For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

b This is the first report of a detailed relationship between triazole treatment history and triazole MICs for 154 Aspergillus fumigatus clinical isolates. The duration of itraconazole dosage increased as the itraconazole MIC increased, and a positive correlation was observed (r ‫؍‬ 0.5700, P < 0.0001). The number of itraconazole-naïve isolates dramatically decreased as the itraconazole MIC increased, particularly for MICs exceeding 2 g/ml (0.5 g/ml versus 2 g/ml, P ‫؍‬ 0.03). We also examined the relationship between cumulative itraconazole usage and the MICs of other azoles. A positive correlation existed between itraconazole dosage period and posaconazole MIC (r ‫؍‬ 0.5237, P < 0.0001). The number of itraconazole-naïve isolates also decreased as the posaconazole MIC increased, particularly for MICs exceeding 0.5 g/ml (0.25 g/ml versus 0.5 g/ml, P ‫؍‬ 0.004). Conversely, the correlation coefficient obtained from the scattergram of itraconazole usage and voriconazole MICs was small (r ‫؍‬ ؊0.2627, P ‫؍‬ 0.001). Susceptibility to three triazole agents did not change as the duration of voriconazole exposure changed. In addition, we carried out detailed analysis, including microsatellite genotyping, for isolates obtained from patients infected with azole-resistant A. fumigatus. We confirmed the presence of acquired resistance to itraconazole and posaconazole due to a G54 substitution in the cyp51A gene for a patient with chronic pulmonary aspergillosis after oral itraconazole therapy. We should consider the possible appearance of azole-resistant A. fumigatus if itraconazole is used for extended periods.

We investigated the triazole, amphotericin B, and micafungin susceptibilities of 196 A. fumigatus clinical isolates in Nagasaki, Japan. The percentages of non-wild-type (non-WT) isolates for which MICs of itraconazole, posaconazole, and voriconazole were above the ECV were 7.1%, 2.6%, and 4.1%, respectively. A G54 mutation in cyp51A was detected in 64.2% (9/14 isolates) and 100% (5/5 isolates) of non-WT isolates for itraconazole and posaconazole, respectively. Amphotericin B MICs of >2 g/ml and micafungin minimum effective concentrations (MECs) of >16 g/ml were recorded for two and one isolates, respectively.

Patients with chronic pulmonary aspergillosis (CPA) have a poor prognosis and CPA occurs in patients with various underlying diseases. Recently, the number of patients with CPA complicated by nontuberculous mycobacteria (NTM) has increased. Additionally, complications of both diseases have several problems like drug interactions. Since the impact of NTM on the outcome of CPA is not well understood, we investigated the risk factors for developing CPA and the clinical characteristics of CPA patients with or without NTM. We retrospectively investigated the medical records of NTM and CPA patients who were admitted to Nagasaki University Hospital between April 2008 and September 2013. Comorbid diseases, causative microorganisms, radiological findings, and outcomes were evaluated. During the study period, 82 and 41 patients were diagnosed as having NTM and CPA, respectively. Nine patients were coinfected with NTM and CPA, and cavitary type NTM and steroid usage were independent risk factors of development of CPA. Mortality rates in the coinfection group were significantly higher than those of the NTM without CPA group (P = .003, log-rank test). The rate of treatment initiation in the co-infection group (33.3%) was significantly lower than in the CPA without NTM group (84.4%) (P = .006). However, there were no significant differences in cumulative survival rate between both groups (P = .760, log-rank test). Cavity formation and steroid usage were the independent risk factors for NTM patients to develop CPA within long observation period, and development of CPA made outcomes poor. It is important to diagnose the development of CPA early and initiate treatment for CPA.

BACKGROUND Pneumonia is a common and serious illness in the elderly with poorly characterized long-term impact on health-related quality of life (HRQoL). The Japanese Goto Epidemiology Study is a prospective, active, population-based surveillance study of adults with X-ray/CT-scan–confirmed community-onset pneumonia, assessing the HRQoL outcome quality-adjusted life years (QALYs). Here we report QALY scores and losses among a subset of participants in the Goto Study. METHODS QALYs were derived from responses to the Japanese version of the EuroQol-5D-5L health-state classification instrument at days 0, 7, 15, 30, 90, 180 and 365 after pneumonia diagnosis from participants enrolled from June 2017 to May 2018. We used patients as their own controls, calculating comparison QALYs by extrapolating EuroQol-5D-5L scores for Day −30 accounting for mortality and changes in scores with age. RESULTS Of 405 participants, 85% were aged ≥65 years, 58% were male, and 69% were hospitalized for clinical and radiological confirmed pneumonia. Compliance with interviews by either patients or proxies was 100%. Adjusted EuroQol-5D-5L scores were 0.759 at day −30, 0.561 at diagnosis, 0.702 by day 180 and .689 by day 365. Average scores at all time points remained below the average day −30 scores (P ≤ .001). Pneumonia resulted in a mean adjusted loss of 0.13 QALYs (~47.5 quality-adjusted days lost) at 365 days (P &lt; .001). CONCLUSIONS Substantial QALY losses were observed among Japanese adults following pneumonia diagnosis; on average, scores had not returned to pre-diagnosis levels at one-year post-diagnosis. QALY scores and cumulative losses were comparable to those in US adults with chronic heart failure, stroke, or renal failure.

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Background: Imatinibmesylate (imatinib) is a small molecule tyrosine kinase inhibitor administered to patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. Although imatinib-associated interstitial lung disease is uncommon, a few cases have been reported so far. However, in all these cases interstitial lung disease developed during the use of imatinib. The present case is the first report of imatinib-induced interstitial lung disease developing after discontinuation of the drug. Case presentation: A 51-year-old woman was administered oral imatinib for gastrointestinal stromal tumor. Ten weeks later, imatinib was discontinued because of facial edema. On this occasion, chest radiography showed no abnormal findings. However, 2 weeks after discontinuation of imatinib, she developed fever, dry cough, and dyspnea. Chest radiography and computed tomography showed diffuse interstitial infiltrates in both lungs. Examination of bronchoalveolar lavage fluid showed an increased proportion of lymphocytes. Imatinib-induced interstitial lung disease was suspected, because no other cause was evident. After administration of corticosteroids, her clinical condition and chest radiographic findings improved. Conclusion: We report a unique case of imatinib-induced interstitial lung disease that developed 2 weeks after discontinuation of the drug. Physicians should consider occurrence of imatinib-induced interstitial lung disease even after discontinuation of the drug.