Onlinization of a simulation course that includes minor emergency procedures.

Aim: We attempted to convert a simulation course held on-site for primary care physicians to learn about the initial treatment of minor emergencies, including some common surgical procedures, to an online format. Methods: We reviewed the subjects covered in the course and evaluated whether it was "decision-making" or "technical skills" that had been primarily taught as simulation-based training for each subject, and then supplemented the contents accordingly. Results: As a result, satisfaction levels with the online course were comparable to those with the on-site course as measured by a postcourse questionnaire (97.6% [83/85 participants] rating it as "excellent" or "good" on a 5-point Likert scale postcourse questionnaire). Conclusion: We showed that it is reasonable to offer simulation in place of in-person training even for some procedures that were once assumed to be difficult to teach online. Of note, the online course is not just a replacement for the on-site course; it can offer other benefits, including opportunities for those who have difficulty attending courses due to distance or work-related reasons. After the COVID-19 pandemic period, both onsite and online courses can be held, allowing participants to choose the style of course that best suits their situation.

Association Between Varicella-Zoster Virus Vaccination and Patient Experience in Elderly Japanese Outpatients: A Case-Control Study.

BACKGROUND: This study examined the association between patient experience (PX, events experienced by patients during primary care that are an indicator of patient-centered quality) of primary care and varicella-zoster virus (VZV) vaccine uptake in older adults. METHODS: A case-control study of VZV vaccination was conducted at a community hospital in Ibaraki, Japan. Patients aged 65 years or older who had continuously been patients of the hospital between April 2018 and April 2021 were included in the study. The vaccinated group consisted of 166 VZV-vaccinated patients. The controls consisted of 29 age- and sex-matched patients who did not receive VZV vaccination. A self-administered questionnaire was distributed between August and September 2021. It included the Japanese version of the Primary Care Assessment Tool Short Form (JPCAT-SF) to evaluate PX and included questions about recommendations for VZV vaccination by a physician and the vaccination history of relatives. Multivariable and intermediate factor analyses were used to assess whether there was an association between VZV vaccination and PX. RESULTS: Questionnaires were sent to 457 subjects. Responses from 228 (116 in the vaccination group and 112 in the non-vaccinated group) were included in the analysis. Multivariable analysis, which excluded physician recommendation for VZV vaccination as a variable because it was an intermediate factor in the analysis, showed an association between PX and VZV vaccination (odds ratio, 1.38; 95% confidence interval, 1.00-1.92; P = .049). CONCLUSIONS: PX was associated with past VZV vaccination. Physician recommendation for VZV vaccination was an intermediate factor between PX and VZV vaccination.

A qualitative study of factors promoting EBM learning among medical students in Japan.

Objectives: To identify the elements needed to facilitate undergraduate EBM learning among Japanese medical students. Methods: We conducted a qualitative study based on individual semi-structured interviews. Participants were physicians working at universities, teaching hospitals, or clinics who teach EBM to medical students. Purposive sampling was used to recruit participants via email through the researchers' acquaintances. Six physicians agreed to participate in the study and were interviewed individually from October 2019 to January 2020. The interviewees were asked about their own EBM learning and teaching experiences, what they kept in mind when teaching EBM to medical students, and what they felt was needed to improve current undergraduate EBM education. Interviews were recorded. Transcripts were analysed using thematic analysis. Results: Thematic analysis extracted five themes: finding foreground questions, observing role models, active learning, understanding patient backgrounds, and understanding the reason for learning EBM. To promote EBM education for medical students, it is first necessary for students to actively participate in clinical practice and identify foreground questions by observing their supervisors practicing EBM. In addition to acquiring skills in information retrieval and critical appraisal, understanding a patient's background leads to understanding the significance of learning EBM, which improves students' motivation to learn EBM. Conclusions: This study identified five themes that promote undergraduate EBM education. Curriculum development incorporating these elements would improve EBM education in Japan and other countries.

Evaluation of changes in prescription among Japanese elderly patients before and after transition to home care.

Background: Most patients receiving home care have multimorbidity and tend to be prescribed multiple drugs with the complicated regimen. Family physicians (FPs) are responsible for patients' prescriptions after transition to home care. This study aimed to assess changes in medication regimen complexity and potentially inappropriate medications (PIMs) made by FPs before and after transition to home care. Methods: A retrospective cohort study was conducted in six home care clinics in Ibaraki Prefecture, Japan. Data from patients aged 65 years and older taking any medication who initiated home care between April 2018 and March 2019 were collected using medical records. The medication regimen complexity index-Japanese version (MRCI-J) score and the presence of PIMs were assessed before and 3 months after transition to home care. Results: The mean age of 169 patients was 84.0 years. MRCI-J score and percentage of PIMs remained unchanged between before and 3 months after home care initiation. However, MRCI-J score significantly decreased among patients with polypharmacy, but significantly increased among patients with nonpolypharmacy. In multiple regression analysis, a greater number of medications before home care initiation was associated with a decreasing MRCI-J score, but pharmacist home visit services were not associated with changes in MRCI-J score. Conclusions: Our results suggest that FPs involved in home care are trying to adjust prescriptions by simplifying the medication regimen of patients with polypharmacy, and adding symptomatic drugs to those with nonpolypharmacy.

Enhancing the blood safety program in Myanmar: Report on projects of global extension of medical technologies of Japan.

The National Center for Global Health and Medicine has long collaborated with the blood program in Myanmar, and the Center started a new project in 2015 to enhance blood transfusion safety as part of a new set of projects of global extension of medical technologies that aims to improve public health and medicine in developing countries under public-private partnerships. The project resulted in remarkable achievements, including maintaining a high proportion of voluntary blood donations despite a rapidly growing demand for blood, ensuring blood safety from the donor to the recipient, and creating public-private partnerships. The project supported the introduction of blood grouping using the tube method at hospital blood banks, safety measures during blood transfusions, and effective use of blood products including component blood. The project identified the need for medical devices such as leukocyte filters, serofuges, and refrigerators to store blood products. The success of the project may depend on mutual understanding and trust based on the duration of collaboration, improvement of the requirement for medical safety (including blood safety) in the country, and shifting the mindset of partner companies in public-private partnerships to create new demand by encouraging improvement of the quality of care and requiring the safety of medical care. In this era of sustainable development goals, the hopes are that these experiences will help other countries seeking to improve their public health through public-private partnerships.

Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class.

A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC50 values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC50 values in the low nanomolar range.

Discovery of a novel unsymmetrical structural class of HCV NS5A inhibitors with low picomolar antiviral activity.

A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC50 values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC50 in the low nanomolar range.

Optimization of oxadiazole derivatives with a spirocyclic cyclohexane structure as novel GPR119 agonists.

We describe here a novel GPR119 agonist 24, which showed a potent and long-acting hypoglycemic effect in rats via oral dosing. For the discovery of 24, we chose compound 5, which possessed an oxadiazole linker, as a lead compound among our spirocyclic cyclohexane GPR119 agonist series, taking into account its lower plasma protein binding nature. 3,5-Difluoro and 4-methylsulfonylmethy groups on the left side phenyl group, and a gem-difluoro group on the right side of 24 are important for its agonist potency and metabolic stability, respectively.

Lead generation and optimization of novel GPR119 agonists with a spirocyclic cyclohexane structure.

We describe here the generation of a lead compound and its optimization studies that led to the identification of a novel GPR119 agonist. Based on a spirocyclic cyclohexane structure reported in our previous work, we identified compound 8 as a lead compound, being guided by ligand-lipophilicity efficiency (LLE), which linked potency and lipophilicity. Subsequent optimization studies of 8 for improvement of solubility afforded representative 21. Compound 21 had no inhibitory activity against six CYP isoforms and showed favorable pharmacokinetic properties and hypoglycemic activity in rats.

Discovery of potent liver-selective stearoyl-CoA desaturase-1 (SCD1) inhibitors, thiazole-4-acetic acid derivatives, for the treatment of diabetes, hepatic steatosis, and obesity.

SCD1 is a rate-limiting enzyme in the conversion of saturated fatty acids to monounsaturated fatty acids. SCD1 inhibitors have potential effects on obesity, diabetes, acne, and cancer, but the adverse effects associated with SCD1 inhibition in the skin and eyelids are impediments to clinical development. To avoid mechanism-based adverse effects, we explored the compounds that selectively inhibit SCD1 in the liver in an ex vivo assay. Starting from a systemically active lead compound, we focused on the physicochemical properties tPSA and cLogP to minimize exposure in the off-target tissues. This effort led to the discovery of thiazole-4-acetic acid analog 48 as a potent and liver-selective SCD1 inhibitor. Compound 48 exhibited significant effects in rodent models of diabetes, hepatic steatosis, and obesity, with sufficient safety margins in a rat toxicology study with repeated dosing.

First report of the isolation of Balamuthia mandrillaris in the northern region of Japan.

Balamuthia mandrillaris is a free-living amoeba that lives in soil and water near human settlements. B. mandrillaris was first isolated from a mandrill baboon that died at the San Diego Zoo Wildlife Park in California in 1986, and the first human infection was reported in 1990. Although reported B. mandrillaris infections are often not properly characterized, it appears that B. mandrillaris invades the living body from the soil and water, either via a wound or the nasal cavity. Most confirmed infections have originated in South and North America. B. mandrillaris inhabits warm climates and is recognized as a pathogen in warm areas such as desert climates and tropical climates. B. mandrillaris has been isolated from environmental samples since 2000, most of which originated from warm areas such as step climates, tropical climates, and desert climates. However, B. mandrillaris may survive in diverse environments, although fewer granulomatous amebic encephalitis patients have been reported in colder Japanese and Northern European regions. In the present study, we conducted a survey of 13 soil samples in Aomori Prefecture located at the northernmost tip of Japan Honshu and successfully isolated one strain of B. mandrillaris from soil for the first time in Japan. In addition, B. mandrillaris gene was detected from several soils. This confirms that B. mandrillaris is capable of spreading to a wider climatic region.

Design and synthesis of novel and potent GPR119 agonists with a spirocyclic structure.

Exploration of alternative structures of the substituted piperidine or piperazine ring which are characteristic in most of the reported GPR119 agonists provided novel spirocyclic cyclohexane derivatives. The representative 17 with a high three-dimensionality exhibited potent agonistic activity (EC50 = 4 nM) with no CYP inhibitory activity (IC50 >10 µM). Compound 17 also displayed hypoglycemic activity with insulin secretion dependent on glucose concentration in an intraperitoneal glucose tolerance test in rats.

Discovery of 6-phenylpyrimido[4,5-b][1,4]oxazines as potent and selective acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors with in vivo efficacy in rodents.

The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.

Discovery of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: novel and highly selective aggrecanase inhibitors.

Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.

Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate).

Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) represents a promising strategy for the discovery of a new generation of anticancer chemotherapeutics. Our synthetic efforts, beginning from the lead compound 2, were directed at improving antiproliferative activity against cancer cells as well as various drug properties. These efforts led to the discovery of N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide solvate (GSK1120212, JTP-74057 DMSO solvate; 1), a selective and highly potent MEK inhibitor with improved drug properties. We further confirmed that the antiproliferative activity correlates with cellular MEK inhibition and observed significant antitumor activity with daily oral dosing of 1 in a tumor xenograft model. These qualities led to the selection of 1 for clinical development.

Discovery of pyrrolopyridazines as novel DGAT1 inhibitors.

A new structural class of DGAT1 inhibitors was discovered and the structure-activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC(50) values ranging from >10 µM to 48 nM.

Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates as ADAMTS-5 (Aggrecanase-2) inhibitors.

A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 with an Agg-2 IC50=7.4 nM, the most potent ADAMTS-5 inhibitor reported so far.

Novel N-substituted 2-phenyl-1-sulfonylamino-cyclopropane carboxylates as selective ADAMTS-5 (Aggrecanase-2) inhibitors.

A series of N-substituted sulfonylamino-alkanecarboxylate ADAMTS-5 (Aggrecanase-2) inhibitors has been synthesized and the in vitro enzyme SAR is discussed. This report is the first example of carboxylate-based ADAMTS-5 inhibitors which show strong potency of IC(50)<0.1muM with excellent selectivity over MMP-1 and TACE.

One-step synthesis of heteroaromatic-fused pyrrolidines via cyclopropane ring-opening reaction: application to the PKCbeta inhibitor JTT-010.

A ring-opening reaction of cyclopropanes with five-membered heteroaromatics having a leaving group at C(2) was found to provide heteroaromatic-fused pyrrolidines in one step. This reaction was successfully applied to the synthesis of the protein kinase C-beta inhibitor JTT-010, which possesses a dihydropyrrolo[1,2-a]indole core.

An evolutionary 'intermediate state' of mitochondrial translation systems found in Trichinella species of parasitic nematodes: co-evolution of tRNA and EF-Tu.

EF-Tu delivers aminoacyl-tRNAs to ribosomes in the translation system. However, unusual truncations found in some animal mitochondrial tRNAs seem to prevent recognition by a canonical EF-Tu. We showed previously that the chromadorean nematode has two distinct EF-Tus, one of which (EF-Tu1) binds only to T-armless aminoacyl-tRNAs and the other (EF-Tu2) binds to D-armless Ser-tRNAs. Neither of the EF-Tus can bind to canonical cloverleaf tRNAs. In this study, by analyzing the translation system of enoplean nematode Trichinella species, we address how EF-Tus and tRNAs have evolved from the canonical structures toward those of the chromadorean translation system. Trichinella mitochondria possess three types of tRNAs: cloverleaf tRNAs, which do not exist in chromadorean nematode mitochondria; T-armless tRNAs; and D-armless tRNAs. We found two mitochondrial EF-Tu species, EF-Tu1 and EF-Tu2, in Trichinella britovi. T.britovi EF-Tu2 could bind to only D-armless Ser-tRNA, as Caenorhabditis elegans EF-Tu2 does. In contrast to the case of C.elegans EF-Tu1, however, T.britovi EF-Tu1 bound to all three types of tRNA present in Trichinella mitochondria. These results suggest that Trichinella mitochondrial translation system, and particularly the tRNA-binding specificity of EF-Tu1, could be an intermediate state between the canonical system and the chromadorean nematode mitochondrial system.