Perspectives on Collaboration between Physicians and Nurse Practitioners in Japan: A Cross-Sectional Study.

BACKGROUND: Nurse practitioners (NPs) are known as effective healthcare providers worldwide. In Japan, nurse practitioner adoption is considered to be in a shaky period. Although nurse practitioners were introduced approximately 10 years ago at the initiative of educational institutions in Japan, the full extent of this trend is not known. Therefore, we have clarified the whole picture of nurse practitioners from two directions: the perception of nurse practitioners in Japan and the perception of physicians who work with nurse practitioners. This will inform discussions regarding the recruitment of nurse practitioners at the national level in Japan. METHODS: From 18 June to 24 July 2021, we administered a nationwide cross-sectional survey of NPs and physicians working in the same clinical settings as NPs in Japan. The domains of the survey included "scope and content of work", "perceptions of NPs' clinical practice", and "individual clinical practice characteristics". The survey was distributed and collected digitally. RESULTS: The total number of respondents to the survey was 281, including 169 NPs and 112 physicians; the percentage of NPs who responded was 50.5%. The number of valid responses was 164 NPs and 111 physicians, for a total of 275 respondents. Approximately 60% of NPs are concentrated in Tokyo, the capital of Japan, and the three prefectures adjacent to Tokyo. They also worked fewer hours per week, cared for fewer patients per day, and earned less money than physicians. More physicians than NPs indicated that "more NPs would improve the quality of care". A total of 90.1% of physicians and 82.3% of NPs agreed that "Nurse practitioners should practice to the full extent of their education and training," and 73.9% of physicians and 81.7% of NPs agreed that "Nurse practitioners' scope of practice should be uniformly defined at a national level". CONCLUSIONS: This study clarified the present working conditions of NPs from NPs' and physicians' perspectives in Japanese contexts. Japanese NPs may be able to work effectively in collaboration with physicians. Therefore, the implementation of NPs in Japanese medical conditions should be discussed further for better healthcare.

Coexistence of Pancytopenia and Myositis After Developing COVID-19.

COVID-19 causes not only acute but also subacute medical conditions during the clinical course. COVID-19 causes severe inflammatory conditions; therefore, patients may develop long-term complications. Among patients with acute COVID-19, some patients can experience persistent symptoms, such as fatigue, joint pain, and smell and taste abnormalities, known as the long COVID-19 syndrome. The symptoms can be severe and require continuous medical care. Patients with severe clinical courses of COVID-19 may have critical symptoms again after the cure of the acute infections, especially among older patients. We encountered a case of neutropenia and myositis one month after contracting COVID-19. An 89-year-old man presented to our hospital with acute-onset systemic muscle pain and difficulty in movement and speaking. The patient had neutropenia and myositis with an extremely high level of immunoglobulin G caused by COVID-19. A granulocyte colony-stimulating factor could be effective for treating neutropenia. Besides, prednisolone was effective for treating myositis. In community hospitals, after developing COVID-19, appropriate history taking and physical examination should be performed in older patients with ambiguous symptoms, as they might have critical medical conditions such as neutropenia and myositis. The appropriate diagnosis and treatments of older patients with the complications of COVID-19 should be performed.

Pseudogout as a Cause of Fever of Unknown Origin Following Staphylococcal Bacteremia in an Older Patient.

The causes of fevers in older adults are numerous and diverse, resulting in fevers of unknown origin that complicate the diagnosis process. Compared to young adults, older adults are characterized by comorbidities, aging-induced physiological changes, decreased homeostasis, reduced activities of daily living, and a diminished quality of life due to disease and aging. Thus, diverse perspectives are required to facilitate the accurate diagnosis of fever in older adults. In this study, we experienced a case of epidermal staphylococcal bacteremia of unknown cause with a persistent fever that eventually led to the diagnosis of cervical pseudogout. A 94-year-old bedridden woman visited our hospital with a chief complaint of persistent fever. She was diagnosed with cervical pseudogout after closely examining the prolonged fever following Staphylococcus epidermidis bacteremia. Noninfectious diseases are frequent causes of unexplained fever in older adults, and systemic inflammatory diseases, such as cervical pseudogout, should be considered during examination.

Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor.

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B-cell lymphoma cells harboring gain-of-function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL-AF9, MLL-AF4, and AML1-ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications.

Discovery of R-142086 as a factor Xa (FXa) inhibitor: syntheses and structure-activity relationships of cinnamyl derivatives.

To develop a novel and effective anticoagulant with potent and selective factor Xa (FXa) inhibitory activity, a new series of cinnamyl derivatives with enhanced lipophilicity and prodrug forms were synthesized and their biological activities were evaluated. As a result, we found that cinnamyl derivative (N-[4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl]-N-[(Z)-3-(3-amidinophenyl)-2-fluoro-2-propenyl]sulfamoyl)acetic acid dihydrochloride (26d, R-142086) with a fluorine atom on the double bond exhibited potent anticoagulant activity and no mutagenic potential. Moreover, orally administered R-142086 exhibited potent anti-FXa activity and anticoagulant activity in dogs.

Cinnamyl derivatives: synthesis and factor Xa (FXa) inhibitory activities.

To develop a potent and oral anticoagulant, a series of compounds with cinnamyl moiety was synthesized and their factor Xa (FXa) inhibitory activities were examined. As a result, some cinnamyl derivatives showed potent FXa inhibitory activities in vitro. Among them, compounds with substituent at the 3-position on the central benzene ring represented by (N-{4-[1-(acetimidoyl)piperidin-4-yloxy]-3-chlorophenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45b) and (N-{4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45j) exhibited potent FXa inhibitory activities with IC(50) values of less than 10 nM in vitro. These compounds also showed potent anticoagulant activities both in vitro and ex vivo. Furthermore, these compounds exhibited no lethal toxicity (30 mg/kg, i.v.).

Cinnamylindoline derivatives: synthesis and factor Xa (FXa) inhibitory activities.

A series of cinnamylindoline derivatives were synthesized, and their factor Xa (FXa) inhibitory activities and selectivity over trypsin were evaluated. Among them, some novel derivatives showed potent FXa inhibitory activities and good selectivity over trypsin. Especially, (E)-2-{5-[1-(acetimidoyl)piperidin-4-yloxy]-2-[2-(5-amidino-2-hydroxyphenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetic acid (22f) having 2-hydroxycinnamyl moiety exhibited the most potent FXa inhibitory activity in vitro. Furthermore, 22f also exhibited potent anticoagulant activities in vitro.

Indoline derivatives II: synthesis and factor Xa (FXa) inhibitory activities.

Factor Xa (FXa) is well known to play a pivotal role in blood coagulation, so FXa inhibitor is a promising drug candidate for prophylaxis and treatment of thromboembolic diseases. In the course of our research, we have found that (R)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)-1-(ethanesulfonyl)indoline ((R)-1) showed potent FXa inhibitory activity in vitro. However, single oral administation (RS)-1 showed high toxicity in mice. Among newly synthesized compounds, ({(RS)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)indolin-1-yl}sulfonyl)acetic acid ((RS)-11d) showed more potent FXa inhibitory activity and higher safety than (RS)-1. The R-isoform of compound 11d ((R)-11d) exhibited potent in vitro anticoagulant activity in human and hamster plasma. Orally administered (R)-11d also showed dose-dependent potent anticoagulant activity in hamsters, marmosets and cynomolgus monkeys. Compound (R)-11d with potent anticoagulant activity and high safety is therefore favorable as a novel oral FXa inhibitor.

Indoline derivatives I: synthesis and factor Xa (FXa) inhibitory activities.

A series of bisamidine derivatives each having a ring structure in the center of the molecule was synthesized and their Factor Xa (FXa) inhibitory activities were evaluated. Among them, some indoline derivatives showed potent inhibitory activities in vitro. In particular, (R)-18a having an (R)-configuration at the 2-position of the indoline ring exhibited the most potent FXa inhibitory activity in vitro, more potent than DX-9065a. Furthermore, (R)-18a exhibited more potent anticoagulant activity than DX-9065a. We also succeeded in obtaining an X-ray crystal structure of FXa bound with (R)-18a.