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Background and Objectives: A pharmacokinetic model has been developed to quantify the drug–drug interactions of tacrolimus with concentration-dependent inhibition of cytochrome P450 (CYP) 3A4 from voriconazole and clarithromycin based on the CYP3A5 and CYP2C19 genotypes. Methods: This retrospective study recruited unrelated bone marrow transplant recipients receiving oral tacrolimus concomitantly with voriconazole and clarithromycin. The published population pharmacokinetic model that implemented genotypes of CYP3A5 (tacrolimus) and CYP2C19 (voriconazole) was integrated. The tested CYP3A4 inhibition models (Sigmoid efficacy maximum [Emax], Emax, log-linear, and linear) were a function of competitive inhibition of voriconazole and mechanism-based inhibition of clarithromycin in a virtual enzyme compartment. Results: The total tacrolimus trough concentrations were 119 points, with a median of 4.3 (range: 2.0–9.9) ng/mL (n= 3). The final model comprised the Sigmoid Emaxmodel for voriconazole and clarithromycin, which depicted time-course alterations in tacrolimus concentration and clearance when given voriconazole and clarithromycin. Conclusions: These findings could facilitate the model-informed precision dosing of tacrolimus after unrelated bone marrow transplant.

Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by ciliary structural abnormalities and dysfunction, leading to chronic rhinosinusitis, otitis media with effusion, bronchiectasis, and infertility. Approximately half of Japanese PCD cases are attributed to variants in the dynein regulatory complex subunit 1 (DRC1) gene, predominantly featuring homogeneous deletions of exons 1–4 spanning 27,748 base pairs on chromosome 2. Here, we report 10 new PCD cases (9 families) in addition to 29 previously reported cases (24 families) caused by DRC1variants. Among these 39 cases, biallelic DRC1exon 1–4 deletions were detected in 38 (97.4%). These DRC1deletions exhibited an identical breakpoint in all PCD cases in the Japanese and Korean populations, strongly suggesting a founder effect. In this study, we performed haplotype analysis, using a whole-exome sequencing dataset of 18 Japanese PCD patients harboring large biallelic DRC1deletions. We estimated that the founder allele likely emerged 115.1 generations ago (95% confidence interval: 33.7–205.1), suggesting an origin of approximately 3050 years ago, coinciding with the transition from the Jomon period to the early Yayoi period in Japan. Considering the formation of the modern Japanese population, the founder with the DRC1exon 1–4 deletion likely lived on the Korean peninsula, with the allele later transmitted to Japan through migration. This study provides insights into the origin of the DRC1copy number variant, the most frequent PCD variant in the Japanese and Korean populations, highlighting the importance of understanding population-specific genetic variations in the context of human migration and disease prevalence.

Primary ciliary dyskinesia (PCD) is a hereditary disease caused by pathogenic variants in genes associated with motile cilia. Some variants responsible for PCD are reported to be ethnic-specific or geographical-specific. To identify the responsible PCD variants of Japanese PCD patients, we performed next-generation sequencing of a panel of 32 PCD genes or whole-exome sequencing in 26 newly identified Japanese PCD families. We then combined their genetic data with those from 40 Japanese PCD families reported previously, for an overall analysis of 66 unrelated Japanese PCD families. We conducted Genome Aggregation Database and TogoVar database analyses to reveal the PCD genetic spectrum of the Japanese population and compare with other ethnic groups worldwide. We identified 22 unreported variants among the 31 patients in the 26 newly identified PCD families, including 17 deleterious variants estimated to cause lack of transcription or nonsense-mediated mRNA decay and 5 missense mutations. In all 76 PCD patients from the 66 Japanese families, we identified 53 variants on 141 alleles in total. Copy number variation in DRC1is the most frequent variant in Japanese PCD patients, followed by DNAH5c.9018C>T. We found 30 variants specific to the Japanese population, of which 22 are novel. Furthermore, 11 responsible variants in the Japanese PCD patients are common in East Asian populations, while some variants are more frequent in other ethnic groups. In conclusion, PCD is genetically heterogeneous between different ethnicities, and Japanese PCD patients have a characteristic genetic spectrum.

Primary ciliary dyskinesia (PCD) is a genetic disease with chronic airway infection and inflammation caused by ciliary ultrastructural defects and impairment in ciliary function.

Investigate the characteristics and serology of pregnant women with cytomegalovirus (CMV) immunoglobulin (Ig)G seroconversion during pregnancy to understand the risk factors associated with primary CMV infection and the occurrence of fetal congenital CMV infection.

The usefulness of lupus anticoagulant (LA) and several antibodies for predicting thrombosis was assessed in patients with idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), lupus like disease (LLD), recurrent abortion and primary antiphospholipid syndrome (APS). LA was measured using the diluted Russell Viper Venom test (DRVVT) and the diluted prothrombin time (dPT).In healthy volunteers, the median (range) of the DRVVT and dPT ratio were 0.97 (0.88 - 1.08) and 1.05 (0.85 - 1.29), respectively. The positive percent of dPT ratio was high in patients with ITP, SLE, recurrent abortion and primary APS. The sensitivity for thrombosis was highest for the dPT ratio and the specificity for thrombosis was highest for the DRVVT ratio. The sensitivity and the Odd’s ratio for both the dPT and DRVVT ratio were high. A positive predictive value in DRVVT and a negative predictive value in dPT were high. The receiver operating characteristic (ROC) curve analysis indicates that the dPT ratio might be more useful for predicting thrombosis than the DRVVT ratio. The DRVVT and dPT ratios are useful for both the diagnosis of APS as well as predicting thrombosis.

Procalcitonin (PCT) is a marker of severe bacterial infections and organ failure due to sepsis. The purpose of the present study was to identify the appropriate cutoff level of PCT based on the findings of a blood culture and polymerase chain reaction (PCR). The PCT levels were measured in 116 patients in an intensive care unit who were suspected of having bacteremia, to examine its relationship with a blood culture or PCR. The PCT levels were significantly high in patients with bacteremia, but they were also moderately high in some patients who were positive for fungus DNA. The area under the curve was significantly higher for PCT than for C-reactive protein. The appropriate cutoff values of PCT for bacteremia were 0.38 g/L for the high negative predictive value and 0.83 g/L for the high positive predictive value. Procalcitonin was slightly related to mortality, and the combination of a blood culture and PCR was thus found to increase the sensitivity for mortality. These findings suggest that PCT is useful for the diagnosis of bacteremia and that the diagnostic value of PCT in combination a with blood culture and PCR for bacterial infection or mortality further increases.

Primary ciliary dyskinesia (PCD) is diagnosed through multiple methods, including transmission electron microscopy (TEM), a high-speed video microscopy analysis (HSVA), immunofluorescence (IF), and genetic testing. A primary cell culture has been recommended to avoid the misdiagnosis of secondary ciliary dyskinesia derived from infection or inflammation and improve diagnostic accuracy. However, primary cells fail to differentiate into ciliated cells through repeated passages. The conditional reprogramming culture (CRC) method, a combination of a Rho-kinase inhibitor and fibroblast feeder cells, has been applied to cystic fibrosis. The goal of this study was to evaluate the value of CRC in diagnosing PCD in Japanese patients.

The photon-excited growth of ZnTe on the (100) GaAs substrate has been studied at a very low pressure of ∼ 10−5Torr using synchrotron radiation as a light source. Diethylzinc and diethyltelluride were used as source materials, while hydrogen was employed as a carrier gas. The epitaxial layer of ZnTe can be obtained even at room temperature. It is expected that the surface excitation plays an important role in the growth, whereas thermal or gas phase excitation does not contribute. The quantum yield for forming ZnTe molecules by photons is estimated to be higher than 0.7%.

Multifaceted analysis is recommended for the diagnosis of primary ciliary dyskinesia (PCD). A 31-year-old woman had situs inversus, bronchiectasis, family history of PCD, and compound heterozygous mutations in DNAH5. Her cilia were immotile. Defects in the outer dynein arms were revealed by transmission electron microscopy and loss of DNAH5 proteins in the entire length of axonemes using immunofluorescence (IF). A 17-year-old boy had bronchiectasis and heterozygous mutations in DNAH11. His cilia were motile with normal ultrastructure. The loss of DNAH11 proteins at the proximal region of cilia was revealed by IF. IF could be useful to support PCD diagnosis.

Naoe: Chugai Pharm. Co.: Research Funding; Zenyaku-Kogyo Co.: Research Funding; Kyowa-Kirin Co.: Research Funding; Dainippon-Sumitomo Pharm. Co.: Research Funding; Novartis Pharm. Co.: Research Funding; Janssen Pharm. Co.: Research Funding. Matsushita:Pfizer Co.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Co.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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