Characteristics and risk of interstitial lung disease in dermatomyositis and polymyositis: a retrospective cohort study in Japan.

Dermatomyositis and polymyositis are rare, idiopathic inflammatory myopathies. Interstitial lung disease is one of the most common and potentially severe extra-muscular manifestations of dermatomyositis and polymyositis and is strongly linked to poor prognosis and early mortality. We aimed to characterise the demographic and clinical characteristics, incidence, and treatment of interstitial lung disease in patients with dermatomyositis or polymyositis. We conducted a retrospective cohort study using the Japan Medical Data Center healthcare claims database. Patients in the database with dermatomyositis (International Classification of Disease version 10 M33.0, M33.1, M33.9) or polymyositis (M33.2) from 01-Jan-2011 until 31-Dec-2019 were identified and followed-up for interstitial lung disease (J84.x) until death, dis-enrolment, or study end (31 December 2020). Cumulative risk curves compared interstitial lung disease risk in dermatomyositis versus polymyositis. Risk factors were evaluated by Cox proportional hazard models. There were 886 patients with dermatomyositis and 745 patients with polymyositis included in the cohort analysis. Mean (standard deviation) age at dermatomyositis/polymyositis diagnosis was 46.0 (16.0)/49.7 (13.3) years and 300 (34%)/104 (14%) developed interstitial lung disease during follow-up. The incidence rate of interstitial lung disease per 100 person-years was 18.42 (95% CI 16.42-20.59) for dermatomyositis and 5.39 (95% CI 4.43-6.50) for polymyositis. In the analysis adjusted for sex, age, and comorbidity score, the risk of interstitial lung disease was significantly higher in patients with dermatomyositis than with polymyositis (hazard ratio 2.72, 95% CI 2.18-3.41). The rate diverged markedly between the groups in the first year after diagnosis. Risk factors for interstitial lung disease were older age in dermatomyositis, female sex and rheumatoid arthritis in polymyositis. Glucocorticoids with/without tacrolimus were the most common newly prescribed drugs after the interstitial lung disease diagnosis. In conclusion, the risk of developing interstitial lung disease was significantly higher in patients with dermatomyositis than with polymyositis, and risk factors were different in the 2 patient groups.

Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study of ustekinumab in Japanese patients with active polymyositis and dermatomyositis who have not adequately responded to one or more standard-of-care treatments.

OBJECTIVES: To evaluate the efficacy and safety of ustekinumab (UST) in a multicentre, randomised, double-blind, placebo-controlled trial in adult Japanese patients with active polymyositis (PM) and dermatomyositis (DM). METHODS: Fifty-one Japanese adults diagnosed with active PM/DM who did not respond adequately to one or more standard-of-care treatments were randomised 1:1 to receive UST (n=25) or placebo (n=26). Participants received body weight-range based intravenous administration of UST (6 mg/kg) or placebo at week 0 followed by 90 mg subcutaneous (SC) administration of UST or placebo every 8 weeks from week 8 to week 24. At week 24, placebo group crossed over to receive body weight-range based intravenous administration of UST, and thereafter, all participants received/were to receive SC administration of UST 90 mg every 8 weeks (week 32 through to week 72). The primary efficacy endpoint was the proportion of participants who achieved minimal improvement (≥20) in the International Myositis Assessment and Clinical Studies Total Improvement Score (IMACS TIS) at week 24. RESULTS: No statistically significant difference was seen in the proportion of participants who achieved minimal improvement (≥20) in IMACS TIS at week 24 between the treatment groups (UST 64.0% vs placebo 61.5%, p=0.94) based on the primary estimand of the primary endpoint analysis. CONCLUSIONS: UST was safe and well tolerated but did not meet the primary efficacy endpoint in adult Japanese participants with active PM/DM based on the primary analysis at week 24 in the study. TRIAL REGISTRATION NUMBER: NCT03981744.

Safety, reactogenicity, and immunogenicity of Ad26.COV2.S: Results of a phase 1, randomized, double-blind, placebo-controlled COVID-19 vaccine trial in Japan.

BACKGROUND: This study evaluated safety, reactogenicity, and immunogenicity of a 2-month homologous booster regimen of Ad26.COV2.S in Japanese adults. METHODS: In this multicenter, placebo-controlled, Phase 1 trial, adults (Cohort 1, aged 20-55 years, N = 125; Cohort 2, aged ≥ 65 years, N = 125) were randomized 2:2:1 to receive Ad26.COV2.S 5 × 1010 viral particles (vp), Ad26.COV2.S 1 × 1011 vp, or placebo, followed by a homologous booster 56 days later. Safety, reactogenicity, and immunogenicity were assessed. RESULTS: Two hundred participants received Ad26.COV2.S and 50 received placebo. The most frequent solicited local adverse event (AE) was vaccination-site pain, and the most frequent solicited systemic AEs were fatigue, myalgia, and headache. After primary vaccination, neutralizing and binding antibody levels increased through Day 57 (post-prime) in both cohorts. Fourteen days after boosting (Day 71), neutralizing antibody geometric mean titers (GMTs) had almost reached their peak value in Cohort 1 (5 × 1010 vp: GMT = 1049; 1 × 1011 vp: GMT = 1470) and peaked in Cohort 2 (504; 651); at Day 85, GMTs had declined minimally in Cohort 2. For both cohorts, binding antibody levels peaked at Day 71 with minimal decline at Day 85. CONCLUSION: A single dose and homologous Ad26.COV2.S booster increased antibody responses with an acceptable safety profile in Japanese adults (ClinicalTrials.gov Identifier: NCT04509947).

Development of a useful single-reference HPLC method for therapeutic drug monitoring of phenytoin and carbamazepine in human plasma.

A single reference high-performance liquid chromatographic (SR-HPLC) method was developed and validated for the therapeutic drug monitoring (TDM) of phenytoin (PHT) and carbamazepine (CBZ) in plasma from patients. The analytical parameters evaluated were linearity, limit of quantification (LOQ), selectivity, accuracy, and stability according to the US Food and Drug Administration (FDA) guideline. The developed method shows good linearity (r2 > 0.999; LOQ-50 µg/mL), and LOQ values were 1.56 µg/mL for PHT and 0.40 µg/mL for CBZ at 254 nm. For the development of SR-HPLC method, we evaluated to improve the detection wavelength, stirred retention time, and stability for SR, and selected 5-(p-methylphenyl)-5-phenylhydantoin for PHT (relative molar sensitivity, RMS = 0.848) and 10-methoxyiminostilbene for CBZ (RMS = 0.263). The established differential definite quantities of PHT and CBZ in plasma samples were similar using the RMS and absolute calibration methods based on RSD < 5.10%. A preliminary application was performed using chemiluminescent immunoassay and SR-HPLC method, in which the detectable values of the correlation coefficient and the slope of the intercept were PHT: 0.964 and 0.992647, and CBZ: 0.969 and 1.072089, respectively. Based on these results, we propose that the SR-HPLC method with RMS would be offered to the useful and accurate TDM of various medicines in plasma/serum samples.

A Prospective Observational Study on the Tolerability of Transnasal Bronchoscopy With a Surgical Mask for Aerosol Control.

Background As far as we know, there are no reports comparing the safety and cough frequency of transnasal bronchoscopy (TNB) with transoral bronchoscopy (TOB). Methods The subjects were 50 patients who underwent either TNB or TOB and completed the pain score questionnaire between May and November 2020. Complications, pain scores, and cough frequency (times per minute) were compared between the patients with TNB and TOB. A surgical mask was worn over the mouthpiece during the examination. Results Thirty-two and 18 patients underwent TNB and TOB, respectively. Between the two groups, there were no significant differences in examination time and frequency of serious complications. In pain scores, there were no significant differences in terms of anesthesia suffering, several pains during the examination, and availability of re-examination. The TNB group did not feel the prolonged examination time compared to the TOB group (p=0.04). Cough frequency was lower in the TNB group than in the TOB group (0.36 vs 0.73, p=0.027). Moreover, cough frequency in the 25 TNB patients who underwent thin bronchoscopy was significantly lower (0.19 vs 0.73, p<0.01). Conclusions TNB with a surgical mask was well tolerated and safe. Cough frequency in the transnasal thin bronchoscopy was extremely low, suggesting aerosol reduction can be expected.

A Case of Asymptomatic Pulmonary Nocardia cyriacigeorgica Infection With Mild Diabetes Mellitus.

Nocardiosis is a relatively rare opportunistic infection, ranging from localized to systemic diseases, commonly occurring in immunocompromised patients with high mortality rates. We present a case of a 61-year-old man who received medical treatment for type 2 diabetes mellitus and underwent a physical examination that showed abnormal chest shadows on radiography. Chest computed tomography revealed bronchiectasis and infiltration in the left lower lobe. Nocardia spp. was detected in the bronchial washes, and he was started on sulfamethoxazole-trimethoprim under the diagnosis of pulmonary nocardiosis. 16S ribosomal RNA gene sequencing analysis identified the species as Nocardia cyriacigeorgica. His pulmonary lesions successfully improved after treatment for six months. Pulmonary nocardiosis often presents with symptoms such as hemoptysis and blood-tinged sputum, and bronchiectasis has been identified as an underlying condition. Even in hosts without underlying immunocompromising conditions, Nocardia spp. can be a causative microorganism of pulmonary infections, and it should be considered in the differential diagnoses.

A case of pulmonary foreign body granuloma formation after transcatheter arterial chemoembolization for hepatocellular carcinoma.

We experienced a case of pulmonary foreign body granuloma diagnosed by bronchoscopy in a patient with multiple lung lesions after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma. We speculate that the lesions may be caused by transarterial migration of the materials used for TACE.

A Case of Guillain-Barré Syndrome and Stevens-Johnson Syndrome/Toxic Epidermal Necrosis Overlap After Pembrolizumab Treatment.

A 76-year-old man was admitted to our hospital with Guillain-Barré syndrome (GBS), presenting with facial palsy, dysarthria, and dysphagia as Grade 3 immune-related adverse events (irAEs) due to pembrolizumab administration for Stage IV lung adenocarcinoma. Although prednisolone (1 mg/kg) was started for GBS due to the irAE, dark erythema and skin eruptions appeared on the patient's torso. Then erosion was observed on 18% of the body surface area and skin biopsy was performed. Finally, the patient was diagnosed with Stevens-Johnson syndrome/toxic epidermal necrosis overlap. Intravenous immunoglobulin therapy was started, and the skin symptoms improved, with the erosion becoming epithelial. He died of aspiration pneumonia related to GBS, although his neurological symptoms had improved after steroid and intravenous immunoglobulin therapy. This is the first reported case of pembrolizumab-induced GBS and Stevens-Johnson syndrome/toxic epidermal necrosis overlap. It is necessary to be careful that the possibility of other severe irAEs may occur simultaneously.

Formation of PbCl2-type AHF (A = Ca, Sr, Ba) with partial anion order at high pressure.

The high-pressure structures of alkaline earth metal hydride-fluorides (AHFs) (A = Ca, Sr, Ba) were investigated up to 8 GPa. While AHF adopts the fluorite-type structure (Fm3[combining macron]m) at ambient pressure without anion ordering, the PbCl2-type (cotunnite-type) structure (Pnma) is formed by pressurization, with a declining trend of critical pressure as the ionic radius of the A2+ cation increases. In contrast to PbCl2-type LaHO and LaOF whose anions are fully ordered, the H-/F- anions in the high-pressure polymorph of SrHF and BaHF are partially ordered, with a preferential occupation of H- at the square-pyramidal site (vs. tetrahedral site). First-principles calculations partially support the preferential anion occupation and suggest occupation switching at higher pressure. These results provide a strategy for controlling the anion ordering and local structure in mixed-anion compounds.

A case of hyperprogressive disease following atezolizumab therapy for pulmonary pleomorphic carcinoma with epidermal growth factor receptor mutation.

A 66-year old man with non-smoking history was diagnosed with pulmonary pleomorphic carcinoma of the right lower lobe. The carcinoma metastasized to the brain, lungs, pleura, and mediastinal lymph nodes. It was positive for epidermal growth factor receptor (EGFR) L858R mutation, and tumor cells highly expressed programmed death-ligand 1(PD-L1). Atezolizumab was initiated as the fourth treatment. After three days, he developed cardiac tamponade and immediately underwent pericardial drainage. Computed tomography showed bilateral ground-glass opacity (GGO), significant worsening of multiple lung metastases, and increased size of metastatic lesions. Newly developed metastasis was noted in the lung, and the patient's respiratory condition rapidly deteriorated. He died of respiratory failure on day 13 after atezolizumab administration. The autopsy showed widespread metastasis in all lobes of the bilateral lungs, cardiac tamponade due to carcinomatous pericarditis, carcinomatous lymphangiopathy, and multiple lung metastases, which were thought to be comprehensively the cause of death. These symptoms suggested hyperprogressive disease (HPD). Hence, we report the first case of HPD following atezolizumab therapy for pulmonary pleomorphic carcinoma with EGFR mutation.

A Case of Intravascular Diffuse Large B-Cell Lymphoma Initially Suspected as Interstitial Pneumonia Associated With Systemic Scleroderma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse LBCL. The patient was a 71-year-old female admitted to our hospital with hypoxia. On admission, chest computed tomography revealed a ground-glass opacity. Interstitial pneumonia associated with systemic scleroderma was suspected because of positive anti-centromere antibody. Thereafter, steroid pulse therapy and plasma exchange were performed. Although ground-glass opacity improved, bilateral pleural effusion appeared, so we performed a random skin biopsy because of her elevated serum lactate dehydrogenase and soluble interleukin-2 receptor levels. The patient was diagnosed with IVLBCL with symptoms improving after 6 cycles of rituximab plus chemotherapy treatment.

A case report of aspergillosis accompanied by saccular bronchodilation after bronchial thermoplasty in a 19-year-old woman.

BACKGROUND: Fungal infections are rarely reported as a complication of bronchial thermoplasty (BT) in patients without immunosuppressive comorbidity. CASE PRESENTATION: A 19-year-old woman college student was admitted to our hospital owing to uncontrolled severe asthma despite using the maximum dose of steroid inhalation. She experienced asthmatic attacks more frequently while cheerleading, which is an extracurricular activity. She received BT because she wanted to continue cheerleading. After the second BT session, she developed more sputum and cough. During the third session, white secretion and saccular bronchodilation appeared in the left lower bronchus. Aspergillus fumigatus was detected in the culture of the bronchial lavage sample, and saccular bronchodilation in the affected bronchus was observed on computed tomography (CT). Five months after the start of oral itraconazole, her subjective symptoms as well as her CT findings improved. Her asthma condition improved enough for the patient to continue cheerleading without exacerbation. CONCLUSIONS: It is necessary to consider the possibility of respiratory tract infections including fungal infections after BT. Detailed observations of the entire bronchus and sample collection for microbial culture are highly recommended.

Breakthrough and persistent bacteremia due to serotype K1 Klebsiella pneumoniae in an immunocompetent patient.

Herein, we report a case of breakthrough and persistent bacteremia due to serotype K1 Klebsiella pneumoniae in an immunocompetent 53- year-old man. He was diagnosed with pyogenic spondylitis owing to back pain and based on magnetic resonance imaging findings. On admission, several imaging studies were taken to search for other abscesses and infective endocarditis; however, there were no significant findings. Additionally, blood cultures were negative. Upon treatment with intravenous ampicillin/sulbactam, the patient's symptoms improved. However, eleven days after admission, the patient experienced a fever and worsening back pain. Blood cultures were taken again, and K. pneumoniae was detected, which showed sensitivity to ampicillin/sulbactam. Fourteen days after admission, K. pneumoniae was detected again, suggesting breakthrough and persistent bacteremia with K. pneumoniae. The source of the K. pneumoniae infection was unknown. The antimicrobial regimen was changed to a combination of ceftriaxone and gentamicin. Sixty days after admission, the patient was discharged without any sequelae. The isolated K. pneumoniae strains were found to carry rmpA and were confirmed as serotype K1; thus, detected hypervirulent K. pneumoniae (HvKP). HvKP is an increasingly recognized pathotype of K. pneumoniae characterized clinically by its ability to cause organ- or life-threatening infections in healthy persons. To the best of our knowledge, our case is the first report of spondylitis due to confirmed HvKP. Moreover, HvKP caused breakthrough and persistent bacteremia on an immunocompetent patient.

A case of congenital bronchial atresia patient with subclinical infection who underwent lung resection.

Congenital bronchial atresia, CBA, is rare and has often asymptomatic benign condition. The CBA condition usually arose during the formation of bronchi, but the CBA patients are able to live well into adulthood. This case highlights a potential surgical intervention for a CBA patient with subclinical infection. A 55-year-old Japanese male had abnormal findings on his chest X-ray at an annual health check-up in March 2018. His chest computed tomography (CT) revealed bronchial stenosis and infiltrative shadow in the right inferior lobe. He was referred to our hospital for further investigation and was diagnosed CBA after a variety of examinations including bronchoscopy. His dilated bronchi were filled with mucus, the end of one of the bronchi had obstructive pneumonia, and subclinical infection in the CBA lesion was suspected. Also, the result of bronchoscopy disclosed intrabronchial infection with Gram-positive bacteria so we performed lobectomy onto the lower lobe. Although no protocol had been established, a surgical intervention would be necessary for this case.

Tripartite Motif Containing 24 Acts as a Novel Coactivator of the Constitutive Active/Androstane Receptor.

The constitutive androstane receptor (CAR) is a nuclear receptor that acts as a transcription factor for a variety of genes, including genes encoding xenobiotic, steroid, and drug-metabolizing enzymes and transporters. Transactivation of a target gene by a transcription factor is generally mediated through the concerted and stepwise recruitment of various proteins termed coregulators, including coactivators and corepressors. In this study, TRIM24 (also known as transcriptional intermediary factor 1 alpha) was found to interact with the CAR. TRIM24 enhanced the CAR-dependent transactivation in reporter assays using the direct repeat-4 motif, a binding site of the CAR. This enhancement was synergistically augmented in the presence of steroid receptor coactivator (SRC) 1 or SRC2, both of which are coactivators of the CAR. In addition, TRIM24 was recruited to the CAR-binding element of the CYP2B6 promoter together with the CAR. We also noted that knockdown of TRIM24 suppressed CAR-induced CYP2B6 mRNA expression in HepTR/CAR and HepaRG cells and suppressed CAR-induced CYP3A4 mRNA expression in HepaRG cells but not HepTR/CAR cells. From these results, we suggest that TRIM24 is a novel coactivator of the CAR that is involved in cell- and/or promoter- selective transactivation.

Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin.

Plasmepsin (Plm) is a potential target for new antimalarial drugs, but most reported Plm inhibitors have relatively low antimalarial activities. We synthesized a series of dipeptide-type HIV protease inhibitors, which contain an allophenylnorstatine-dimethylthioproline scaffold to exhibit potent inhibitory activities against Plm II. Their activities against Plasmodium falciparum in the infected erythrocyte assay were largely different from those against the target enzyme. To improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity. These results suggest that auxiliary substituents on a specific basic group contribute to deliver the inhibitors to the target Plm.

Additional interaction of allophenylnorstatine-containing tripeptidomimetics with malarial aspartic protease plasmepsin II.

Based on a highly potent allophenylnorstatine-containing inhibitor, KNI-10006, against the plasmepsins of Plasmodium falciparum, we synthesized a series of tripeptide-type compounds with various N-terminal moieties and evaluated their inhibitory activities against plasmepsin II. Certain phenylacetyl derivatives exhibited extremely high affinity with K(i) values of less than 0.1n M suggesting successful hydrophobic interactions.