (© 2023 The Author(s).)

Breakthrough candidemia (BrC) is a significant problem in immunocompromised patients, particularly those with hematological disorders. To assess the characteristics of BrC in patients with hematologic disease treated with novel antifungal agents, we collected clinical and microbiological information on said patients from 2009 to 2020 in our institution. Forty cases were identified, of which 29 (72.5%) received hematopoietic stem cell transplant (HSCT)-related therapy. At BrC onset, the most administered class of antifungal agents were echinocandins, administered to 70% of patients. Candida guilliermondii complex was the most frequently isolated species (32.5%), followed by C. parapsilosis (30%). These two isolates were echinocandin-susceptible in vitro but had naturally occurring FKS gene polymorphisms that reduced echinocandin susceptibility. Frequent isolation of these echinocandin-reduced-susceptible strains in BrC may be associated with the widespread use of echinocandins. In this study, the 30-day crude mortality rate in the group receiving HSCT-related therapy was significantly higher than in the group not receiving it (55.2% versus 18.2%, P = .0297). Most patients affected by C. guilliermondii complex BrC (92.3%) received HSCT-related therapy and had a 30-day mortality rate of 53.8%; despite treatment administration, 3 of 13 patients had persistent candidemia. Based on our results, C. guilliermondii complex BrC is a potentially fatal condition in patients receiving HSCT-related therapy with echinocandin administration., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Objective: To analyze the effects of in-person attendance at an academic conference held during the Covid-19 pandemic on the health of the attendees, as assessed based on symptoms such as fever and cough attributed to infection with the Covid-19 virus., Methods: A questionnaire was used to survey the members of the Japan Society of Obstetrics and Gynecology (JSOG) about their health during the period from August 7 to August 12, 2022, after the 74th Annual Congress of the JSOG, which was held August 5 to 7., Results: Our survey yielded responses from 3054 members (1566 of whom had attended the congress in person and 1488 of whom had not attended in person); 102 (6.5%) of the in-person attendees and 93 (6.2%) of the people who did not attend in person reported problems with their health. No statistically significant difference was found between these two groups (p = 0.766). In a univariate analysis of factors affecting the presence of health problems, attendees with age ≥60 years had significantly fewer health problems than attendees who were in their 20s (odds ratio: 0.366 [0.167-0.802; p = 0.0120]). In a multivariate analysis, attendees who had received four vaccine shots had significantly fewer health problems than attendees who had received three shots (odds ratio: 0.397 [0.229-0.690, p = 0.0010])., Conclusion: Congress attendees who took precautions at the congress to avoid being infected and who had a high vaccination rate did not develop significantly more health problems associated with in-person attendance at the congress., (© 2023 Japan Society of Obstetrics and Gynecology.)

Background: A cost-effective and eco-friendly method is needed for the assessment of humoral immunity against SARS-CoV-2 in large populations., Objective: We investigated the performance of an ELISA that uses silkworm-produced proteins to quantify the strain-specific anti-Spike IgG (anti-S IgG) titer., Methods: The OD values for the anti-His-tag antibody, a standard material of ELISA quantification, were measured. Correlations between the ELISA for each strain and the Abbott SARS-CoV-2 IgG II Quant assay for the wild type were evaluated with serum samples from nine participants with various infection and vaccination statuses., Results: Linear dose-responses were confirmed by high coefficients of determination: 0.994, 0.994, and 0.996 for the wild-type, Delta, and Omicron (BA.1) strain assays, respectively. The coefficient of determination for the wild-type and Delta strain assays was high at 0.959 and 0.892, respectively, while the Omicron strain assay had a relatively low value of 0.563. Booster vaccinees showed similar or higher titers against all strains compared to infected persons without vaccination. The Omicron-infected persons without vaccination had lower antibody titers against wild type than did the vaccinated persons., Conclusions: This study provides data indicating that the ELISA with silkworm-produced proteins makes it possible to discriminate and quantify the strain-specific anti-S IgG antibody induced by vaccination or infection.

The relation between pre-vaccination antipyretic use and antibody responses to SARS-CoV-2 vaccination has been unclear. We measured the pre- and post-BNT162b2 booster spike-specific IgG titers and recorded antipyretic use and adverse reactions for SARS-CoV-2-naive hospital healthcare workers. The data of 20 cases who used antipyretics within 24 h before vaccination were compared to that of 281 controls. The post-booster geometric mean IgG titers were 15,559 AU/mL (95 % CI, 11,474-21,203) for the cases and 16,850 AU/mL (95 % CI, 15,563-18,243) for the controls (p = 0.622). No significant reduction in the frequency or severity of any of the solicited adverse reactions was found for the cases. Similar results were obtained after adjustment with propensity-score matching for demographic characteristics, baseline IgG titer, and post-vaccination antipyretic use. Antipyretic use within 24 h before vaccination would not affect mRNA COVID-19 vaccine-induced specific antibody responses and that postponement of vaccination due to pre-vaccination antipyretic use would be unnecessary., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Objectives: Many countries are administering a third dose of some coronavirus disease 2019 (COVID-19) vaccines, but the evaluation of vaccine-induced immunity after boosting in East Asia is insufficient. This study aimed to evaluate anti-spike immunoglobulin G [IgG(S)] titers after the third BNT162b2 vaccination., Methods: The dynamics of IgG(S) titers were assessed two months following the third BNT162b2 vaccination in 52 participants. All participants received the primary series of vaccination with BNT162b2 and received the third dose eight months after the second vaccination. Associations among the IgG(S) titer, baseline characteristics, and adverse reactions were also evaluated., Results: The geometric mean titer of IgG(S) one month after the third vaccination was 17,400 AU/ml, which increased by approximately 30 times that immediately before the third vaccination. The rate of IgG(S) titer decline was significantly slower after the third vaccination (35.7%) than after the second vaccination (59.1%). The IgG(S) titer was significantly negatively associated with age ( r = -0.31). Participants who had a headache at the time of vaccination showed significantly higher IgG(S) titers than those without a headache., Conclusions: The IgG(S) titer induced by primary immunization with BNT162b2 waned over time. The third dose of BNT162b2 substantially increased the IgG(S) titer, with a slower rate of decline., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Objectives: Differences in virulence genes, including psm-mec, which is a phenol-soluble modulin-mec (PSM-mec) encoding gene, of predominant staphylococcal cassette chromosome mec (SCCmec) types II and IV Methicillin-resistant Staphylococcus aureus (MRSA) may contribute to the virulence and clinical features of MRSA in Japan. We aimed to clarify the clinical characteristics and risk factors of infection among SCCmec types II and IV MRSA isolates from a Japanese secondary acute care hospital., Methods: We analysed 58 SCCmec type II and 83 SCCmec type IV MRSA isolates collected from blood, central venous catheter tips, deep or superficial tissues, and sputum., Results: SCCmec type II MRSA risk factors for progression to infection were seb, enterotoxin gene cluster, psm-mec mutation, and vancomycin minimum inhibitory concentrations (MIC) of 1 or 2 mg/L as virulence factors (adjusted odds ratio [aOR] = 11.8; 95% confidence interval [CI]: 2.49-77.7; P = 0.004); solid tumour was a host factor (aOR = 25.9; 95% CI: 3.66-300; P = 0.003). SCCmec type IV MRSA risk factors were sea, cna, and vancomycin MIC of 1 or 2 mg/L as virulence factors (aOR = 3.14; 95% CI: 1.06-10.6; P = 0.049) and intravascular indwelling catheter as host factors (aOR = 3.78; 95% CI: 1.03-14.5; P = 0.045). Compared with SCCmec type II, SCCmec type IV MRSA resulted in more frequent bloodstream infections and higher Sequential Organ Failure Assessment scores., Conclusion: We found that factors related to virulence genes and bacteriological and host characteristics are associated with SCCmec types II and IV MRSA infection and severity. These risk factors may be useful criteria for designing infection control programs., Competing Interests: Competing interests None declared., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Infection control during COVID-19 outbreaks in nursing facilities is a critical public health issue. Antibody responses before and after the third (booster) dose of SARS-CoV-2 vaccination in nursing home residents have not been fully characterized., Methods: This study included 117 individuals: 54 nursing home residents (mean age, 83.8 years; 39 SARS-CoV-2-naive and 15 previously infected) and 63 healthcare workers (mean age, 45.8 years; 32 SARS-CoV-2-naive and 31 previously infected). Anti-spike (receptor-binding domain [RBD]) and anti-nucleocapsid antibody responses to BNT162b2 mRNA vaccination and their related factors were evaluated using pre- (shortly and 6 months after the second dose) and post-booster vaccination samples., Results: The median anti-spike (RBD) IgG level in SARS-CoV-2-naive residents 6 months after the second dose was the lowest among the four groups, with a decreasing rate of over 90%. The median rate of increase before and after the third dose in SARS-CoV-2-naive residents was significantly higher than that in SARS-CoV-2-naive healthcare workers (64.1- vs. 37.0-fold, P = 0.003), with the highest level among the groups. The IgG ratio of SARS-CoV-2-naive residents to healthcare workers after the second and third doses changed from one-fifth (20%) to one-half (50%). The rate of increase after the third dose in previously infected individuals was three- to fourfold, regardless of residents or healthcare workers., Conclusions: Advanced aged nursing home residents, poor responders in the initial SARS-CoV-2 vaccine series, could obtain sufficient antibody responses with the additional booster dose, despite more than 6 months after the second., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine booster elicits sufficient antibody responses that protect against coronavirus disease 2019, whereas adverse reactions such as fever have been commonly reported. Associations between adverse reactions and antibody responses have not been fully characterized, nor has the influence of antipyretic use., Methods: This is a prospective observational cohort study in Japan, following our prior investigation of BNT162b2 2-dose primary series. Spike-specific immunoglobulin G (IgG) titers were measured for SARS-CoV-2-naive hospital healthcare workers who received a BNT162b2 booster. The severity of solicited adverse reactions, including the highest body temperature, and self-medicated antipyretics were reported daily for 7 days following vaccination through a web-based self-reporting diary., Results: The data of 281 healthcare workers were available. Multivariate analysis extracted fever after the booster dose (β = .305, P < .001) as being significantly correlated with the specific IgG titers. The analysis of 164 participants with data from the primary series showed that fever after the second dose was associated with the emergence of fever after the booster dose (relative risk, 3.97 [95% confidence interval, 2.48-6.35]); however, the IgG titers after the booster dose were not associated with the presence or degree of fever after the second dose. There were no significant differences in the IgG titers by the use, type, or dosage of antipyretic medication., Conclusions: These results suggest an independent correlation between mRNA vaccine-induced specific IgG levels and post-booster vaccination fever, without any significant influence of fever after the primary series. Antipyretic medications for adverse reactions should not interfere with the elevation of specific IgG titers., Competing Interests: Potential conflicts of interest. The authors declare no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

A 53-year-old male Japanese patient with COVID-19 was admitted to our hospital after his respiratory condition worsened on day 9 of the disease. With the diagnosis of severe COVID-19, treatment with remdesivir, dexamethasone, and unfractionated heparin was started for the prevention of thrombosis. Although the patient's respiratory status data improved after treatment, severe respiratory failure persisted. Thrombocytopenia and D-dimer elevation were observed on day 8 after heparin therapy initiation. Heparin-induced thrombocytopenia (HIT) antibody measured by immunological assay was positive, and contrast computed tomography showed pulmonary artery thrombus. The patient was diagnosed with HIT because the pre-test probability score (4Ts score) for HIT was 7 points. Heparin was changed to apixaban, a direct oral anticoagulant, which resulted in a reduction of the pulmonary thrombus and improvement of the respiratory failure. In patients with COVID-19, anticoagulant therapy with heparin requires careful monitoring of thrombocytopenia and elevated D-dimer as possible complications related to HIT. (151/250 words)., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Waning humoral immunity after mRNA vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a significant problem for public health. Breakthrough infection in hospitals over several months after vaccination has not been fully characterized, especially against the delta (B.1.617.2) variant. Here, we describe an outbreak in our hospital in September of 2021, mainly through serological evaluation of the breakthrough infection. This retrospective observational study was done at an emergency and acute care hospital with 204 beds and 486 staff members where most staff members (92.6%) had had their second BNT162b2 vaccination by May of 2021. The peri-infection anti-spike RBD protein IgG (anti-S IgG) titers (lowest values between 11 days before and 7 days after onset or diagnosis) of serum samples from the breakthrough-infected persons were quantified. We also logarithmically estimated the anti-S IgG titers during the exposure period in September of uninfected staff members from their samples collected in May and December 2021. Whole-genome sequencing was done on obtained samples. In this outbreak, twelve persons (ten inpatients and two staff members) were diagnosed with SARS-CoV-2 infection by Loop-Mediated Isothermal Amplification (LAMP) or RT-PCR, eight of whom had been vaccinated twice. Peri-infection anti-S IgG titers could be determined in seven of the eight breakthrough cases, with a geometric mean titer (GMT) of 1,034 AU/ml (95% confidence interval [CI], 398 to 2,686). Among 289 uninfected staff members with data from the two sampling points, the GMT of the estimated anti-S IgG titers during the exposure period in 51 staff members, who were working at the outbreak ward and potentially exposed but uninfected, and 238 other unexposed staff members were 1,458 AU/ml (95% CI, 1,196 to 1,777) and 1,628 AU/ml (95% CI, 1,500 to 1,766), respectively. All viruses from the eight samples for which whole-genome sequencing was available were identified as delta variants. Of the infected persons, one remained asymptomatic throughout the course of treatment, and eleven had an illness of mild to moderate severity, including ten who received monoclonal antibody cocktail (Casirivimab/imdevimab) therapy. Measurement and estimation of anti-spike antibody levels after SARS-CoV-2 vaccination would be helpful for evaluating the risk of breakthrough infection and for determining the necessity of booster vaccination., Competing Interests: The authors have declared that no competing interests exist.

Daptomycin is used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. Current guidelines recommend higher daptomycin doses (8-10 mg/kg) for severe infections; however, pharmacokinetic (PK) and pharmacodynamic-based dosing strategies are still limited. Therefore, we designed a new optimal daptomycin dosing regimen for patients with MRSA infections using a population PK modeling approach. A total of 110 plasma concentrations from 47 adult patients who received daptomycin in general wards were enrolled for population PK modeling. The target area under the concentration-time curve/minimum inhibitory concentration (MIC) ratio, target peak/MIC ratio, and threshold of the trough concentration for safety were set to >666, >60, and 24.3 mg/L, respectively. Renal function was indicated as a significant covariate for daptomycin clearance. The simulated probability of target attainment was more than 90% at MIC values of 0.25 and 0.5 mg/L in all patients at the standard dose (6 mg/kg). In contrast, comprehensive simulation assessments recommended 10 mg/kg every 24 h in patients with creatinine clearance >60 mL/min for MIC values of 1.0 mg/L. We propose a new simplified daptomycin dosing regimen stratified by renal function and MIC values based on PK model-based simulation analyses. The proposed regimen is expected to maximize clinical efficacy and minimize adverse events., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)