Reduction of adverse reactions and correlation between post-vaccination fever and specific antibody response across successive SARS-CoV-2 mRNA vaccinations.

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.

Correlation between specific antibody response to wild-type BNT162b2 booster and the risk of breakthrough infection with omicron variants: Impact of household exposure in hospital healthcare workers.

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.

Tacrolimus Treatment for Post-COVID-19 Interstitial Lung Disease.

With expansion of the COVID-19 pandemic, reports of post-COVID-19 interstitial lung disease (ILD) have been emerging. However, there are few reports regarding treatment. Some reports indicate that corticosteroids are effective for post-COVID-19 ILD, but the use of long-term corticosteroid carries risks of side effects. We administered tacrolimus to an elderly patient with post-COVID-19 ILD who suffered a respiratory failure relapse during steroid tapering. The respiratory status improved with tacrolimus in the post-acute phase, but pulmonary fibrosis progressed in the late phase. Tacrolimus may be effective for treating post-COVID-19 ILD in the post-acute phase, but it does not halt progression of pulmonary fibrosis.

A Refractory, Infected Lung Bulla and an Abscess Treated Using Percutaneous Drainage in a Patient With Human T-Lymphotropic Virus Type 1-Associated Myelopathy.

We present a case of a 54-year-old Japanese woman with established human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy who developed a refractory infected lung bulla and lung abscess caused by Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, and Aspergillusspecies. Since antibiotic treatment alone failed to resolve the infection, percutaneous drainage of the infected bulla was performed. Although a prolonged treatment period was necessary, the infected lung bulla and the lung abscess were eventually resolved. During her illness, the patient also developed arthritis, possibly related to the HTLV-1 infection. Thus, persons infected with HTLV-1 can develop refractory infections, myelopathy, and arthritis. Percutaneous drainage is an option to treat refractory infected lung bullae.

Successful treatment with mepolizumab for allergic bronchopulmonary mycosis complicated with bilateral septic arthritis of the knee joints caused by Methicillin-resistant Staphylococcus aureus.

We report the case of a 50-year-old man with allergic bronchopulmonary mycosis (ABPM) complicated with bilateral septic arthritis of the knees caused by Methicillin-resistant Staphylococcus aureus (MRSA). He had a background of bronchial asthma and end-stage renal failure on maintenance dialysis. He was treated with 30 mg/day of prednisolone for 14 days for ABPM. He developed bilateral septic arthritis of the knees, caused by MRSA during prednisolone treatment. He underwent bilateral arthroscopic washout with a 2-week course of intra-articular arbekacin, concomitantly treated with a 6-week course of intravenous teicoplanin and oral rifampicin, subsequently followed by oral linezolid treatment. However, he suffered exacerbation of ABPM during treatment of septic arthritis. Because of these serious infectious complications, he was treated with mepolizumab instead of corticosteroids for the ABPM, which resolved all symptoms and clinical features. This case highlights mepolizumab treatment as an alternative to corticosteroid therapy for treatment of ABPM in patients with comorbidities such as infection.

Gastrointestinal Graft-versus-Host Disease Is a Risk Factor for Postengraftment Bloodstream Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants.

PPARα-dependent cholesterol/testosterone disruption in Leydig cells mediates 2,4-dichlorophenoxyacetic acid-induced testicular toxicity in mice.

It was reported that 2,4-dichlorophenoxyacetic acid (2,4-D), a commonly used herbicide and a possible endocrine disruptor, can disturb spermatogenesis, but the precise mechanism is not understood. Since 2,4-D is a weak peroxisome proliferator in hepatocytes and peroxisome proliferator-activated receptor α (PPARα) is also expressed in Leydig cells, this study aimed to investigate the link between PPARα and 2,4-D-mediated testicular dysfunction. 2,4-D (130 mg/kg/day) was administered to wild-type and Ppara-null mice for 2 weeks, and the alterations in testis and testosterone/cholesterol metabolism in Leydig cells were examined. Treatment with 2,4-D markedly decreased testicular testosterone in wild-type mice, leading to degeneration of spermatocytes and Sertoli cells. The 2,4-D decreased cholesterol levels in Leydig cells of wild-type mice through down-regulating the expression of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 and reductase, involved in de novo cholesterogenesis. However, the mRNAs encoding the important proteins involved in testosterone synthesis were unchanged by 2,4-D except for CYP17A1, indicating that exhausted cholesterol levels in the cells is a main reason for reduced testicular testosterone. Additionally, pregnancy rate and the number of pups between 2,4-D-treated wild-type male mice and untreated female mice were significantly lower compared with those between untreated couples. These phenomena were not observed in 2,4-D-treated Ppara-null males. Collectively, these results suggest a critical role for PPARα in 2,4-D-induced testicular toxicity due to disruption of cholesterol/testosterone homeostasis in Leydig cells. This study yields novel insights into the possible mechanism of testicular dysfunction and male infertility caused by 2,4-D.

Dissecting the phenotype of supernumerary marker chromosome 20 in a patient with syndromic Pierre Robin sequence: combinatorial effect of gene dosage and uniparental disomy.

Clinical phenotypes in individuals with a supernumerary marker chromosome (SMC) are mainly caused by gene dosage effects due to the genes located on the SMC. An additional effect may result from uniparental disomy (UPD). Consequently, the occurrence of UPD may be a confounding factor in identifying genotype-phenotype correlations in SMC syndromes. Here, we report on a patient that illustrates this problem; the phenotype of this patient was a consequence of a combined effect of gene dosage and UPD. The proband showed facial dysmorphisms, growth retardation and developmental delay. G-band karyotype of the proband's peripheral blood showed the presence of mosaic SMC. A SNP array analysis documented maternal UPD20 and 20p duplication. It is known that maternal UPD20 causes prenatal onset growth retardation and feeding difficulties. By contrast, duplication of 20p causes facial dysmorphisms, micrognathia, cleft palate, developmental delay and vertebral anomalies. Our classification of the proband's phenotype showed a mixture of these two effects. Therefore, we suggest the routine use of genome-wide SNP array towards the detailed genotype-phenotype correlations for SMC syndromes.

Prenatal maternal blood triglyceride and fatty acid levels in relation to exposure to di(2-ethylhexyl)phthalate: a cross-sectional study.

OBJECTIVES: The hypolipidemic effects of di(2-ethylhexyl)phthalate (DEHP) exposure in humans have not been investigated. And the influences of maternal prenatal DEHP exposure on birth outcomes are not well-known. We aimed to estimate prenatal DEHP exposure in maternal blood, and evaluate its relationships to maternal blood triglyceride (TG) and fatty acid (FA) levels and to birth outcomes. METHODS: We studied 318 mother-newborn pairs residing in Sapporo, Japan. Blood was taken one time during pregnancy for each mother. Maternal and infant characteristics were obtained from medical records and questionnaire survey. We measured DEHP metabolite, mono(2-ethylhexyl) phthalate (MEHP), along with TG and 9 FAs using maternal blood, and analyzed associations of MEHP level with maternal blood TG/FA levels and infant birth dimensions. RESULTS: Maternal blood TG and palmitoleic/oleic acid levels were higher, but stearic/docosahexaenoic acids and MEHP were lower during late pregnancy. Maternal blood MEHP levels inversely correlated with TG and palmitic/palmitoleic/oleic/linoleic/α-linolenic acids. After adjustment for confounders, we found that a tenfold increase in blood MEHP levels correlated with a decrease in TG of 25.1 mg/dl [95% confidence interval (CI) 4.8-45.3 mg/dl], and similar relations in palmitic (ß = -581.8; 95 % CI -906.5, -257.0), oleic (ß = -304.2; 95% CI -518.0, -90.5), linoleic (ß = -348.6; 95% CI -510.6, -186.6), and α-linolenic (ß = -6.3; 95% CI -9.5, -3.0) acids. However, we observed no correlations between maternal blood MEHP levels and infant birth weight, length, chest circumference, or head circumference. CONCLUSIONS: Ambient DEHP exposure during pregnancy inversely correlated with maternal blood TG and 4 FA levels, but not birth outcomes.

Does antimicrobial use density at the ward level influence monthly central line-associated bloodstream infection rates?

The aim of this study was to elucidate risk factors, including ward antimicrobial use density (AUD), for central line-associated bloodstream infection (CLABSI) as defined by the Centers for Disease Control and Prevention in a 430-bed community hospital using central venous lines with closed-hub systems. We calculated AUD as (total dose)/(defined daily dose × patient days) ×1,000 for a total of 20 drugs, nine wards, and 24 months. Into each line day data, we inputed AUD and device utilization ratios, number of central line days, and CLABSI. The ratio of susceptible strains in isolates were subjected to correlation analysis with AUD. Of a total of 9,997 line days over 24 months, CLABSI was present in 33 cases (3.3 ‰), 14 (42.4%) of which were on surgical wards out of nine wards. Of a total of 43 strains isolated, eight (18.6%) were methicillin-resistant Staphylococcus aureus (MRSA); none of the MRSA-positive patients had received cefotiam before the onset of infection. Receiver-operating characteristic analysis showed that central line day 7 had the highest accuracy. Logistic regression analysis showed the central line day showed an odds ratio of 5.511 with a 95% confidence interval of 1.936-15.690 as did AUD of cefotiam showing an odds ratio of 0.220 with 95% confidence interval of 0.00527-0.922 (P=0.038). Susceptible strains ratio and AUD showed a negative correlation (R (2)=0.1897). Thus, CLABSI could be prevented by making the number of central line days as short as possible. The preventative role of AUD remains to be investigated.

Nosocomial spread of meticillin-resistant Staphylococcus aureus with ß-lactam-inducible arbekacin resistance.

A meticillin-resistant Staphylococcus aureus (MRSA) strain with additional ß-lactam-inducible aminoglycoside resistance was previously reported by a group at the Kitasato University in Japan. In addition to gentamicin, the 'Kitasato strain' was resistant to arbekacin (ABK), which is primarily used as an anti-MRSA aminoglycoside. No further studies regarding the spread of MRSA strains with the newly identified resistance mechanism have been reported to date. To obtain epidemiological data on MRSA strains with the antagonistic resistance and to analyse their genetic features, we examined the emergence of ß-lactam-inducible ABK-resistant MRSA strains at our university hospital using longitudinal analysis. Among the 396 isolates, 35 (8.8 %) were found to be ABK-resistant MRSA strains (the resistance being induced by ß-lactams). Moreover, based on the pulsed-field gel electrophoresis profiles, the clonality of those MRSA strains changed at different time periods. In the Kitasato strain, the antagonistic mechanism was clearly demonstrated by the integration of transposable elements; a Tn4001-IS257 hybrid structure that contained an aminoglycoside resistance gene cointegrated into a region downstream of the ß-lactamase gene. In most of the MRSA strains detected in our study, the antagonistic interaction was explained by the same mechanism as that found in the Kitasato strain. Interestingly, sequence analysis showed that all of our strains carried IS257 insertion sites which were different from those of the Kitasato strain. This study shows that MRSA strains with the additional antagonistic resistance are not uncommon and have been increasingly disseminating in clinical settings.

[Home nervous intractable diseases patient support system in our hospital-planned respite inpatient system].

The current situation for patients with nervous intractable diseases is that there are few places where they can be hospitalized for a long term,and their family members bear a heavy burden for caring for them. In order to support home care,our hospital is formulating a system in which regular respite hospitalization is possible,and we are supporting home care of many patients with nervous intractable diseases.

[Diagnostic usefulness of FDG-PET/CT in multiple primary osseous Hodgkin lymphoma].

A 66-year-old man presented with a six-month history of periodic fever. A CT scan of the chest and abdomen performed at another hospital one month before admission disclosed no evidence of inflammation or tumor, and at admission he had no symptoms other than the periodic fever. FDG-PET/CT demonstrated increased FDG uptake in multiple vertebrae, ribs, scapulae, pelvis, and femurs. A core needle biopsy of the vertebra showing increased FDG uptake was performed, and he was diagnosed with primary osseous Hodgkin lymphoma. ABVD therapy was begun and the fever resolved immediately. After 6 cycles of ABVD, he achieved complete remission and has maintained remission for five years since diagnosis. Primary osseous Hodgkin lymphoma is rare and its lack of distinguishing clinical and radiological features makes it difficult to achieve an early differential diagnosis. FDG-PET/CT is a useful tool for detecting tumors when periodic fever suggests the possibility of malignant disease but when specific symptoms are absent.

[Influence of inoculum size on MICs for methicillin-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus].

Using 49 clinical methicillin-susceptible Staphylococcus aureus isolates (MSSA) and 54 clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates, we examined the change of MIC using five different inocula (2.5-4 x 10(2) cfu/spot-2.5-4 x 10(6) cfu/spot). We found the big change of the MIC with the increase of the inoculum size in ampicillin against MSSA, and the change was small in cefazolin, meropenem, ciprofloxacin. For anti-MRSA antibiotics, we found the small change with the increase of the inoculums size in vancomycin and arbekacin, and the middle change in teicoplanin and linezolid against MSSA and MRSA. The data from this study suggest that in serious and high inocula infections caused by S. aureus, the presence of an inoculum effect should be considered in curing.

Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice.

Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with adverse effects on offspring, and the metabolites are agonists of peroxisome proliferator-activated receptor (PPAR) α, which exhibits species differences in expression and function. This study aimed to clarify the mechanism of DEHP-induced adverse effects on offspring in relation to maternal mouse and human PPARα. Male and female Sv/129 wild-type (mPPARα), Pparα-null and humanized PPARα (hPPARα) mice were treated with diets containing 0%, 0.01%, 0.05% (medium) or 0.1% (high) DEHP. After 4 weeks, males and females were mated. Dams were killed on gestational day 18 and postnatal day (PND) 2. High-dose DEHP decreased the number of total and live fetuses, and increased resorptions in mPPARα mice. In hPPARα mice, resorptions were increased above the medium dose, and the number of births was decreased at the high dose. The number of live pups on PND2 was decreased over the medium dose in mPPARα and at the high dose in hPPARα mice. No such findings were observed in Pparα-null mice. High-dose DEHP decreased plasma triglyceride in pregnant mPPARα mice, but not in Pparα-null and hPPARα ones. Above the medium dose in mPPARα mice significantly reduced hepatic microsomal triglyceride transfer protein (MTP) expression. Medium- and/or high-dose DEHP increased the levels of maternal PPARα target genes in mPPARα and hPPARα mice. Taken together, PPARα expression is required for the toxicity of DEHP in fetuses and pups and altered plasma triglyceride levels, through regulation of MTP may be important in mPPARα mice and not in hPPARα mice.

Geographic distribution of fluoroquinolone-resistant Escherichia coli strains in Asia.

Fluoroquinolone (FQ) resistance is usually caused by point mutations within the quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC and/or parE. However, little is known about the worldwide increase in FQ-resistant Escherichia coli or, more specifically, about the geographical distribution of QRDR mutations and the clonal spread of isolates. In this study, we analysed 68 FQ-resistant E. coli isolates from eight Asian countries using QRDR amino acid mutation patterns and examined their susceptibility to FQs. Of the isolates, 38% had mutations at S83 and D87 of GyrA and S80 of ParC (MM/-/M-/-) and 34% had mutations at S83 and D87 of GyrA, S80 of ParC and S458 of ParE (MM/-/M-/M). MIC(50) values (minimum inhibitory concentrations for 50% of the isolates) for isolates with at least mutation at S458 of ParE for ciprofloxacin and prulifloxacin were relatively higher than MIC(50) values of isolates without this mutation. Based on their geographic distribution and the QRDR mutation patterns, the isolates were divided into a common type in which the organisms were isolated from three or more countries, and a local type in which the isolates were from one or two countries. Mutation types at S83L and D87N in GyrA and S80I in ParC with no or another site in the QRDR were the most frequent among the FQ-resistant isolates, especially among the common type. Gene typing indicated that isolates in the common type were not similar between countries. These data suggest that the increase in FQ-resistant E. coli strains is mainly generated by mutations in the QRDR in each geographical area rather than through intercontinental spread.