Oral mouthwashes for asymptomatic to mildly symptomatic adults with COVID-19 and salivary viral load: a randomized, placebo-controlled, open-label clinical trial.

BACKGROUND: Recent randomized clinical trials suggest that the effect of using cetylpyridinium chloride (CPC) mouthwashes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in COVID-19 patients has been inconsistent. Additionally, no clinical study has investigated the effectiveness of on-demand aqueous chlorine dioxide mouthwash against COVID-19. METHODS: We performed a randomized, placebo-controlled, open-label clinical trial to assess for any effects of using mouthwash on the salivary SARS-CoV-2 viral load among asymptomatic to mildly symptomatic adult COVID-19-positive patients. Patients were randomized to receive either 20 mL of 0.05% CPC, 10 mL of 0.01% on-demand aqueous chlorine dioxide, or 20 mL of placebo mouthwash (purified water) in a 1:1:1 ratio. The primary endpoint was the cycle threshold (Ct) values employed for SARS-CoV-2 salivary viral load estimation. We used linear mixed-effects models to assess for any effect of the mouthwashes on SARS-CoV-2 salivary viral load. RESULTS: Of a total of 96 eligible participants enrolled from November 7, 2022, to January 19, 2023, 90 were accepted for the primary analysis. The use of 0.05% CPC mouthwash was not shown to be superior to placebo in change from baseline salivary Ct value at 30 min (difference vs. placebo, 0.640; 95% confidence interval [CI], -1.425 to 2.706; P = 0.543); 2 h (difference vs. placebo, 1.158; 95% CI, -0.797 to 3.112; P = 0.246); 4 h (difference vs. placebo, 1.283; 95% CI, -0.719 to 3.285; P = 0.209); 10 h (difference vs. placebo, 0.304; 95% CI, -1.777 to 2.385; P = 0.775); or 24 h (difference vs. placebo, 0.782; 95% CI, -1.195 to 2.759; P = 0.438). The use of 0.01% on-demand aqueous chlorine dioxide mouthwash was also not shown to be superior to placebo in change from baseline salivary Ct value at 30 min (difference vs. placebo, 0.905; 95% CI, -1.079 to 2.888; P = 0.371); 2 h (difference vs. placebo, 0.709; 95% CI, -1.275 to 2.693; P = 0.483); 4 h (difference vs. placebo, 0.220; 95% CI, -1.787 to 2.226; P = 0.830); 10 h (difference vs. placebo, 0.198; 95% CI, -1.901 to 2.296; P = 0.854); or 24 h (difference vs. placebo, 0.784; 95% CI, -1.236 to 2.804; P = 0.447). CONCLUSIONS: In asymptomatic to mildly symptomatic adults with COVID-19, compared to placebo, the use of 0.05% CPC and 0.01% on-demand aqueous chlorine dioxide mouthwash did not lead to a significant reduction in SARS-CoV-2 salivary viral load. Future studies of the efficacy of CPC and on-demand aqueous chlorine dioxide mouthwash on the viral viability of SARS-CoV-2 should be conducted using different specimen types and in multiple populations and settings.

Clostridium butyricum Bacteremia Associated with Probiotic Use, Japan.

Clostridium butyricum, a probiotic commonly prescribed in Asia, most notably as MIYA-BM (Miyarisan Pharmaceutical Co., Ltd.; https://www.miyarisan.com), occasionally leads to bacteremia. The prevalence and characteristics of C. butyricum bacteremia and its bacteriologic and genetic underpinnings remain unknown. We retrospectively investigated patients admitted to Osaka University Hospital during September 2011-February 2023. Whole-genome sequencing revealed 5 (0.08%) cases of C. butyricum bacteremia among 6,576 case-patients who had blood cultures positive for any bacteria. Four patients consumed MIYA-BM, and 1 patient consumed a different C. butyricum-containing probiotic. Most patients had compromised immune systems, and common symptoms included fever and abdominal distress. One patient died of nonocclusive mesenteric ischemia. Sequencing results confirmed that all identified C. butyricum bacteremia strains were probiotic derivatives. Our findings underscore the risk for bacteremia resulting from probiotic use, especially in hospitalized patients, necessitating judicious prescription practices.

Protocol for a Randomized, Open-Label Clinical Trial on the Effect of Mouthwash on Salivary SARS-CoV-2 Load.

Mouthwashes containing cetylpyridinium chloride (CPC) or on-demand aqueous chlorine dioxide (ACD) have potential to reduce the salivary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) load in individuals with SARS-CoV-2 infection. This study will evaluate the effect of CPC and on-demand ACD mouthwashes on salivary SARS-CoV-2 levels in individuals with acute asymptomatic or mild SARS-CoV-2 infection (COVID-19) staying in a residential recuperation facility in Osaka, Japan. This randomized, open-label clinical trial will include three equal-sized groups (CPC mouthwash, on-demand ACD mouthwash, and placebo), with 30 participants per group. A stratified replacement block method will be used to ensure balanced allocation based on symptom presence and days since symptom onset. Participants will use mouthwash at set times for 7 days or until the end of recuperation. Saliva samples will be collected at multiple time points and tested for SARS-CoV-2 using quantitative reverse transcription polymerase chain reaction. The primary outcome will be changes in salivary SARS-CoV-2 viral load 2 h after the first mouthwash use compared with the pre-mouthwash level. Secondary outcomes will include changes in salivary viral load and clinical parameters at different time points. This study was registered with the Japan Registry of Clinical Trials on 18 October 2022 (jRCTs051220107).

Aneurysm Infection Caused by Desulfovibrio desulfuricans.

An 84-year-old man in Japan who had undergone endovascular aortic repair 9 years earlier had an infected aneurysm develop. We detected Desulfovibrio desulfuricans MB at the site. The patient recovered after surgical debridement, artificial vessel replacement, and appropriate antimicrobial therapy. Clinicians should suspect Desulfovibrio spp. infection in similar cases.

Cutaneous nontuberculous mycobacterial infections in Japan: Review of the Japanese literature.

Nontuberculous mycobacteria cause a wide range of infections, including cutaneous infections, in both immunocompromised and immunocompetent patients. Although pulmonary nontuberculous mycobacterial infections have increased significantly in Japan in recent years, there is less evidence on clinical and microbiological characteristics of cutaneous nontuberculous mycobacterial infections in Japan. We reviewed 86 Japanese cases reported between July 2016 and November 2021 and analyzed them in conjunction with the eight patients from our institution who were diagnosed with cutaneous nontuberculous mycobacterial infections by culture between 2015 and 2021. In the aggregate series, the average patient age was 60 years, and the ratio of immunocompromised hosts was 53%, both of which were higher than those in previous reports from other countries. No female predominance was observed, unlike in pulmonary nontuberculous mycobacteria infections. Rapidly growing mycobacteria accounted for 58% of the cases (n = 54), whereas slowly growing mycobacteria for 43% (n = 40). Mycobacterium marinum (also known as Mycobacteroides marinum) (n = 20, 21%) was the most common cause, followed by Mycobacterium chelonae (n = 18, 19%), Mycobacterium abscessus (also known as Mycobacteroides abscessus) (n = 15, 16%), and Mycobacterium ulcerans (n = 11, 12%). While clinical appearance was variable, M ulcerans infections usually presented with ulcers, while nodules were common among infections caused by M chelonae and M marinum. Disseminated infections involving multiple organs were observed in 23 patients (24%). Thirty-two cases (30%) were preceded by exposure, including raising or handling fish, trauma, and invasive medical procedures. Most patients were treated with more than two antibiotics and responded to therapy.

Gender Differences in Anxiety Among COVID-19 Inpatients Under Isolation: A Questionnaire Survey During the First and Second Waves of the COVID-19 Pandemic in Japan.

This study assesses the gender differences in health and anxiety, especially pertaining to mental health problems and time-course effects. We surveyed 121 patients admitted to a hospital with a COVID-19 diagnosis between March 1 and August 31, 2020. Their mental status was evaluated on admission using the Japanese General Health Questionnaire-28 (GHQ-28) and State-Trait Anxiety Inventory-Form JYZ (STAI). The patients were divided into two groups depending on the period of prevalence, that is, the first and second waves of the pandemic in Japan (from the beginning of March to the end of May 2020, Time 1 = T1; and from the beginning of June to the end of August 2020, Time 2 = T2). A multivariate analysis of covariance revealed significant differences in gender by time interactions in the GHQ-28 subscale "Insomnia and anxiety" and STAI subscale "State-Anxiety." Post-hoc t-tests revealed that the scores of "Insomnia and Anxiety" and "State-Anxiety" were higher in women than in men at T1. However, no difference was observed at T2. Further, "Insomnia and Anxiety" and "State-Anxiety" were significantly higher at T1 than at T2 in female patients. There was no significant difference in males. Thus, female patients were more anxious and depressed in the early phase of the pandemic, whereas male patients had difficulties in coping with anxiety. We suggest more gender-specific mental care, particularly for women at the early stages of infection.

Shortening antibiotic duration in the treatment of acute cholangitis: rationale and study protocol for an open-label randomized controlled trial.

BACKGROUND: Antimicrobial therapy with appropriate biliary drainage is considered the standard of care for acute cholangitis, but the optimal duration of antimicrobial therapy remains unknown. Seven to 10 days of antimicrobial therapy are common for the treatment of acute cholangitis, but a recent retrospective cohort study suggested a shorter duration might be effective. A shorter duration of antimicrobial therapy can be beneficial in decreasing the length of hospital stay, improving patients' quality of life, decreasing adverse effects, and even contributing to a decrease in the occurrence of antimicrobial resistance. METHODS/DESIGN: We will conduct a multi-centre, open-label, randomized, non-inferiority trial to compare short-course therapy (SCT) with conventional long-course therapy (LCT) in treating patients with acute cholangitis. SCT consists of 5-day intravenous antimicrobial therapy if the patients had clinical improvement, while at least 7 days of intravenous antibiotics will be provided to the LCT group. The primary outcome is clinical cure at 30 days after onset. Patients will be randomly assigned in an open-label fashion. A total sample size of 150 was estimated to provide a power of 80% with a one-sided α level of 2.5% and a non-inferiority margin of 10%. DISCUSSION: This trial is expected to reveal whether SCT is non-inferior to conventional LCT or not, and may provide evidence that one can shorten the treatment duration for acute cholangitis for the benefit of patients. TRIAL REGISTRATION: University Hospital Medical Information Network, UMIN000028382. Registered on 30 August 2017.

[Necrotizing Soft Tissue Infection Caused by Serratia marcescens in a Patient Treated with Tocilizumab].

We report herein on a case of community-acquired necrotizing soft tissue infection caused by Serratia marcescens. The patient had been treated with prednisolone, tocilizumab and tacrolimus for rheumatoid arthritis. Since Gram staining of the tissue revealed Gram negative rod bacteria, ceftriaxone and clindamycin were administered as empiric therapy. Tissue culture revealed S. marcescens. Ceftriaxone was continued according to the antibiotic sensitivity. She underwent debridement of necrotic tissue and continued ceftriaxone for 17 days. She recovered and was discharged after skin grafting.

Disseminated nocardiosis during systemic steroid therapy for the prevention of esophageal stricture after endoscopic submucosal dissection.

An 85-year-old man underwent endoscopic submucosal dissection for a large superficial esophageal epithelial neoplasm, which required removal of 95% of the circumference of the esophageal mucosa. Steroids were given orally to prevent esophageal stricture starting on day 3 postoperatively. In the 6th week of steroid treatment, he developed high fever without other symptoms. Chest computed tomography revealed a nodular lesion in the lung. Sputum sample showed Gram-positive, branching, filamentous bacteria, and a diagnosis of nocardiosis was suspected. Brain magnetic resonance imaging revealed multiple focal lesions which indicated dissemination of nocardiosis. Trimethoprim-sulfamethoxazole was immediately started, which led to the disappearance of pulmonary and cerebral nocardiosis with alleviation of fever. Recently, oral steroid treatment has been widely used for the prevention of esophageal stricture. However, the present case indicates the risk of life-threatening infection and the importance of close monitoring of this treatment.

Impact of peginterferon alpha-2b and entecavir hydrate combination therapy on persistent viral suppression in patients with chronic hepatitis B.

The ideal approach to treat chronic hepatitis B remains controversial. This pilot study aimed to evaluate the effectiveness of peginterferon (PEG-IFN) α-2b and entecavir hydrate (ETV) as a combination therapy for patients with chronic hepatitis B, particularly in the context of virological response and the reduction of intrahepatic covalently closed circular DNA (cccDNA). A total of 17 patients with hepatitis B virus (HBV) genotype C were enrolled in this study. All subjects were treated with this combination therapy for 48 weeks and observed for an additional 24 weeks. All patients underwent liver biopsy before and after the therapy period. Changes in cccDNA levels and liver histology were monitored between biopsies. Among the 11 patients who exhibited pre-therapy hepatitis B e antigen (HBeAg), 8 (73%) showed evidence of HBeAg seroconversion by the end of the follow-up period. Serum HBV DNA levels decreased by 5.2 and 3.3 log copies/ml (mean) by the end of the therapy and follow-up periods, respectively. In addition, intrahepatic cccDNA decreased significantly to 1.4 log copies/µg (mean) by the end of the therapy period. Among the 11 patients who did not experience viral relapse, only 2 (18%) exhibited high levels of cccDNA (>4.5 log copies/µg) by the end of the treatment period. In contrast, all relapsed subjects exhibited significantly higher levels of cccDNA than subjects who did not relapse (P = 0.027). The combination regimen is a promising approach to treat chronic hepatitis B and may achieve significant reduction in serum HBV DNA and intrahepatic cccDNA. Wiley Periodicals, Inc.

Visualization of blood drainage area from hypervascular hepatocellular carcinoma on ultrasonographic images during hepatic arteriogram: Comparison with depiction of drainage area on contrast-enhanced ultrasound.

AIM: Corona enhancement is the visualized drainage area from a hypervascular tumor observed on single-level dynamic computed tomography during hepatic arteriography (CTHA) and is thought to be a high-risk area for micrometastases. However, because it cannot be visualized with ordinary ultrasonography (US), we aimed to visualize corona enhancement on US by means of arterial injection of the contrast material and to measure its thickness. METHOD: Forty-one hypervascular hepatocellular carcinoma (HCC) cases were prospectively investigated. US during hepatic arteriography (USHA) was executed by means of selective injection of the contrast material perfluorobutane (Sonazoid) from the hepatic artery. Ordinary contrast-enhanced US with venous administration of contrast material and single-level dynamic CTHA were also performed. RESULTS: Corona enhancement was observed in 36 cases (88%) on USHA and in 25 cases (61%) on single-level dynamic CTHA. The thickness of corona enhancement of 36 cases visualized with USHA ranged 3.1-18.4 mm and the mean thickness ± standard deviation was 6.0 ± 3.0 mm. Thickness of corona enhancement was less than 10.0 mm in 34 cases (94%). CONCLUSION: Corona enhancement could be visualized even on US images, and the average thickness of them was 6 mm.

[A case of primary liver carcinoma of intermediate (hepatocyte-cholangiocyte) phenotype: comparison of hemodynamics and histopathology].

A 58-year-old man was followed up for HBV-associated chronic hepatitis. A low echoic hepatic nodule 1.6cm in diameter developed in segment 8 of the liver. The tumor was hypervascular and showed enhancement on CV during hepatic arteriography (CTHA) and a defect on CT during arterial portography (CTAP). Strong enhancement, which lasted for 30 seconds, was observed at the margin of the tumor on single-level dynamic CTHA. The resected tumor was whitish, had no capsule, and consisted mainly of intermediate immature cells together with HCC-like and CCC-like tumor cells. These findings led to the diagnosis of primary liver carcinoma of intermediate (hepatocyte-cholangiocyte) phenotype. Cytokeratin (CK) 7, CK8, CK19, EMA and vimentin were positive and HP-1 and c-kit tests were negative on immunohistochemical staining. Staining with CD34+alphaSMA showed more muscular arterial vessels and sinusoid-like vessels in the peripheral zone of the tumor than in the central zone. Six months after the resection of the tumor, swollen abdominal lymph nodes were observed on US and CT, which aspiration needle biopsy showed to be metastasis of a hepatic tumor.

[Seven cases of gemcitabine-induced lung injury during treatment for pancreatic or biliary tract cancers].

Gemcitabine is an anti-cancer drug known to be safe and effective for pancreatic or biliary tract cancers, but lung injury is also known to be a rare side effect that sometimes becomes severe. Here we report seven cases of lung injury during gemcitabine treatment. Drug-induced lung injury was suspected in all cases. The male: female ratio was 5:2, and the average patient age was 71. Four had pancreatic cancers and three had biliary tract cancers. Gemcitabine had been administered an average 5.9 times at a dose of 1,141 mg. Patients showed a diffuse or patchy shadow mainly in the lower lung on computed tomography examination. Grades of adverse events were greater than 3 in all cases. Three patients died of the lung injury. Five cases had pulmonary emphysema, 2 had metastatic lung tumor as underlying pulmonary lesions, and these were assumed to have been important risk factors for drug-induced interstitial lung injury during gemcitabine treatment.

[A case of focal nodular hyperplasia presenting corona enhancement on single-level dynamic CT during hepatic arteriography].

A hepatic nodule was detected in segment 5/6 on abdominal US study in a 28 year-old male. The nodule was 7cm in diameter and the early phase of contrasted US, CT and MRI images showed spoke-wheel like vessels radiating from the center. No defect images were observed on postvascular phase contrasted US and SPIO MRI, which indicated the presence of Kupffer cells in the nodule. The nodule was diagnosed as a focal nodular hyperplasia (FNH) based on histological findings. The late phase of single level dynamic CT during hepatic arteriography (CTHA) showed corona enhancement of the nodule, which is considered to be characteristic of hypervascular metastatic liver tumors, hyperplastic nodules and HCCs. In our case, the drainage flow from the nodule may have been visualized as corona enhancement via the pathway from the sinusoid in the nodular periphery to the one in the adjacent and contiguous parenchyma.

[Case of moderately differentiated hepatocellular carcinoma with gastric metastasis].

A solitary liver nodule about 1cm in diameter was detected in a 68-year-old male HBV carrier during therapy for advanced lung cancer. A multiple IIc-like depressed lesion originating in the stomach soon became elevated as the liver lesion progressed. HE staining produced hepatoma-like histological findings for the tumors of the lung, liver and stomach, while immunohistochemical staining showed them to be positive for PIVKA-II and weakly positive for HP-1. Autopsy led to a diagnosis of a moderately differentiated hepatocellular carcinoma producing bile juice with metastasis to the lung and stomach. It is not clear why advanced metastasis in the lung occurred while the hepatocellular carcinoma in the liver was still small, but one possible explanation lies in the localization of the hepatic cancer: the tumor was located near a branch of the hepatic vein and vascular invasion may have caused early pulmonary metastasis via the hepatic venous flow.