Intra- and inter-day variations in oral metabolites from mouth-rinsed water determined using capillary electrophoresis-mass spectrometry metabolomics.

BACKGROUND AND AIMS: Collecting clinical samples without inconveniencing participants is desirable. The profile of metabolites in mouth-rinsed water is similar to that in saliva. However, the intra- and inter-day variations in unstimulated or stimulated saliva metabolites from mouth-rinsed water have yet to be clarified. Thus, we aimed to fill this research gap using capillary electrophoresis-mass spectrometry metabolomics. MATERIALS AND METHODS: We collected mouth-rinsed water from 15 healthy participants at 9:00, 11:30, 14:00, and 16:30 daily for 3 days. In total, 509 metabolite concentrations from 180 samples were obtained using capillary electrophoresis time-of-flight mass spectrometry. Variations in each metabolite were evaluated using the Wilcoxon signed-rank test to determine at which time/day significant differences occurred after removing metabolites without significant changes using the Friedman test. RESULTS: Of 167 frequently detected metabolites, 100 exhibited intra-day variations, and none exhibited inter-day variations. Intra-day variations were classified into four patterns, and the intra-day variation in each metabolite was assessed. The variations may reflect elapsed time after meals, oral cleaning, or circadian rhythms. CONCLUSION: This study could serve as a reference for improving the design of future clinical trials and the accuracy of metabolome analysis of mouth-rinsed water samples collected at different dates and times.

Assessing the effectiveness of menstrual health education in Japan: A non-randomized comparative study of adolescent girls with typical development and those with intellectual disabilities and high support needs.

This study elucidates the effectiveness of a menstrual education program with segmented MHM procedure on the MHM skills of girls with intellectual disabilities/HSN compared with those with typical development. Participants in a nonrandomized comparative study included nine adolescent girls with intellectual disabilities/HSN and ten with typical development. They practiced MHM on dolls three times: before, immediately after, and three months after participating in the educational program. Although the total MHM scores were significantly higher after both groups attended the program, the girls with intellectual disabilities/HSN had significantly lower total and mean scores on MHM items than girls with typical development. They still required instruction on the majority of the items after 3 months. Meanwhile, girls with intellectual disabilities/HSN showed a significant improvement in napkin changing skills and maintained post-course scores 3 months later, similar to those with typical development.

Intra- and inter-examiner Reproducibility of the menstrual hygiene management skills' rating by prepubescent girls in Japan.

Prepubescent girls with intellectual disabilities and high support needs encounter difficulties with menstrual hygiene management (MHM) and require individualized education. However, no clear methodology exists for assessing the reliability and validity of premenstrual MHM skills. We developed a 17-item MHM assessment tool to determine the intra- and inter-examiner reproducibility of MHM skills. Prepubescents-9 with intellectual disabilities and 10 with typical development-were educated on menstruation and assessed by three examiners. The intra-class correlation coefficient (ICC) showed high reproducibility, with intra-examiner reproducibility (ICC [1.1]) ranging from 0.87 to 0.99, regardless of disability. Conversely, inter-examiner reproducibilities were ICC (2.1) = 0.69-0.92 and 0.50-0.94 and Kappa coefficients were 0.54-0.81 and 0.37-1.00 for girls with intellectual disability and others, respectively. Items such as lowering underwear and wrapping napkins were less reproducible despite disability. Ability did not affect reproducibility and was useful for identifying MHM changes pre- and post-menstrual education.

Circadian Rhythms Fluctuate the Treatment Effects of Intravesical Treatments on Rat Urinary Frequency Models.

Objectives: It is still not clear how the intravesical instillation of drugs affects rat urinary frequency. This study aimed to examine the dynamics of intravesical treatments' treatment effect on rat urinary frequency models by real-time and extended monitoring using a novel continuous urination monitoring system. Methods: Nine eleven-week-old female Wistar rats were divided into three groups to receive intravesical instillation of 0.1% acetic acid (AA), 1.0% AA, or phosphate-buffered saline (PBS). Thirty minutes later, these drugs were voided, and rats were moved to a continuous urination monitoring system, UM-100. UM-100 monitored rat urination quantitatively and continuously for 24 hours. Rats were then euthanized, and histopathologic examinations using a damage score validated the severity of bladder inflammation. We used nine additional rats to determine the treatment effect of various drugs against the urinary frequency. These rats were also treated with 1.0% AA in the same way and divided into three groups (n = 3 each) to receive intravesical instillation of lidocaine, silver nitrate (AgNO3), or dimethyl sulfoxide (DMSO), respectively. Thirty minutes later, rats were catheterized again and moved to the UM-100, and their voiding was monitored for 24 hours. Results: Intravesical instillation of AA increased the urinary frequency and decreased the mean voided volume (VV) in a concentration-dependent manner, with statistical significance at a concentration of 1.0% (urinary frequency; p=0.0007, mean VV; p=0.0032, respectively) compared with PBS. Histopathological analysis of these models demonstrated a significantly higher damage score of bladder mucosa in both 0.1% AA and 1.0% AA compared with PBS, with the severity in concordance with the clinical severity of urinary frequency (0.1% AA: p < 0.0001, 1.0% AA: p < 0.0001). Moreover, intravesical instillation of lidocaine, AgNO3, and DMSO decreased the urinary frequency. Continuous monitoring with UM-100 also demonstrated that the treatment effect of these intravesically instilled drugs occurred only at night. Conclusions: The extended monitoring of rat urination by UM-100 revealed a significant fluctuation in the treatment effect of intravesically instilled drugs between day and night. These findings may help establish novel therapies for urinary frequency.

Effect of Antacids on the Survival of Patients With Metastatic Urothelial Carcinoma Treated With Pembrolizumab.

INTRODUCTION: Concomitant medications can affect the efficacy of immune checkpoint inhibitors. The association between histamine-2 receptor antagonists (H2RAs), major antacids similar to proton pump inhibitors (PPIs), and the efficacy of pembrolizumab for metastatic urothelial carcinoma (mUC) treatment has been poorly evaluated. We evaluated the impact of PPIs and H2RAs on oncological outcomes in mUC patients treated with pembrolizumab. PATIENTS AND METHODS: This retrospective multicenter study included patients with mUC treated with pembrolizumab. Patients prescribed PPIs or H2RAs within 30 days before and after the initial administration were extracted. The overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and objective response rates (ORR) were assessed. Kaplan-Meier survival curve analysis and multivariable Cox proportional hazard models were employed to assess the association between PPIs or H2RAs and survival outcomes. RESULTS: Overall, 404 patients were eligible for this study; 121 patients (29.9%) used PPIs, and 34 (8.4%) used H2RAs. Kaplan-Meier analysis showed significantly worse OS, CSS, and PFS in patients using PPIs compared to no PPIs (P = .010, .018, and .012, respectively). In multivariable analyses, the use of PPIs was a significant prognostic factor for worse OS (HR = 1.42, 95% CI 1.08-1.87, P = .011), CSS (HR = 1.45, 95% CI 1.09-1.93, P = .011), and PFS (HR = 1.35, 95% CI 1.05-1.73, P = .020). PPIs were not associated with ORRs. The use of H2RAs was not associated with survival or ORRs. CONCLUSION: PPIs were significantly associated with worse survival of patients with mUC treated with pembrolizumab, and H2RAs could be an alternative during administration. Both the oncological and gastrointestinal implications should be carefully considered when switching these antacids.

Isobutyric acid enhances the anti-tumour effect of anti-PD-1 antibody.

The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

[TWO CASES OF LARYNGEAL EDEMA CAUSED BY SUBLINGUAL ALLERGEN IMMUNOTHERAPY].

Sublingual immunotherapy is a widely used treatment, and serious adverse reactions such as anaphylaxis are rare. We report two cases of laryngeal edema as adverse reactions to sublingual immunotherapy, which could be continued due to a change in the administration method. Case 1 presents a 15-year-old male suspected to have had anaphylaxis due to the dust at the age of 6 years. He started treatment with Miticure® and developed laryngeal edema 30 minutes after taking the 10000JAU dose on the 10th day. laryngeal edema was treated with intravenous infusion. Case 2 presents a 48-year-old woman. She started treatment with Cidacure® and developed respiratory distress and laryngeal edema 1 hour after taking the 5000JAU dose on the 5th day. she had resolved mildly without therapeutic intervention. In both cases, the patients were switched to sublingual spitting, resumed with the initial dose cautiously, and were able to continue. Sublingual immunotherapy is a safe treatment, but sudden adverse reactions may occur. Laryngeal symptoms may be treated by changing to the sublingual spitting method, but laryngeal findings should be examined, and the dosage should be carefully increased.

Discrimination of the moving direction is improved depending on the pattern of the mechanical tactile stimulation intervention.

BACKGROUND: The mechanical tactile stimulation, such as plastic pins and airflow-driven membrane, induces cortical activity. The cortical activity depends on the mechanical tactile stimulation pattern. Therefore, the stimulation pattern of mechanical tactile stimuli intervention may influence its effect on the somatosensory function. However, the effect of the mechanical tactile stimulation input pattern on the somatosensory function has not yet been investigated at the behavioral level. The present study aimed to clarify the effects of mechanical tactile stimuli intervention with different stimulation patterns on the ability to discriminate moving directions. RESULTS: Twenty healthy adults participated in the experiment. Three conditions were used for mechanical tactile stimuli intervention: (1) the whole stimulus surface was stimulated, (2) the stimulus moved within the stimulus surface, and (3) a no-stimulus condition. The effects of mechanical tactile stimuli intervention on tactile discrimination were evaluated using a simple reaction task and a choice reaction task to discriminate the movement direction. Reaction time, correct rate, and rate correct score were calculated to measure task performance. We examined the effects of mechanical tactile stimuli intervention on the ability to discriminate the moving direction for a certain period under three intervention conditions. The results showed that the mean reaction time during the simple reaction task did not differ significantly before and after the intervention under all intervention conditions. Similarly, we compared the data obtained before and after the intervention during the choice reaction task. Our results revealed that the mean reaction time and correct rate did not differ significantly under vertical and horizontal conditions. However, the rate correct score showed a significant improvement after the horizontal moving tactile stimulation intervention under both vertical and horizontal conditions. CONCLUSIONS: Our results showed that the effect of mechanical tactile stimuli intervention on mechanical tactile stimulation moving direction discrimination function depended on the input pattern of mechanical tactile stimuli intervention. Our results suggest the potential therapeutic benefits of sustained tactile stimulation intervention. This study revealed that it is possible to change behavioral levels via mechanical tactile stimuli intervention as well as the potential of mechanical tactile stimuli intervention in the field of rehabilitation.

Current status and future perspectives on robot-assisted kidney autotransplantation: A literature review.

This review presents the latest insights on robot-assisted kidney autotransplantation (RAKAT). RAKAT is a minimally invasive surgical procedure and represents a promising alternative to conventional laparoscopic nephrectomy followed by open kidney transplantation for the treatment of various complex urological and vascular conditions. RAKAT can be performed either extracorporeally or intracorporeally. Additionally, a single-port approach can be performed through one small incision without the need to reposition the patient. Of 86 patients undergoing RAKAT, 8 (9.3%) developed postoperative > Grade 2 Clavien-Dindo (CD) complications. Although the feasibility of RAKAT was established in 2014, the long-term efficacy and safety along with outcomes of this surgical approach are still being evaluated, and additional studies are needed. With improvements in the technology of RAKAT and as surgeons gain more experience, RAKAT should become increasingly used and further refined, thereby leading to improved surgical outcomes and improved patients' quality of life.

Pharmacokinetics of monoclonal antibodies locally-applied into the middle ear of guinea pigs.

Countless therapeutic antibodies are currently available for the treatment of a broad range of diseases. Some target molecules of therapeutic antibodies are involved in the pathogenesis of sensorineural hearing loss (SNHL), suggesting that SNHL may be a novel target for monoclonal antibody (mAb) therapy. When considering mAb therapy for SNHL, understanding of the pharmacokinetics of mAbs after local application into the middle ear is crucial. To reveal the fundamental characteristics of mAb pharmacokinetics following local application into the middle ear of guinea pigs, we performed pharmacokinetic analyses of mouse monoclonal antibodies to FLAG-tag (FLAG-mAbs), which have no specific binding sites in the middle and inner ear. FLAG-mAbs were rapidly transferred from the middle ear to the cochlear fluid, indicating high permeability of the round window membrane to mAbs. FLAG-mAbs were eliminated from the cochlear fluid 3 h after application, similar to small molecules. Whole-body autoradiography and quantitative assessments of cerebrospinal fluid and serum demonstrated that the biodistribution of FLAG-mAbs was limited to the middle and inner ear. Altogether, the pharmacokinetics of mAbs are similar to those of small molecules when locally applied into the middle ear, suggesting the necessity of drug delivery systems for appropriate mAb delivery to the cochlear fluid after local application into the middle ear.

Residual nasal polyp tissue following dupilumab therapy is associated with periostin-associated fibrosis.

PURPOSE: Dupilumab, an anti-interleukin-4 receptor alpha monoclonal antibody, is a new treatment for severe uncontrolled chronic rhinosinusitis with nasal polyps. However, data on the effect of dupilumab on histological changes in nasal polyp tissue are lacking. We aimed to investigate the effect of dupilumab on real-life clinical conditions and nasal polyp tissues from patients with eosinophilic chronic rhinosinusitis (ECRS), which is a refractory subtype. METHODS: We conducted an open-label, prospective, observational, single-centre study on 63 patients with refractory ECRS on the basis of the criteria of the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study. These patients had a history of surgery and received dupilumab for 24 weeks. Patient-reported sinonasal symptoms, T&T olfactometry and nasal polyp scores were prospectively evaluated. In 23 patients with residual nasal polyps following dupilumab treatment, changes in systemic and local periostin expression, and total collagen deposition in nasal polyp tissues were investigated before and after dupilumab administration. RESULTS: Dupilumab rapidly improved sinonasal symptoms and reduced the nasal polyp score 24 weeks after initiation. 40 (63.5%) patients had resolution of nasal polyps, but the reduction was limited in the remaining 23 (36.5%) patients. Periostin expression in serum and nasal lavage fluid was decreased, whereas periostin and the total collagen deposition area in subepithelial tissues in residual nasal polyps were enhanced after dupilumab administration. CONCLUSION: Dupilumab improves sinonasal symptoms and reduces the nasal polyp score in refractory ECRS. Periostin-associated tissue fibrosis may be involved in the differential effect of dupilumab on nasal polyp reduction.

Long-Term Outcomes of Simple Endovascular Aneurysm Repair Based on the Initial Aortic Diameter.

PURPOSE: We aimed to investigate the effects of initial abdominal aortic aneurysm (AAA) diameter on aneurysmal sac expansion/shrinkage, endoleaks, and reintervention postelective simple endovascular aneurysm repair (EVAR). METHODS: Overall, 228 patients monitored for >1 year after EVAR were analyzed. Male and female participants with initial AAA diameters <55 mm and <50 mm, respectively, composed the small group (group S), while those with initial AAA diameters ≥55 mm (men) and ≥50 mm (women) composed the large group (group L). Aneurysmal sac expansion of 10 mm and/or reintervention during follow-up (composite event) and its related factors were evaluated. RESULTS: The 5-year freedom from composite event rate was significantly higher in group S (92.4 ± 2.8%) than that in group L (79.1 ± 4.9%; P <0.01). Multivariate analysis revealed AAA diameters before EVAR in group S (hazard ratio, 0.38; 95% confidence interval, 0.18-0.81; P = 0.01) and type II endoleak (T2EL) at discharge (hazard ratio, 2.83; 95% confidence interval, 1.29-6.20; P <0.01) as factors associated with the composite event. The freedom from composite event rate decreased to 51 ± 13% at 5 years in group L with T2EL. CONCLUSIONS: Group S had high freedom from composite event rate; in group L, the rate decreased to 51% at 5 years with T2EL at discharge.

Prognostic impact of radiological tumor burden in patients with metastatic urothelial carcinoma treated with pembrolizumab.

PURPOSE: Radiological tumor burden has been reported to be prognostic in many malignancies in the immunotherapy era, yet whether it is prognostic in patients with metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains uninvestigated. We sought to assess the predictive and prognostic value of radiological tumor burden in patients with mUC. METHODS: We performed a retrospective analysis of 308 patients with mUC treated with pembrolizumab. Radiological tumor burden was represented by baseline tumor size (BTS) and baseline tumor number (BTN). Optimal cut-off value of BTS was determined as 50 mm using the Youden index (small BTS: n = 194, large BTS: n = 114). Overall (OS), cancer-specific (CSS), progression-free survival (PFS), and objective response rate (ORR) were compared. Non-linear associations between BTS and OS and CSS were evaluated using restricted cubic splines. RESULTS: Patients with large BTS were less likely to have undergone the surgical resection of the primary tumor (P = 0.01), and more likely to have liver metastasis (P < 0.001) and more metastatic lesions (P < 0.001). On multivariable analyses controlling for the effects of confounders (resection of primary tumor, metastatic site, number of metastases and lactate dehydrogenase level), large BTS and high BTN were independently associated with worse OS (HR 1.52; P = 0.015, and HR 1.69; P = 0.018, respectively) and CSS (HR 1.59; P = 0.01, and HR 1.66; P = 0.031, respectively), but not PFS. Restricted cubic splines revealed BTS was correlated with OS and CSS in linear relationships. Additionally, large BTS was significantly predictive of lower ORR and complete response rate on univariable analyses (P = 0.041 and P = 0.032, respectively), but its association disappeared on multivariable analyses. CONCLUSION: Radiological tumor burden has independent prognostic value with a linear relationship in pembrolizumab-treated patients with mUC and might help drive the earlier introduction of second-line pembrolizumab and/or switching to subsequent therapies.

The Diagnosis and Treatment Approach for Oligo-Recurrent and Oligo-Progressive Renal Cell Carcinoma.

One-third of renal cell carcinomas (RCCs) without metastases develop metastatic disease after extirpative surgery for the primary tumors. The majority of metastatic RCC cases, along with treated primary lesions, involve limited lesions termed "oligo-recurrent" disease. The role of metastasis-directed therapy (MDT), including stereotactic body radiation therapy (SBRT) and metastasectomy, in the treatment of oligo-recurrent RCC has evolved. Although the surgical resection of all lesions alone can have a curative intent, SBRT is a valuable treatment option, especially for patients concurrently receiving systemic therapy. Contemporary immune checkpoint inhibitor (ICI) combination therapies remain central to the management of metastatic RCC. However, one objective of MDT is to delay the initiation of systemic therapies, thereby sparing patients from potentially unnecessary burdens. Undertaking MDT for cases showing progression under systemic therapies, known as "oligo-progression", can be complex in considering the treatment approach. Its efficacy may be diminished compared to patients with stable disease. SBRT combined with ICI can be a promising treatment for these cases because radiation therapy has been shown to affect the tumor microenvironment and areas beyond the irradiated sites. This may enhance the efficacy of ICIs, although their efficacy has only been demonstrated in clinical trials.

Integrated analysis of the oral and intestinal microbiome and metabolome of elderly people with more than 26 original teeth: a pilot study.

Elderly subjects with more than 20 natural teeth have a higher healthy life expectancy than those with few or no teeth. The oral microbiome and its metabolome are associated with oral health, and they are also associated with systemic health via the oral-gut axis. Here, we analyzed the oral and gut microbiome and metabolome profiles of elderly subjects with more than 26 natural teeth. Salivary samples collected as mouth-rinsed water and fecal samples were obtained from 22 healthy individuals, 10 elderly individuals with more than 26 natural teeth and 24 subjects with periodontal disease. The oral microbiome and metabolome profiles of elderly individuals resembled those of subjects with periodontal disease, with the metabolome showing a more substantial differential abundance of components. Despite the distinct oral metabolome profiles, there was no differential abundance of components in the gut microbiome and metabolomes, except for enrichment of short-chain fatty acids in elderly subjects. Finally, to investigate the relationship between the oral and gut microbiome and metabolome, we analyzed bacterial coexistence in the oral cavity and gut and analyzed the correlation of metabolite levels between the oral cavity and gut. However, there were few associations between oral and gut for bacteria and metabolites in either elderly or healthy subjects. Overall, these results indicate distinct oral microbiome and metabolome profiles, as well as the lack of an oral-gut axis in elderly subjects with a high number of natural teeth.

Dysbiosis of oral microbiome persists after dental treatment-induced remission of periodontal disease and dental caries.

IMPORTANCE: We characterized the oral conditions, salivary microbiome, and metabolome after dental treatment by investigating the state after treatment completion and transition to self-care. Dental treatment improved oral health conditions, resulting in oral disease remission; however, the imbalanced state of the salivary microbiome continued even after remission. Although the results of this study are preliminary, owing to the small number of participants in each group when compared to larger cohort studies, they indicate that the risk of disease may remain higher than that of healthy participants, thereby demonstrating the importance of removing dental plaque containing disease-related bacteria using appropriate care even after treatment completion. We also identified bacterial species with relative abundances that differed from those of healthy participants even after remission of symptoms, which may indicate that the maturation of certain bacterial species must be controlled to improve the oral microbiome and reduce the risk of disease recurrence.

Alkalized lidocaine in a tapered cuff suppresses endotracheal tube-induced hemodynamic changes: a randomized controlled trial.

PURPOSE: The use of an endotracheal tube (ET) cuff filled with alkalized lidocaine (AL) can suppress ET-induced emergence phenomena, such as hypertension, tachycardia and coughing, and postoperative sore throat (POST) and hoarseness (PH). The efficacy of intracuff lidocaine may vary depending on the cuff shape, but there has been no study on the effects of a tapered cuff filled with AL. We examined whether intracuff AL suppresses ET-induced emergence phenomena, POST and PH. METHODS: Sixty-two patients were enrolled in this study and the patients were randomly allocated to a group in which the tapered cuff was filled with AL (Group AL) and a group in which the tapered cuff was filled with normal saline (Group S). The primary outcomes of this study were changes in mean blood pressure (MBP) and heart rate (HR) at extubation. MBP, HR and the number of coughs were recorded before and up to 10 min after extubation. The degree of POST and the incidences of POST and PH were recorded at 15 min, 2 h and 24 h after extubation. RESULTS: Changes in MBP before extubation and HR before and after extubation were significantly lower in Group AL than in Group S (p < 0.025). The number of coughs at extubation and the incidence of PH at 2 h after extubation were significantly lower in Group AL than in Group S (p < 0.0001 and p = 0.014, respectively). CONCLUSION: AL in a tapered cuff significantly suppresses ET-induced cardiovascular changes in MBP and HR.

Eosinophilic granulomatosis with polyangiitis developed after dupilumab administration in patients with eosinophilic chronic rhinosinusitis and asthma: a case report.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small-to-medium vessel vasculitis associated with asthma, rhinosinusitis, and eosinophilia. EGPA is often difficult to distinguish from severe asthma and eosinophilic chronic rhinosinusitis (ECRS) in cases when there are no findings that suggest vasculitis. Dupilumab, an anti-IL-4Rα monoclonal antibody, is expected to be effective in eosinophilic airway inflammatory diseases, such as refractory asthma and chronic rhinosinusitis (CRS). Although transient eosinophilia and eosinophilic pneumoniae have been reported in patients with refractory asthma and CRS associated with dupilumab, few studies have examined the development of EGPA. CASE PRESENTATION: We report a case of a 61-year-old woman treated with dupilumab for refractory ECRS and eosinophilic otitis media (EOM) complicated by severe asthma. Although she had a previous history of eosinophilic pneumoniae and myeloperoxidase (MPO) ANCA positivity, there were no apparent findings of vasculitis before the initiation of dupilumab. After the second administration of dupilumab, several adverse events developed, including worsening of ECRS, EOM and asthma, and neuropathy. A blood test showed an eosoinophilia and re-elevation of MPO-ANCA levels after the administration of dupilumab. Therefore, dupilumab was discontinued owing to the development of EGPA, and prednisolone and azathioprine administration was initiated for a remission induction therapy. CONCLUSION: To the best of our knowledge, this is the first case report that suggests that dupilumab may directly trigger the manifestation of vasculitis in patients who were previously MPO-ANCA-positive. Although the precise mechanism of how dupilumab could trigger the development of EGPA requires further elucidation, measuring MPO-ANCA in patients with multiple eosinophilic disorders before the initiation of dupilumab might be helpful when considering the possibility of a latent EGPA. When administering dupilumab to patients with a previous history of MPO-ANCA positivity, clinicians must carefully monitor and collaborate with other specialists in the pertinent fields of study for appropriate usage.

The Genotypic and Phenotypic Characteristics Contributing to Flomoxef Sensitivity in Clinical Isolates of ESBL-Producing E. coli Strains from Urinary Tract Infections.

We carried out a molecular biological analysis of extended-spectrum ß-lactamase (ESBL)-producing E. coli strains and their sensitivity to flomoxef (FMOX). Sequence type (ST) analysis by multilocus sequence typing (MLST) and classification of ESBL genotypes by multiplex PCR were performed on ESBL-producing E. coli strains isolated from urine samples collected from patients treated at our institution between 2008 and 2018. These sequences were compared with results for antimicrobial drug susceptibility determined using a micro-liquid dilution method. We also analyzed cases treated with FMOX at our institution to examine its clinical efficacy. Of the 911 E. coli strains identified, 158 (17.3%) were ESBL-producing. Of these, 67.7% (107/158) were strain ST-131 in ST analysis. Nearly all (154/158; 97.5%) were CTX-M genotypes, with M-14 and M-27 predominating. The isolated strains were sensitive to FMOX in drug susceptibility tests. Among the patient samples, 33 cases received FMOX, and of these, 5 had ESBL-producing E. coli. Among these five cases, three received FMOX for surgical prophylaxis as urinary carriers of ESBL-producing E. coli, and postoperative infections were prevented in all three patients. The other two patients received FMOX treatment for urinary tract infections. FMOX treatment was successful for one, and the other was switched to carbapenem. Our results suggest that FMOX has efficacy for perioperative prophylactic administration in urologic surgery involving carriers of ESBL-producing bacteria and for therapeutic administration for urinary tract infections. Use of FMOX avoids over-reliance on carbapenems or ß-lactamase inhibitors and thus is an effective antimicrobial countermeasure.

S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters.

In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622 (ensitrelvir), an inhibitor of SARS-CoV-2 main protease (Mpro; also known as 3C-like protease), decreases viral load and ameliorates disease severity in SARS-CoV-2-infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to submicromolar concentrations in cells. Oral administration of S-217622 demonstrated favorable pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern, including the highly pathogenic Delta variant and the recently emerged Omicron BA.5 and BA.2.75 variants. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase 3 clinical trial (clinical trial registration no. jRCT2031210350), has remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.