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Abstract Background Elevated serum immunoglobulin G4 (IgG4) concentrations are one of the characteristic findings in IgG4-related disease (IgG4-RD). This study investigated the frequency of elevated serum IgG4 levels and associated factors in a general Japanese population. Methods Serum IgG4 concentrations were measured in 1,201 residents of Ishikawa prefecture who underwent general medical examinations. Factors associated with elevated serum IgG4 concentrations were assessed by logistic regression analysis. Participants with elevated serum IgG4 were subjected to secondary examinations. Results The mean serum IgG4 concentration was 44 mg/dL, with 42 (3.5%) participants having elevated serum IgG4 levels. Age- and sex-adjusted logistic regression analyses showed that male sex, older age, and lower intake of lipids and polyunsaturated fatty acids and higher intake of carbohydrates in daily diet were associated with elevated serum IgG4 concentration. Subgroup analyses in men showed that older age, lower estimated glomerular filtration rates based on serum cystatin C (eGFR-cysC) levels, and higher hemoglobin A1c (HbA1c) levels were associated with elevated serum IgG4 concentration. Analyses in women showed that lower intake of lipids and fatty acids and higher intake of carbohydrates were significantly associated with elevated serum IgG4 concentration. One of the 15 participants who underwent secondary examinations was diagnosed with possible IgG4-related retroperitoneal fibrosis. Conclusions Elevated serum IgG4 levels in a Japanese general population were significantly associated with older age, male gender, and dietary intake of nutrients, with some of these factors identical to the epidemiological features of IgG4-RD.

Abstract Background Ruthenibacterium lactatiformans, a Gram-stain-negative, rod-shaped, obligate anaerobic bacterium of the Oscillospiraceae family, has not been previously reported in human infections. This study reports the first case of bacteraemia and potential vertebral osteomyelitis caused by Ruthenibacterium lactatiformans. Case presentation An 82-year-old man with a history of diabetes, chronic renal failure, and prior spinal surgery for spondylolisthesis and spinal stenosis presented with fever and lower back pain. Magnetic resonance imaging revealed multiple vertebral osteomyelitis lesions. Initial blood cultures identified methicillin-resistant Staphylococcus aureus (MRSA), which prompted vancomycin treatment. However, repeated blood cultures not only confirmed persistent MRSA, but also detected Gram-negative bacilli (GNB). Despite surgical removal of the spinal hardware and antimicrobial therapy, the patient’s osteomyelitis worsened, necessitating transfer for further management. Subsequent analysis using 16S rRNA gene sequencing identified the GNB as Ruthenibacterium lactatiformans. Conclusions This is the first documented instance of human infection with Ruthenibacterium lactatiformans, signifying its pathogenic potential in vertebral osteomyelitis. The involvement of anaerobic bacteria and the possibility of polymicrobial infections complicate the diagnosis and treatment of vertebral osteomyelitis. This report underscores the need for caution when identifying the causative organism and selecting an appropriate treatment.

Abstract Effective treatment for advanced lung cancer and idiopathic interstitial pneumonia (IIP) remains an unmet medical need. The relationship between chemotherapy’s effectiveness in advanced lung cancer and the risk of acute exacerbation of IIP is poorly investigated. There is limited evidence that patients who experience an acute exacerbation of IIPs during cytotoxic chemotherapy have poorer outcomes than those who do not. Among 1004 patients with advanced lung cancer and IIPs enrolled in our published multi-centre retrospective study from 110 Japanese institutions, 708 patients (male: female, 645:63; mean age, 70.4) received first-line chemotherapy. The occurrence of chemotherapy-triggered acute exacerbations of IIPs and overall survival (OS) were analysed. The OS between groups of patients with and without the occurrence of acute exacerbation was compared at four landmark time points (30, 60, 90, and 120 days), starting from the first-line chemotherapy, using the landmark method. The incidence of acute exacerbation in patients who received first-line chemotherapy with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was more frequent in NSCLC patients than in SCLC (4.2% vs 12.6%; odds ratio [OR]: 3.316; 95% confidence interval [CI] 1.25–8.8). Median survival time was 9.9 months (95% CI 9.2–10.7). Patients who experienced acute exacerbation had significant worse survival outcomes than those who did not at various time points (30 days, hazard ratio [HR]: 5.191, 95% CI 2.889–9.328; 60 days, HR: 2.351, 95% CI 1.104–5.009; 90 days, HR: 2.416, 95% CI 1.232–4.739; and 120 days, HR: 2.521, 95% CI 1.357–4.681). Acute exacerbation during first-line chemotherapy can predict poor survival. Trial Registration number: UMIN000018227.

Abstract 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, 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.

Abstract Methods for identifying bacterial pathogens are broadly categorised into conventional culture-based microbiology, nucleic acid-based tests, and mass spectrometry. The conventional method requires several days to isolate and identify bacteria. Nucleic acid-based tests and mass spectrometry are relatively rapid and reliable, but they require trained technicians. Moreover, mass spectrometry requires expensive equipment. The development of a novel, inexpensive, and simple technique for identifying bacterial pathogens is needed. Through combining micropore technology and assembly machine learning, we developed a novel classifier whose receiver operating characteristic (ROC) curve showed an area under the ROC curve of 0.94, which rapidly differentiated between Staphylococcus aureus and Staphylococcus epidermidis in this proof-of-concept study. Morphologically similar bacteria belonging to an identical genus can be distinguished using our method, which requires no specific training, and may facilitate the diagnosis and treatment of patients with bacterial infections in remote areas and in developing countries.

Introduction: Elucidating the characteristic odors of microbes can facilitate microorganism identification. This study aimed to evaluate the accuracy of microbial identification based on odor and its association with years of experience among microbiological technologists. Methods: A cross-sectional study was conducted on February 19, 2023, in Osaka, Japan, in a laboratory capable of handling microorganisms that were rated at or below biosafety level 2. This study included 70 microbiological technologists (including 45 women) with a mean experience of 7.1 years (standard deviation, 5.7). Ten bacterial strains with distinct odors were selected. Participants were blindfolded and asked to identify the bacterial strains based on odor of cultured microbes alone. Linear and logistic regression analyses were used for data analysis. The primary outcome was the number of accurately identified bacterial strains per year of experience. Results: The number of years of experience was not significantly associated with the accuracy of odor identification (regression coefficient = 0.037 [95 % confidence interval: 0.038 to 0.113]). Additionally, generally low accuracy was noted in the identification of individual microbial species. Conclusions: Our findings indicate that microorganism identification based solely on odor is challenging. Incorporating additional information, such as visual cues, may enhance the identification accuracy.

Abstract A 72‐year‐old man with productive cough and wheezing was referred to our institution for a growing mass shadow and central bronchiectasis in the right lower lobe on computed tomography. Based on the symptoms, elevated Aspergillus‐specific immunoglobulin E levels, and radiological findings, allergic bronchopulmonary mycosis (ABPM) was suspected according to the Japanese clinical diagnostic criteria. The patient refused bronchoscopic examination, and oral prednisolone (0.5 mg/kg/day) improved the symptoms; however, the mass shadow continued to grow. Subsequently, bronchoscopy revealed mucus plugs and an endobronchial tumour with a whitish surface. The tumour was surgically resected, and the pathological diagnosis was a coexistence of ABPM and pulmonary pleomorphic carcinoma. To the best of our knowledge, this is the first case of ABPM developing at the site of pulmonary pleomorphic carcinoma. Careful bronchoscopic examinations and histopathological evaluations of the surgical specimen led to a prompt and accurate diagnosis.

Summary: Pneumolysin (Ply) is an indispensable cholesterol-dependent cytolysin for pneumococcal infection. Although Ply-induced disruption of pneumococci-containing endosomal vesicles is a prerequisite for the evasion of endolysosomal bacterial clearance, its potent activity can be a double-edged sword, having a detrimental effect on bacterial survivability by inducing severe endosomal disruption, bactericidal autophagy, and scaffold epithelial cell death. Thus, Ply activity must be maintained at optimal levels. We develop a highly sensitive assay to monitor endosomal disruption using NanoBiT-Nanobody, which shows that the pneumococcal sialidase NanA can fine-tune Ply activity by trimming sialic acid from cell-membrane-bound glycans. In addition, oseltamivir, an influenza A virus sialidase inhibitor, promotes Ply-induced endosomal disruption and cytotoxicity by inhibiting NanA activity in vitro and greater tissue damage and bacterial clearance in vivo. Our findings provide a foundation for innovative therapeutic strategies for severe pneumococcal infections by exploiting the duality of Ply activity.

Abstract Background Although vaccination is recommended for protection against invasive pneumococcal disease, the frequency of pneumococcal pneumonia is still high worldwide. In fact, no vaccines are effective for all pneumococcal serotypes. Fusion pneumococcal surface protein A (PspA) has been shown to induce a broad range of cross-reactivity with clinical isolates and afford cross-protection against pneumococcal challenge in mice. Furthermore, we developed prime-boost-type mucosal vaccines that induce both antigen-specific IgG in serum and antigen-specific IgA in targeted mucosal organs in previous studies. We investigated whether our prime-boost-type immunization with a fusion PspA was effective against pneumococcal infection in mice and cynomolgus macaques. Methods C57BL/6 mice were intramuscularly injected with fusion PspA combined with CpG oligodeoxynucleotides and/or curdlan. Six weeks later, PspA was administered intranasally. Blood and bronchoalveolar lavage fluid were collected and antigen-specific IgG and IgA titers were measured. Some mice were given intranasal Streptococcus pneumoniae and the severity of infection was analyzed. Macaques were intramuscularly injected with fusion PspA combined with CpG oligodeoxynucleotides and/or curdlan at week 0 and week 4. Then, 13 or 41 weeks later, PspA was administered intratracheally. Blood and bronchoalveolar lavage fluid were collected and antigen-specific IgG and IgA titers were measured. Some macaques were intranasally administered S. pneumoniae and analyzed for the severity of pneumonia. Results Serum samples from mice and macaques injected with antigens in combination with CpG oligodeoxynucleotides and/or curdlan contained antigen-specific IgG. Bronchial samples contained antigen-specific IgA after the fusion PspA boosting. This immunization regimen effectively prevented S. pneumoniae infection. Conclusions Prime-boost-type immunization with a fusion PspA prevented S. pneumoniae infection in mice and macaques.

Abstract Background Shoulder injury related to vaccine administration, defined as shoulder pain and limited range of motion occurring after administration in the upper arm, has been previously reported. The symptom resolved completely after treatment with oral nonsteroidal anti-inflammatory drugs or an intraarticular steroid injection, however there have been few reports of long-term symptoms following coronavirus disease 2019 vaccination. This case report describes a healthy, middle-aged, healthcare worker who developed post-vaccination subacromial–subdeltoid bursitis that lasted for more than 6 months after Pfizer–BioNTech coronavirus disease 2019 vaccination. Case presentation A 55-year-old Japanese woman with no significant medical history was vaccinated in the standard site, with the needle direction perpendicular to the skin. Within a few hours after the second vaccination, severe shoulder pain and limited range of motion appeared. Although shoulder range of motion improved, her shoulder pain did not improved for several months, and she consulted an orthopedic doctor 5 months later. Radiographs of her left shoulder did not provide helpful diagnostic information. High intensity in the subacromial–subdeltoid space was seen on short TI inversion recovery of magnetic resonance imaging, showing subacromial–subdeltoid bursitis. She was diagnosed with a shoulder injury related to vaccine administration. The patient was started on an oral anti-inflammatory drug, and the left subacromial space was injected with 2.5 mg of betamethasone with 3 ml of 1% lidocaine without epinephrine every 2 weeks. One month after starting this treatment, since her shoulder pain had not improved, the oral anti-inflammatory drug was switched to tramadol hydrochloride acetaminophen. However, 3 months after switching medication, the shoulder pain continued, and she worked so as to have minimal impact on her shoulder. Conclusion A case of subacromial–subdeltoid bursitis following a second dose of the Pfizer–BioNTech coronavirus disease 2019 vaccine that lasted many months is reported. Injection technique is a modifiable risk factor, the adverse effects of which could potentially be mitigated with appropriate and relevant training of healthcare providers. To prevent this type of case, the appropriate landmark, needle length, and direction should be confirmed.

Abstract There have been several reports of drug‐induced lung injury caused by molecular‐targeted agents. Additionally, medical history of interstitial lung disease and chest irradiation are established risk factors for the development and progression of drug‐induced lung injury. Moreover, the presence of fibrosis on chest computed tomography before treatment is a predictive factor for the appearance of pneumonia induced by anticancer drugs. Accordingly, patients with a history of interstitial lung disease or pneumonitis were excluded from clinical trials of dabrafenib and trametinib combination therapy for patients with previously treated BRAF V600E‐mutant metastatic non‐small‐cell lung cancer. This article presents a case of successful dabrafenib and trametinib combination therapy in a patient with BRAF V600E‐mutant non‐small‐cell lung cancer who had a history of radiation pneumonitis and developed recurrence after conventional chemoradiotherapy.

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).

Background: this study aimed to evaluate the prognostic factors associated with long-term survival after linear accelerator (linac)-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator for brain metastasis (BM). Methods: This single-center retrospective study included 226 consecutive patients with BM who were treated with linac-based SRS or fSRT with a micro-multileaf collimator between January 2011 and December 2018. Long-term survival (LTS) was defined as survival for more than 2 years after SRS/fSRT. Results: The tumors originated from the lung (n = 189, 83.6%), breast (n = 11, 4.9%), colon (n = 9, 4.0%), stomach (n = 4, 1.8%), kidney (n = 3, 1.3%), esophagus (n = 3, 1.3%), and other regions (n = 7, 3.1%). The median pretreatment Karnofsky performance scale (KPS) score was 90 (range: 40–100). The median follow-up time was 13 (range: 0–120) months. Out of the 226 patients, 72 (31.8%) were categorized in the LTS group. The median survival time was 43 months and 13 months in the LTS group and in the entire cohort, respectively. The 3-year, 4-year, and 5-year survival rate in the LTS group was 59.1%, 49.6%, and 40.7%, respectively. Multivariate regression logistic analysis showed that female sex, a pre-treatment KPS score ≥ 80, and the absence of extracranial metastasis were associated with long-term survival. Conclusions: female sex, a favorable pre-treatment KPS score, and the absence of extracranial metastasis were associated with long-term survival in the current cohort of patients with BM.

Terminator-assisted solid-phase cDNA amplification and sequencing (TASseq) uses a terminator, terminal transferase and bead-based platform to improve generation of single-cell RNA-seq libraries.

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.

In medicinal chemistry, the copper-catalyzed click reaction is used to prepare ligand candidates. This reaction is so clean that the bioactivities of the products can be determined without purification. Despite the advantages of this in situ screening protocol, the applicability of this method for transmembrane proteins has not been validated due to the incompatibility with copper catalysts. To address this point, we performed ligand screening for the µ, δ, and κ opioid receptors using this protocol. As we had previously reported the 7-azanorbornane skeleton as a privileged scaffold for the G protein-coupled receptors, we performed the click reactions between various 7-substituted 2-ethynyl-7-azanorbornanes and azides. Screening assays were performed without purification using the CellKeyTM system, and the putative hit compounds were re-synthesized and re-evaluated. Although the “hit” compounds for the µ and the δ receptors were totally inactive after purifications, three of the four “hits” for the κ receptor were true agonists for this receptor and also showed activities for the δ receptor. Although false positive/negative results exist as in other screening projects for soluble proteins, this in situ method is effective in identifying novel ligands for transmembrane proteins.

Although immune checkpoint inhibitors (ICIs) can be used for lung cancer treatment, the activated immune response may cause immune-related adverse effects (irAEs). We present here a case of cytomegalovirus (CMV) enterocolitis during steroid therapy for an irAE. A 70-year-old man diagnosed with small-cell lung carcinoma (limited disease) received radiotherapy plus two chemotherapy cycles of cisplatin and etoposide. The tumor exhibited complete response but recurred after 3 years. After treatment with two cycles of carboplatin, etoposide, and atezolizumab, an inhibitors of programmed cell death receptor-1, he was switched to atezolizumab every 3 weeks for maintenance therapy. Diarrhea occurred after nine atezolizumab doses. With a strong suspicion of ICI-induced colitis, we administered methylprednisolone 500 mg for 3 days, followed by oral prednisolone 40 mg/day. Total colonoscopy during the treatment revealed mucosal inflammation of the total colon, suggesting immune-related colitis. Biopsies from the ulceration revealed crypt abscess with highly infiltrative plasma cells and lymphocytes. Furthermore, immunohistochemical staining showed positivity for CMV. With no improvement in watery diarrhea, the prednisolone dose was increased to 80 mg/day on the 11th day, and ganciclovir was additionally administered twice daily on the 26th day. On the 28th day, the patient had abdominal pain, and abdominal computed tomography revealed free air, resulting in the diagnosis of colon perforation. He underwent subtotal colectomy followed by ileostomy as emergency surgery. A colon specimen revealed colitis with CMV infection. We describe colon perforation in a patient with CMV enterocolitis complicated by refractory immune-related colitis.

Background: This study aimed to assess the clinical outcomes of salvage surgical resection (SSR) after stereotactic radiosurgery and fractionated stereotactic radiotherapy (SRS/fSRT) for newly diagnosed brain metastasis. Methods: Between November 2009 and May 2020, 318 consecutive patients with 1114 brain metastases were treated with SRS/fSRT for newly diagnosed brain metastasis at our hospital. During this study period, 21 of 318 patients (6.6%) and 21 of 1114 brain metastases (1.9%) went on to receive SSR after SRS/fSRT. Three patients underwent multiple surgical resections. Twenty-one consecutive patients underwent twenty-four SSRs. Results: The median time from initial SRS/fSRT to SSR was 14 months (range: 2–96 months). The median follow-up after SSR was 17 months (range: 2–78 months). The range of tumor volume at initial SRS/fSRT was 0.12–21.46 cm3 (median: 1.02 cm3). Histopathological diagnosis after SSR was recurrence in 15 cases, and radiation necrosis (RN) or cyst formation in 6 cases. The time from SRS/fSRT to SSR was shorter in the recurrence than in the RNs and cyst formation, but these differences did not reach statistical significance (p = 0.067). The median survival time from SSR and from initial SRS/fSRT was 17 and 74 months, respectively. The cases with recurrence had a shorter survival time from initial SRS/fSRT than those without recurrence (p = 0.061). Conclusions: The patients treated with SRS/fSRT for brain metastasis need long-term follow-up. SSR is a safe and effective treatment for the recurrence, RN, and cyst formation after SRS/fSRT for brain metastasis.

Abstract A 28‐year‐old man with ankylosing spondylitis (AS) who was treated with a tumour necrosis factor‐alpha (TNF‐α) inhibitor, adalimumab, presented with newly detected multiple bilateral pulmonary nodules on chest computed tomography (CT). We suspected bacterial infection, including those caused by acid‐fast bacilli, or adalimumab‐related condition, such as sarcoidosis. After adalimumab cessation, no resolution of the pulmonary shadows was observed. Moreover, pulmonary cavitation appeared on chest CT at 7 weeks, prompting surgical lung biopsy. Acid‐fast bacteria culture of the lung tissue showed negative results. Pathological examination suggested that confluent granulomas associated with sarcoidosis might have obstructed the blood vessels, causing necrosis and lung cavitation. Consequently, prednisolone was initiated, and these shadows were reduced. After administering anti‐interleukin (IL)‐17A antibody for treatment of AS and prednisolone withdrawal, these shadows were not exacerbated. TNF‐α inhibitor‐induced sarcoidosis could cause cavitary lesions due to vascular invasion of granulomas.

Introduction: A percutaneous endoscopic transforaminal lumbar interbody fusion (PETLIF) procedure has been previously developed. During postoperative follow-up, in some patients, bone fusion occurred between opened facet joints, despite not having bone grafting in the facet joints. Here, we investigated facet fusion's frequency and tendencies following PETLIF. Methods: A retrospective analysis was conducted on a prospectively collected, nonrandomized series of patients. Forty-two patients (6 males and 36 females, average age: 69.9 years) who underwent single-level PETLIF at our hospital from February 2016 to March 2019 were included in this study. Patients were assessed with lumbar X-ray images and computed tomography (CT) prior to, immediately after, and 1 year after surgery. Results: Pseudarthrosis was not observed in any patients, and facet fusion was observed in 26 of 42 post-PETLIF patients (61.9%) by CT 1 year postoperatively. The average interfacet distance increased from 1.3 mm preoperatively to 4.5 mm postoperatively, and facet fusion was observed under the opened conditions of 3.8 mm at 1 year. Segmental lordotic angle of the fusion segment in the lumbar X-ray images was significantly larger in the facet fusion subgroup prior to surgery, immediately following surgery, and 1 year after surgery compared to the facet non-fusion group (p=0.02, p

Ectopic ACTH (adrenocorticotrophic hormone) syndrome (EAS) is rarely associated with small-cell lung cancer (SCLC). Although chemotherapy is initially effective for SCLC, complicated EAS scarcely improves. Recently, immune checkpoint inhibitors have been used to treat SCLC. Atezolizumab plus chemotherapy for SCLC improved progression-free survival compared to conventional chemotherapy. However, little has been reported on the efficacy of the combination therapy for SCLC with EAS. We report a 72-year-old male who presented with 4-week history of leg oedema, proximal myopathy, weight loss, and worsened symptoms of diabetes and hypertension. Laboratory findings revealed hypokalaemia, increased plasma ACTH, and serum cortisol levels. Cortisol levels were not suppressed by the high-dose dexamethasone test. Chest and abdominal CT revealed a right lower lobe tumour with multiple metastases on the hilar lymph nodes, liver, lumbar spine, and bilateral enlarged adrenal glands. The patient was diagnosed with stage 4B SCLC with EAS. Hypercortisolaemia was then treated with metyrapone and atezolizumab plus chemotherapy, which was started for SCLC. After 10 days, the tumour shrank noticeably, and the ACTH level drastically decreased concomitantly with low cortisol levels with symptoms of fever, appetite loss, and general fatigue. Hydrocortisone treatment was initiated, and the symptoms resolved immediately. We describe a case of SCLC with EAS treated with atezolizumab plus chemotherapy, presenting with adrenal insufficiency. Close observation is required for patients with adrenal insufficiency receiving atezolizumab plus chemotherapy because of its stronger effect. Furthermore, advances in cancer therapy and care for endocrine paraneoplastic syndrome needs to be adapted.

Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of lung sarcomatoid carcinoma that has a poor prognosis, and no standard therapy has been established. Here, we report the case of a 74-year-old man with PCC who showed rare duodenal metastasis. He was referred to our hospital with a mass shadow in the right lung. The patient was diagnosed with PPC clinical stage II B on the basis of immunohistochemical staining from bronchoscopy, and the tumor proportion score of programmed death-ligand 1 was 80%. He did not want any treatment. A year and a half later, progressive anemia was detected. The primary tumor was stable; however, abdominal computed tomography and esophagogastroduodenoscopy revealed a duodenal tumor with stenosis. He was diagnosed with duodenal metastasis from PPC, and he underwent gastrojejunal bypass surgery to prevent bowel obstruction. After surgery, he received pembrolizumab for chemotherapy. However, owing to the progression of peritoneum dissemination, he died 2 months later due to the onset of melena.

Rapid, accurate and specific point-of-care diagnostics can help manage and contain fast-spreading infections. Here, the authors present a nanopore-based system that uses artificial intelligence to discriminate between four coronaviruses in saliva, with little need for sample pre-processing.

Abstract Background Schaaf‐Yang syndrome (SYS) is a rare hereditary disease caused by truncating point mutations of the paternal allele of melanoma antigen L2 (MAGEL2), one of five protein‐coding genes within the Prader‐Willi syndrome (PWS) critical domain. SYS shares many clinical and molecular characteristics with PWS but has some distinct features, such as joint contractures and autism. Patients with PWS show abnormal electroencephalography (EEG) patterns. However, there are very few reports on EEG findings in patients with SYS. Methods A SYS patient was included in this study. Detailed neurological examinations and EEG were performed from neonate to infant ages. Sanger sequencing was performed. Results Our patient presented abnormal EEG findings and had diffuse brain dysfunction symptoms including a reduced level of consciousness, diminished spontaneous movements, hypotonia, feeding difficulties, and hypoventilation from early after birth. As she grew older and her background activity of EEG normalized, her neurodevelopmental symptoms remained but improved. Sanger sequencing of this patient revealed a novel, heterozygous c.2005C > T, truncating mutation in the MEGAL2 gene. Conclusions We described an SYS‐associated, time‐dependent, EEG pattern in a patient with SYS. Our findings of longitudinal EEG changes in a patient with SYS revealed a specific pattern of how affected individuals develop brain function.

Abstract Nintedanib is a multi‐target receptor tyrosine kinase inhibitor that reduces the decline in forced vital capacity (FVC) and prevents acute exacerbations in idiopathic pulmonary fibrosis (IPF), which is a risk factor for lung cancer. However, it remains unclear whether nintedanib is an effective treatment for lung cancer in patients with IPF. Here, we describe an 82‐year‐old man with non‐small cell lung carcinoma complicated by IPF who was treated with nintedanib. High‐resolution computed tomography (HRCT) showed a subpleural basal‐predominant reticular shadow and traction bronchiectasis with a honeycomb pattern. His FVC decreased over time, and his 6‐min walk test showed oxygen desaturation. Furthermore, an enlarged nodular lesion was detected after 6 months of referral. Biopsy confirmed non‐small cell carcinoma. Because of the risk of acute exacerbation of IPF by chemotherapy, supportive care was selected. Nintedanib was started as treatment for the IPF. Nine months later, HRCT revealed partial remission without exacerbation of IPF. This case indicates the possibility of nintedanib monotherapy in suppressing lung cancer complicated by IPF. Patients with lung cancer complicated by IPF in whom treatment is effective remain unknown. Additional research is needed to identify effective therapy for lung cancer with IPF.

Abstract This study aimed to clarify the factors underlying the discrepancy that has been noted between estimated glomerular filtration ratio (eGFR) measured using serum creatinine (Cr) and eGFR using serum cystatin C (CysC) in patients with rheumatoid arthritis (RA) and to identify those patients whose renal function should be evaluated using CysC. We retrospectively evaluated clinical features, disease activity, Steinbrocker radiological staging, and co-morbidities (diabetes mellitus, hypertension, dyslipidemia) in 238 RA patients. eGFR using serum creatinine (eGFR-Cr) and eGFR using serum cystatin C (eGFR-CysC) were calculated using the new Japanese coefficient-modified Modification of Diet in Renal Disease study equation. To clarify the cause(s) of differences of 20% or more between the two eGFRs, we divided our RA patients into Group A (eGFR-Cr/eGFR-CysC ≥ 1.2) and Group B (eGFR-Cr/eGFR-CysC

Abstract Background Neutrophil extracellular traps (NETs) are fibrous structures released from activated neutrophils. NET formation has been reported to be associated with acute respiratory distress syndrome (ARDS). However, there are no reports dealing with serial changes of NET formation in tracheal aspirate of ARDS patients. Case presentation We report three cases of ARDS. Case 1 is a 69-year-old man with necrotizing fasciitis of the buttocks, case 2 is a 49-year-old woman with extensive burns (80% of total body surface), and case 3 is a 73-year-old woman with severe bacterial pneumonia. We found abundant expression of citrullinated histone H3 (Cit-H3) and the formation of NETs at the onset of ARDS in all cases. The amounts of Cit-H3 and NETs decreased with the amelioration of respiratory failure in cases 1 and 2. In case 2, the amounts of Cit-H3 and NETs increased with aggravation of infection and respiratory status. In case 3, the abundant expression of Cit-H3 and NETs persisted; the patient did not recover from ARDS and eventually died. Cit-H3 and NETs were found in tracheal aspirates even if the patients had no direct injury to the lung as in cases 1 and 2. Conclusions In these three cases, the formation of NETs was observed in tracheal aspirate of patients with ARDS by either direct or indirect insults to the lung. The amount of NET formation changed dynamically over the clinical course of each patient.

Objective: To describe the detailed clinical course of patients with coronavirus disease 2019 (COVID-19) who received invasive mechanical ventilation. Methods: We conducted a case series of patients with COVID-19 who received invasive mechanical ventilation in Osaka, Japan, between January 29 and May 28, 2020. We describe the patient characteristics and clinical course from onset. Additionally, we fitted logistic regression models to investigate the associations between patient characteristics and the 30-day mortality rate. Results: A total of 125 patients who received invasive mechanical ventilation (median age [interquartile range], 68 [57–73] years; male, 77.6%) were enrolled. Overall, the 30-day mortality was 24.0%, and the median (interquartile range) length of ICU stay and length of invasive mechanical ventilation use were 16 (12–29) days and 13 (9–26) days, respectively. From clinical onset, 121 patients (96.8%) were intubated within 14 days. In multivariable logistic regression analysis, age of 65 years or older (odds ratio, 3.56; 95% confidence interval, 1.21–10.49; P = 0.02) and male sex (odds ratio, 3.75; 95% confidence interval, 1.00–11.24, P = 0.04) were significantly associated with a higher 30-day mortality rate. Conclusions: In this case series of patients with COVID-19 who received invasive mechanical ventilation in Japan, the 30-day mortality rate was 24.0%, and age 65 years or older and male sex were associated with higher 30-day mortality rate.

Opioid receptors (ORs) are classified into three types (μ, δ, and κ), and opioid analgesics are mainly mediated by μOR activation; however, their use is sometimes restricted by unfavorable effects. The selective κOR agonist nalfurafine was initially developed as an analgesic, but its indication was changed because of the narrow safety margin. The activation of ORs mainly induces two intracellular signaling pathways: a G-protein-mediated pathway and a β-arrestin-mediated pathway. Recently, the expectations for κOR analgesics that selectively activate these pathways have increased; however, the structural properties required for the selectivity of nalfurafine are still unknown. Therefore, we evaluated the partial structures of nalfurafine that are necessary for the selectivity of these two pathways. We assayed the properties of nalfurafine and six nalfurafine analogs (SYKs) using cells stably expressing κORs. The SYKs activated κORs in a concentration-dependent manner with higher EC50 values than nalfurafine. Upon bias factor assessment, only SYK-309 (possessing the 3S-hydroxy group) showed higher selectivity of G-protein-mediated signaling activities than nalfurafine, suggesting the direction of the 3S-hydroxy group may affect the β-arrestin-mediated pathway. In conclusion, nalfurafine analogs having a 3S-hydroxy group, such as SYK-309, could be considered G-protein-biased κOR agonists.

Introduction: Lumbar interbody fusion is used to treat degenerative lumbar spondylolisthesis with instability. We developed a device that safely expands a percutaneous path through Kambin's triangle and used it via a new technique: percutaneous endoscopic transforaminal lumbar interbody fusion (PETLIF). We report in this study the details and outcomes of this procedure after a one year follow-up. Methods: Twenty-five patients requiring interbody fusion for degenerative spondylolisthesis of the L4 vertebra were enrolled in this study. The procedure involved percutaneous posterior pedicle screw placement to correct spondylolisthesis. After the exterior of the L5 vertebra superior articular protrusion was shaved with a percutaneous endoscopic drill in order to expand the safe zone, the oval sleeve was inserted through Kambin's triangle and was rotated to expand the disk height and create a path toward the vertebral disk. The interbody cage was inserted against the J-shaped nerve retractor, with the exiting nerve root retracted. Indirect decompression of spinal canal stenosis was expected because the vertebral body spondylolisthesis had been corrected and the interbody distance was expanded. Thus, no direct decompression was performed posterolaterally. Results: The mean follow-up period, surgery time, and blood loss were 22.7 months, 125.4 min, and 64.8 mL, respectively. The Japanese Orthopaedic Association score improved from 13.3 to 28.0. The Roland-Morris Disability Questionnaire score improved from 10.3 to 3.3. All items were evaluated both preoperatively and one year postoperatively. Bone fusion was observed one year postoperatively in 22 out of 25 patients. Conclusions: These results demonstrate the feasibility and efficacy of PETLIF for treating degenerative lumbar spondylolisthesis. This minimally invasive procedure is useful and has wide applicability. To obtain safe and favorable results, necessary surgical techniques must be mastered, and surgical equipment, including that for neural monitoring, is required.

Abstract Background Active surveillance has the potential to prevent nosocomial transmission of carbapenem-resistant Acinetobacter baumannii (CRAB). We assessed whether rapid diagnosis using clinical specimen-direct loop-mediated isothermal amplification (LAMP), a rapid molecular diagnostic assay, and subsequent intervention, could reduce CRAB nosocomial transmission in intensive care units (ICUs). Methods A before and after (quasi-experimental) study was conducted in two ICUs at the Mahidol University Faculty of Medicine Ramathibodi Hospital with 3 months of observational period followed by 9 months of interventional period. All patients were screened for CRAB using both the culture and LAMP method from rectal swab and/or bronchial aspirates (intubated patients only) upon admission, weekly thereafter, and upon discharge. During the pre-intervention period, we performed contact precautions based on culture results. In contrast, during the intervention period, we initiated contact precautions within a few hours after sample collection on the basis of LAMP results. Results A total of 1335 patients were admitted to the ICUs, of which 866 patients (pre-intervention period: 187; intervention period: 679) were eligible for this study. Incidence rate of CRAB infection decreased to 20.9 per 1000 patient-days in the intervention period from 35.2 in the pre-intervention period (P

We conducted a nonrandomized, open-label phase I study to assess the safety and immunogenicity of an intradermal coronavirus disease 2019 (COVID-19) DNA vaccine (AG0302-COVID-19) administered using a pyro-drive jet injector at Osaka University Hospital between Yanagida November 2020 and December 2021. Twenty healthy volunteers, male or female, were enrolled in the low-dose (0.2 mg) or high-dose (0.4 mg) groups and administered AG0302-COVID19 twice at a 2-week interval. There were no adverse events that led to discontinuation of the study drug vaccination schedule. A serious adverse event (disc protrusion) was reported in one patient in the high-dose group, but the individual recovered, and the adverse event was not causally related to the study drug. In the analysis of the humoral immune response, the geometric mean titer (GMT) of serum anti-SARS-CoV-2 spike glycoprotein-specific antibody was low in both the low-dose and high-dose groups (246.2 (95% CI 176.2 to 344.1, 348.2 (95% CI 181.3 to 668.9)) at the 8 weeks after first vaccination. Regarding the analysis of the cellular immune, the number of IFN-γ-producing cells responsive to the SARS-CoV-2 spike glycoprotein increased with individual differences after the first dose and was sustained for several months. Overall, no notable safety issues were observed with the intradermal inoculations of AG0302-COVID19. Regarding immunogenicity, a cellular immune response was observed in some subjects after AG0302-COVID19 intradermal inoculation, but no significant antibody production was observed.

Streptococcus pneumoniae (also called pneumococcus) is not only a commensal that frequently colonizes the human upper respiratory tract but also a pathogen that causes pneumonia, sepsis, and meningitis. The mechanism of pneumococcal infection has been extensively studied, but the process of transmission has not been fully elucidated because of the lack of tractable animal models. Novel animal models of transmission have enabled further progress in investigating pneumococcal transmission mechanisms including the processes such as pneumococcal shedding, survival in the external environment, and adherence to the nasopharynx of a new host. Herein, we present a review on these animal models, recent research findings about pneumococcal transmission, and factors influencing the host-pneumococcus interaction.

We describe a case of Trousseau's syndrome in a patient with lung carcinoma. A 69-year-old man presented with pleural effusion. Further evaluation revealed EGFR mutation-positive non-small cell carcinoma in the upper lobe with extensive lymph node, bone, and brain metastases. Administration of osimertinib, an EGFR tyrosine kinase inhibitor, resulted in partial tumor response, but caused osimertinib-induced pneumonitis 10 weeks later. Prednisolone restrained lung injury progression and was gradually tapered. However, he presented with impaired consciousness and right hemiplegia. Magnetic resonance imaging revealed a left middle cerebral artery M1 segment occlusion. D-dimer level was elevated to 19.5 μg/mL. In the absence of atherosclerotic or cardiogenic thrombi, these findings led to the diagnosis of Trousseau syndrome. Endovascular therapy, but not tissue plasminogen activator, improved his condition with no recurrences. These treatment strategies are crucial to restore function in patients with potentially disabling cerebral infarction due to Trousseau syndrome.

Oxytocin (OT) is a 9-amine neuropeptide that plays an essential role in mammalian labor, lactation, maternal bonding, and social affiliation. OT has been reported to exert an analgesic effect in both humans and animals, and the results of certain animal experiments have shown that the analgesic effect of OT is partially blocked by opioid receptor antagonists. To investigate the relationship between OT and μ opioid receptor (MOR), we evaluated how OT affects MOR in vitro by performing an electrical impedance-based receptor biosensor assay (CellKey™ assay), an intracellular cAMP assay, and a competitive receptor-binding analysis by using cells stably expressing human MOR and OT receptor. In both the CellKey™ assay and the intracellular cAMP assay, OT alone exerted no direct agonistic effect on human MOR, but treatment with 10−6 M OT markedly enhanced the MOR signaling induced by 10−6 M endomorphin-1, β-endorphin, morphine, fentanyl, and DAMGO. Moreover, in the competitive receptor-binding assay, 10−6 M OT did not alter the affinity of endomorphin-1 or morphine for MOR. These results suggest that OT could function as a positive allosteric modulator that regulates the efficacy of MOR signaling, and thus OT might represent a previously unrecognized candidate analgesic agent. Keywords: Oxytocin, μ opioid receptor, Positive allosteric modulator, Analgesia, G protein-coupled receptor (GPCR)

The prognoses of patients with non-small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement have dramatically improved with the use of ALK tyrosine kinase inhibitors. Although immunological and nutritional markers have been investigated to predict outcomes in patients with several cancers, their usefulness in targeted therapies is scarce, and their significance has never been reported in patients receiving first-line treatment with alectinib. Meanwhile, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) has been investigated during crizotinib treatment. This multicenter retrospective study evaluated 42 consecutive Japanese patients with ALK-positive NSCLC who received first-line treatment with alectinib. Immunological and nutritional markers were evaluated at baseline and 3 weeks after alectinib introduction, and their significance in predicting progression-free survival (PFS) was explored. PFS duration was significantly associated with baseline PLR (hazard ratio (HR): 2.49, p = 0.0473), systemic immune-inflammation index (SII; HR: 2.65, p = 0.0337), prognostic nutrition index (PNI; HR: 4.15, p = 0.00185), and the 3-week values for SII (HR: 2.85, p = 0.0473) and PNI (HR: 3.04, p = 0.0125). Immunological and nutritional markers could be useful in predicting the outcomes of first-line treatment with alectinib. Since PLR and SII consist of platelet counts, platelet count could be an important constituent of these markers.

Oxytocin (OT) influences various physiological functions such as uterine contractions, maternal/social behavior, and analgesia. Opioid signaling pathways are involved in one of the analgesic mechanisms of OT. We previously showed that OT acts as a positive allosteric modulator (PAM) and enhances μ-opioid receptor (MOR) activity. In this study, which focused on other opioid receptor (OR) subtypes, we investigated whether OT influences opioid signaling pathways as a PAM for δ-OR (DOR) or κ-OR (KOR) using human embryonic kidney-293 cells expressing human DOR or KOR, respectively. The CellKeyTM results showed that OT enhanced impedance induced by endogenous/exogenous KOR agonists on KOR-expressing cells. OT did not affect DOR activity induced by endogenous/exogenous DOR agonists. OT potentiated the KOR agonist-induced Gi/o protein-mediated decrease in intracellular cAMP, but did not affect the increase in KOR internalization caused by the KOR agonists dynorphin A and (-)-U-50488 hydrochloride (U50488). OT did not bind to KOR orthosteric binding sites and did not affect the binding affinities of dynorphin A and U50488 for KOR. These results suggest that OT is a PAM of KOR and MOR and enhances G protein signaling without affecting β-arrestin signaling. Thus, OT has potential as a specific signaling-biased PAM of KOR.

Abstract Background Peritoneal dialysis (PD) for acute kidney injury (AKI) of newborns has been performed safely. AKI occurs in 8 to 24% of extremely low birth weight (ELBW) infants. Although PD has only been used occasionally in ELBW infants, prognosis is poor for ELBW infants with AKI. Several reports have described successful PD in these infants, but no guideline-based evidence concerning indications for renal replacement therapy in ELBW infants are currently available. Here, we report on our experience with PD in an ELBW infant with AKI resulting from septic shock. Case presentation A male was born at 24 weeks and 3 days gestation weighing 264 g by emergency cesarean section due to complications of pregnancy in a patient with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. On day of life (DOL) 15, the inability to ventilate, along with cardiovascular dysfunction, acute kidney injury, and ascites under tension led to the tentative diagnosis of abdominal compartment syndrome (ACS). On DOL 17, placement of a percutaneous drainage tube immediately released compression of the tense abdomen. Although intra-abdominal pressure reduction with percutaneous drainage temporarily improved respiratory status, circulatory impairment persisted and infections were not well controlled. Finally, the patient developed anuria. On DOL 21, peritoneal dialysis (PD) was started by initially inserting a drainage tube. Although the patient had catheter-associated peritonitis, urine output improved by DOL 44 and PD was discontinued on DOL 53. On DOL 75, extubation was conducted without circulatory dysfunction. The patient was discharged on DOL 224. Conclusions We emphasize that starting PD treatment before the onset of anuria is important in ELBW infants with AKI. Although the catheter used in our case was initially inserted for drainage of ascites, this type of catheter is sufficiently useful for PD in ELBW infants, and PD using a drainage tube may represent a safe, effective, and minimally invasive treatment for ELBW infants. To our knowledge, this is the first report to describe the use of a percutaneous tube to conduct successful PD for peritoneal drainage in an ELBW infant. This is the lowest-weight ELBW infant with successful PD reported to date.

A previously healthy 44-year-old Japanese man with a 5-month history of lumbago presented to the emergency department with acute respiratory failure caused by pneumonia, and was immediately intubated. Computed tomography revealed a lung mass, pleural effusion, and multiple osteolytic lesions; however, the results of thoracentesis and bronchial brushing were not definitive. We performed a bone tumor biopsy guided by diffusion-weighted magnetic resonance imaging (DW-MRI) with mechanical ventilation, which enabled the diagnosis of ALK rearrangement-positive lung adenocarcinoma. In the era of precision medicine requiring proper biological tissue collection, DW-MRI was critical for identifying the biopsy site safely and with high precision. Keywords: Anaplastic lymphoma kinase, Biopsy, Computed tomography, Diffusion-weighted magnetic resonance imaging, Lung cancer