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Financial conflicts of interest (FCOI) between pharmaceutical companies and physicians may negatively impact patient care. This is particularly relevant regarding clinical practice guidelines (CPG), where FCOI may inappropriately influence individual drugs' promotion or use. In a cross-sectional analysis of pharmaceutical company payments, we sought to elucidate the extent of FCOI between Japanese hematologists and drug promotion in CPG. Data collected from two professional medical associations and companies belonging to the Japanese Pharmaceutical Manufacturers Association included the type and amount of company payments, individual financial disclosures, and new drug or indication approvals between 2015 and 2017. Of the 74 hematologists drafting CPG, 70 (94.6 %) received at least one payment during the study period. The cumulative median (interquartile range) value of these payments was $31,553 ($11,449-$74,390). Also, during this period, 26 new drugs or indications were approved and discussed in the CPG. Among the 79 pharmaceutical companies, the 11 (13.9 %) with newly approved and discussed drugs in the CPG made median (interquartile range) payments of $210,388 ($85,141-$292,536), while the remaining 68 (86.1 %) made $0 ($0-$9607) in payments. Disclosure of these payments was inconsistent. Such discrepancies suggest an association between pharmaceutical payments and drug approvals that only greater transparency can clarify. Consequently, a comprehensive overhaul of the current framework to control FCOI that includes legal regulation may be necessary.

Background: The problem of the uneven distribution of medical services is drawing much attention worldwide. To reveal how the changes in the specialty training system affected the distribution of doctors in Japan can help us understand this problem. In 2018, a new and standardized specialty training system was implemented by the Japanese Medical Specialty Board, which is recognized by the Ministry of Health, Labor and Welfare. The purpose of this study was to investigate how this has affected the geographical distribution of doctors commencing specialty training (trainees) and choice of specialty in Japan. Methods: Change in the number of trainees between the control period (2012 to 2014) and 2018 was investigated, taking into account prefecture and specialty selected. Population, aging rate, and total number of overall doctors in each prefecture were considered as the background characteristics of each prefecture. The Gini coefficient was used to determine evenness of trainees' distribution. Findings: In 2018, the number of trainees per 100,000 population showed an increase to 6.6 nationwide compared with 5.5 during the control period. The number of trainees per 100,000 population in 2018 showed an increase in prefectures with a large population of ≧ 2,000,000, a low aging rate (< 27%), and a high doctor density (≧ 250 doctors per 100000 population). The Gini coefficient showed an increase to 0.226 in 2018 compared with only 0.160 during the control period. The total number of trainees and that per 100,000 population showed an increase in all specialties. Interpretation: After the implementation of the new training system, the number of doctors enrolling in specialty programs showed an increase. Inequality of distribution urban and rural prefectures worsened, however, indicating the need to explore ways of balancing unevenness of distribution while maintaining optimal opportunities for specialist training. Funding Statement: The authors state: "This research isn’t receiving any funding." Declaration of Interests: Dr. Saito reports honorarium from TAIHO Pharmaceutical Co., Ltd., outside the submitted work. Ethics Approval Statement: The authors state: "Not applicable."

Procyanidins are widely found in plants and have anti-inflammatory activities. Procyanidin B2 (PCB2) inhibits production of proinflammatory cytokines in macrophages. However, there has been no study that has attempted to determine the effects of PCB2 gallates on T cell functions. In the present study, murine splenocytes were isolated and treated with PCB2 or PCB2 gallates in the presence of an anti-CD3 monoclonal antibody (mAb). PCB2 gallates, but not PCB2, inhibited proliferation and T cell activation of splenocytes after stimulation with the anti-CD3 mAb. In addition, PCB2 gallates, particularly 3,3″-di-O-gallate (3,3″-di-OG), significantly inhibited production of interferon (IFN)-γ, interleukin (IL)-12p40, and IL-17 in splenocytes, but did not suppress IL-10 production. Intracellular staining revealed that the expression of IFN-γ and IL-17 in both CD4+ and CD8+ T cells was obviously decreased by PCB2 3,3″-di-OG compared with PCB2, PCB2 3-OG, and PCB2 3″-OG. Treatment of isolated CD4+ and CD8+ T cells with procyanidins in the presence of the anti-CD3 mAb led to significant inhibition of IFN-γ production by PCB2 3,3″-di-OG in both cell types. Furthermore, PCB2 3,3″-di-OG suppressed the expression of transcription factors T-bet and RORγt that regulate IFN-γ and IL-17, respectively. In conclusion, we revealed a new mechanism through which PCB2 gallates inhibit IFN-γ and IL-17 production in T cells by down-regulation of T-bet and RORγt expression. Our results suggest that PCB2 gallates have a potential role in Th1/Th17-mediated diseases such as inflammatory and autoimmune diseases.

Crystallographic position and acidic properties of the Co species in MFI zeolite which was catalytically active for methylation of benzene with methane (CH4 + C6H6 → H3C–C6H5 + H2) were investigated with UV–vis spectroscopy and an ammonia IRMS-TPD method. Among the divalent cation sites in MFI classified into α, β and γ, loading of Co2+ at the α site on the wall of straight channel proceeded mainly in the relatively high Co concentration region (Cozeo/Alzeo > 0.25) without additive or in the low Co concentration region in the co-presence of Mg and Pb. On the other hand, Co2+ on MFI were classified from the view of Lewis acidity into four types (L1S, L1W, L2S and L2W). The L1S type possessing strong base-stabilizing and electron-withdrawing nature showed similar dependency on the Co content to the Co2+ at the α site as well as the catalytic activity for direct methylation of benzene with methane. These observations indicate that the Co2+ at the α site with L1S nature was active for the methylation of benzene with methane, a reaction promising to open a way of utilization of methane as a feedstock of valued chemicals.

Blooms of the dinoflagellate Karenia mikimotoi cause mass mortality of aquaculture fishes and have become a worldwide environmental problem in coastal waters, especially in Asia. One area is Imari Bay, Japan, where blooms have recurrently formed in recent years. This study examines the meteorological and oceanographical conditions causing the recent increase in occurrence. The recent frequency of occurrence (2012–2018) is nearly four-fold previous years (1999–2011). In recent years, total nitrogen increased in the eastern area where the bloom initially develops, and The Tsushima warm current (TWC) have intensified during spring. Spring total nitrogen has increased as a result of climate change involving increasing rainfall and weakening monsoon rather than eutrophication because of the asynchrony between increasing and total nitrogen in rivers. Intensity of TWC changed in synchrony with M 2 amplitude with lunar nodal cycle. Potential methodology for the medium term prediction of blooms is suggested in Imari Bay using environmental parameters.

An oxidative amide formation using N-hydroxysuccinimide and hypervalent iodine reagents was developed. The method enables a wide range of aldehydes and amines to be coupled under mild reaction conditions providing amide in good to excellent yield. The radical species in the reaction mixture was observed for the first time using ESR measurement, and along with other mechanistic investigations, a plausible mechanism of the reaction was proposed.

Ring closing metathesis (RCM) has emerged as a powerful tool to construct macrocyclic ring systems. However, the product distribution of monomer and oligomers is often a problem in the formation of medium to large rings. In the course of synthetic studies on the natural product radicicol and its analogs, we have found that the reaction temperature, along with concentration, has significant impact on the outcome of the product ratio. Specifically, carrying out the RCM reaction in refluxing toluene (110°C) at higher dilution affords improved yields of the monomeric macrocycle. Similar observations for another family of macrolactone natural products, the epothilones, are also reported.