A protocol of an international validation study to assess the clinical accuracy of the eDIS-ICU delirium screening tool.

BACKGROUND: Delirium is a common, yet underdiagnosed neuropsychiatric complication of intensive care unit (ICU) admission, associated with significant mortality and morbidity. Delirium can be difficult to diagnose, with gold standard assessments by a trained specialist being impractical and rarely performed. To address this, various tools have been developed, enabling bedside clinicians to assess for delirium efficiently and accurately. However, the performance of these tools varies depending on factors including the assessor's training. To address the shortcomings of current tools, electronic tools have been developed. AIMS AND OBJECTIVES: The aims of this validation study are to assess the feasibility, acceptability, and generalisability of a recently developed and pilot-tested electronic delirium screening tool (eDIS-ICU) and compare diagnostic concordance, sensitivity, and specificity between eDIS-ICU, Confusion Assessment Method for the ICU (CAM-ICU), and the Diagnostic and Statistical Manual of Mental Disorders - 5th edition (DSM-V) gold standard in diverse ICU settings. METHODS: Seven hundred participants will be recruited across five sites in three countries. Participants will complete three assessments (eDIS-ICU, CAM-ICU, and DSM-V) twice within one 24-h period. At each time point, assessments will be completed within one hour. Assessments will be administered by three different people at any given time point, with the assessment order and assessor for eDIS-ICU and CAM-ICU randomly allocated. Assessors will be blinded to previous and concurrent assessment results. RESULTS: The primary outcome is comparing diagnostic sensitivity of eDIS-ICU and CAM-ICU against the DSM-V. RELEVANCE TO CLINICAL PRACTICE: This protocol describes a definitive validation study of an electronic diagnostic tool to assess for delirium in the ICU. Delirium remains a common and difficult challenge in the ICU and is linked with multiple neurocognitive sequelae. Various challenges to routine assessment mean many cases are still unrecognised or misdiagnosed. An improved ability for bedside clinicians to screen for delirium accurately and efficiently will support earlier diagnosis, identification of underlying cause(s) and timely treatments, and ultimately improved patient outcomes. CLINICAL TRIAL REGISTRATION NUMBER: This study was prospectively registered on the Australian New Zealand Clinical Trials Registry (ANZCTR) on 8th February 2022 (ACTRN12622000220763).

A 1,2,3-triazole-derived pincer-type mesoionic carbene complex of iron(II): carbonyl elimination and hydrosilylation of aromatic aldehydes via the concerted reaction with hydrosilane and a base.

Iron complexes bearing 1,2,3-triazol-5-ylidene were synthesized and applied to the reaction with hydrosilane and homogeneous catalytic hydrosilylation of aromatic ketones and aldehydes. Addition of a free carbene to a solution of Fe(CO)4Br2 yielded an octahedral, diamagnetic and cationic iron(II) complex [Fe(1,2,3-triazolylidene)(CO)2Br]+. Pyrolysis of the dicarbonyl complex eliminated the two CO ligands to form a paramagnetic four-coordinate complex. A theoretical study using DFT calculations indicated that the spin state changed from singlet to quintet during ligand elimination. Investigations of the successful hydrosilylation of acetophenone and benzaldehyde derivatives using MIC-iron(II) bromide suggested the importance of the base for efficient conversion in the catalytic process. The bromide-to-hydride exchange reaction, transmetallation, of MIC-iron(II) bromide in the presence of KOtBu and HSi(OEt)3 which could occur in the initial process of hydrosilylation was proposed, and supported by a theoretical study.

How has the COVID-19 pandemic influenced nursing students' academic experience and career choices? A qualitative descriptive analysis.

COVID-19 control measures influenced education and training environments and profoundly impacted nursing students' career prospects and academic lives. This study intends to elucidate the impact of the COVID-19 pandemic on nursing students' academic experience and career choices. A qualitative descriptive study was conducted at a 4-year university in Japan, using semi-structured interviews with 14 nursing students. Sandelowski's qualitative descriptive analysis was conducted. We identified 11 categories that summarize COVID-19's influence on students' academic experience and career choices: "Forced change to a new learning system," "Difficult learning thoroughly with restricted face-to-face interactions," "Worries regarding teacher evaluations when face-to-face interactions are restricted," "Adapting to changes in the learning environment," "Finding new ways to learn due to the different learning environment," "Worries regarding career decision-making after losing opportunities to obtain career information," "Fully utilizing limited information resources in deciding where to work while being influenced by others," "Coping with a confusing new job hunting system," "Worries about becoming a nurse without enough practical experience," "Conscious of working as a nurse while facing infections," and "Support from those around me is helpful in an unfamiliar environment." The categories comprised four elements: academic impact, employment/career impact, future impact on working as a nurse, and environmental support. Building an online education/training program, ensuring the availability of regular psychological support, providing abundant information on employment, installing an information desk, and providing regular feedback were considered imperative for supporting nursing students.

Impact of the COVID-19 pandemic on the mental health of nursing students in Japan: a cross-sectional study.

BACKGROUND: The effect of the prolonged coronavirus disease (COVID-19) pandemic on the mental health of nursing students is unclear. This study assesses the prevalence of anxiety, depression, and insomnia among nursing students in Japan during the pandemic and determines the risk factors associated with such symptoms. METHODS: An online survey-based cross-sectional study was conducted from August 16 to October 16, 2021. Participants were first- to fourth-year nursing students enrolled in undergraduate programs at the eight universities in Japan. Anxiety, depression, and insomnia were assessed using the Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, and Insomnia Severity Index-7, respectively. We calculated descriptive statistics for each measurement item and performed univariate and logistic regression analyses to evaluate the potential risk factors. RESULTS: We received responses from 1,222 of 3,056 nursing students (response rate: 40.0%). After 25 participants were excluded due to missing outcome values, 1,197 students (valid response rate: 98.0%) were included in the analysis. The prevalence of anxiety, depression, and insomnia was 4.8%, 12.4%, and 18.0%, respectively. The risk of anxiety was lower among participants who did not have any relatives or friends who had been infected with SARS-CoV-2 than among those who did (aOR 0.36, 95% CI 0.14-0.94). The risk of depression was higher among participants whose financial status had worsened during the pandemic than among those whose financial status had not changed (aOR 3.44; 95% CI 1.98-5.96). Common factors that increased the risk of anxiety, depression, and insomnia were life satisfaction and fear of COVID-19. CONCLUSION: Mental health-related symptoms among nursing students in Japan have not necessarily worsened with the spread of COVID-19 but were exacerbated by the intensity of changes in daily living and fear, which are psychosocial effects associated with the pandemic.

Impact of the COVID-19 pandemic on mental health of nursing students in Japan: protocol for a cross-sectional study.

INTRODUCTION: The COVID-19 pandemic is spreading globally with a high risk of mortality. It is also significantly affecting mental health. For nursing students, the impact of COVID-19 on mental health is predicted to be significant; however, sufficient data have not been obtained. Therefore, this study will aim to assess the mental health of nursing students and evaluate the related factors. METHODS AND ANALYSIS: This proposed study is a cross-sectional survey using a self-report questionnaire. An online questionnaire will be distributed among all nursing students of eight universities in Japan. The survey questionnaire will consist of questions related to demography, life satisfaction, fear of COVID-19, mental health and physical activities. The target sample size is 1300 nursing students. We will calculate descriptive statistics for each measurement item and perform univariate and logistic regression analyses to evaluate the potential risk factors for anxiety, depression and insomnia symptoms in nursing students. The strength of association will be assessed using the OR and its 95% CIs. Statistical significance will be set at a p<0.05. ETHICS AND DISSEMINATION: The protocol was approved by the Institutional Review Board (IRB) of the University of Hyogo on 22 March 2021 (ID: 2020F29). In addition, all of the participating facilities required ethical approval from their local IRBs. The findings will be disseminated through peer-reviewed publications and conference presentations. We believe that the proposed large-scale investigation of the mental health of nursing students during the COVID-19 pandemic and the relationship between mental health and fear of COVID-19 are novel and will be a strength of this study.

Fluorine-Substituted Arylphosphine for an NHC-Ni(I) System, Air-Stable in a Solid State but Catalytically Active in Solution.

Monovalent NHC-nickel complexes bearing triarylphosphine, in which fluorine is incorporated onto the aryl groups, have been synthesized. Tris(3,5-di(trifluoromethyl)-phenyl)phosphine efficiently gave a monovalent nickel bromide complex, whose structure was determined by X-ray diffraction analysis for the first time. In the solid state, the Ni(I) complex was less susceptible to oxidation in air than the triphenylphosphine complex, indicating greatly improved solid-state stability. In contrast, the Ni(I) complex in solution can easily liberate the phosphine, high catalytic activity toward the Kumada-Tamao-Corriu coupling of aryl bromides.

Dinuclear Nickel(I) and Palladium(I) Complexes for Highly Active Transformations of Organic Compounds.

In typical catalytic organic transformations, transition metals in catalytically active complexes are present in their most stable valence states, such as palladium(0) and (II). However, some dimeric monovalent metal complexes can be stabilized by auxiliary ligands to form diamagnetic compounds with metal-metal bonding interactions. These diamagnetic compounds can act as catalysts while retaining their dimeric forms, split homolytically or heterolytically into monomeric forms, which usually have high activity, or in contrast, become completely deactivated as catalysts. Recently, many studies using group 10 metal complexes containing nickel and palladium have demonstrated that under specific conditions, the active forms of these catalyst precursors are not mononuclear zerovalent complexes, but instead dinuclear monovalent metal complexes. In this mini-review, we have surveyed the preparation, reactivity, and the catalytic processes of dinuclear nickel(I) and palladium(I) complexes, focusing on mechanistic insights into the precatalyst activation systems and the structure and behavior of nickel and palladium intermediates.

Synthesis and pharmacological evaluation of glycine amide derivatives as novel vascular adhesion protein-1 inhibitors without CYP3A4 and CYP2C19 inhibition.

Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.

Bimetallic Cu(I) complex with a pyridine-bridged bis(1,2,3-triazole-5-ylidene) ligand.

A dinuclear copper(i) complex bearing a mesoionic carbene ligand has been prepared from the corresponding silver analogue and its structure determined spectroscopically. The results revealed that two Cu(i) halide salt molecules were bound to the carbon atoms of the pyridine-bridged bis(triazolylidene) moieties rather than the pyridine. Cyclic voltammogram measurements revealed that the two Cu(i) centres underwent a stepwise oxidation, suggesting that both the triazolylidene rings of the ligand could be on the same expanded π-conjugated system. The catalytic hydroboration of styrene derivatives with bis(pinacolato)diborane in the presence of this complex allowed for the ß-selective formation of the corresponding alkylboronate esters.

Reliability and validity assessment of the Japanese version of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).

OBJECTIVE: Delirium may lead to adverse outcomes in patients with serious conditions, but is often under-diagnosed due to inadequate screening. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is an established method for assessing delirium in the ICU. The validity and reliability of the Japanese version of the CAM-ICU has not, however, been verified, and we undertook this study to verify these parameters. RESEARCH METHODOLOGY: CAM-ICU validity and reliability were assessed in two Japanese ICUs. Using the evaluation of the DMS-IV-TR in the psychiatrists group as the standard criteria for delirium diagnosis, we compared the evaluation of the Japanese version of the CAM-ICU between the research nurses group and the staff nurses group. RESULTS: According to DSM-IV-TR criteria, the prevalence of delirium was 22.0%, and according to CAM-ICU delirium was found in 22.0% with Research Nurses and 19.5% with Staff Nurses. CAM-ICU sensitivity ratings were 83% and 78%, while their specificity ratings were 95% and 97%, respectively. The Kappa inter-rater reliability was good (κ=0.85), and Cronbach's alpha coefficient was 0.69 (95% CI: 0.57-0.79). Mean rating time for the CAM-ICU was 2.5-2.8 minutes for Research Nurses and Staff Nurses, respectively. CONCLUSION: The Japanese version of the CAM-ICU has comparable validity and reliability as a delirium assessment tool in surgical patients in two Japanese ICUs. With training, CAM-ICU can be incorporated into daily clinical practice.

Identification of potent orally active factor Xa inhibitors based on conjugation strategy and application of predictable fragment recommender system.

Anticoagulant agents have emerged as a promising class of therapeutic drugs for the treatment and prevention of arterial and venous thrombosis. We investigated a series of novel orally active factor Xa inhibitors designed using our previously reported conjugation strategy to boost oral anticoagulant effect. Structural optimization of anthranilamide derivative 3 as a lead compound with installation of phenolic hydroxyl group and extensive exploration of the P1 binding element led to the identification of 5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide (33, AS1468240) as a potent factor Xa inhibitor with significant oral anticoagulant activity. We also reported a newly developed Free-Wilson-like fragment recommender system based on the integration of R-group decomposition with collaborative filtering for the structural optimization process.

Novel strategy to boost oral anticoagulant activity of blood coagulation enzyme inhibitors based on biotransformation into hydrophilic conjugates.

The blood coagulation cascade represents an attractive target for antithrombotic drug development, and recent studies have attempted to identify oral anticoagulants with inhibitory activity for enzymes in this cascade, with particular attention focused on thrombin and factor Xa (fXa) as typical targets. We previously described the discovery of the orally active fXa inhibitor darexaban (1) and reported a unique profile that compound 1 rapidly transformed into glucuronide YM-222714 (2) after oral administration. Here, we propose a novel strategy towards the discovery of an orally active anticoagulant that is based on the bioconversion of a non-amidine inhibitor into the corresponding conjugate to boost ex vivo anticoagulant activity via an increase in hydrophilicity. Computational molecular modeling was utilized to select a template scaffold and design a substitution point to install a potential functional group for conjugation. This strategy led to the identification of the phenol-derived fXa inhibitor ASP8102 (14), which demonstrated highly potent anticoagulant activity after biotransformation into the corresponding glucuronide (16) via oral dosing.

Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists. Part 2.

We previously reported that the novel dual 5-HT2B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT2B and 5-HT7 receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT7), Tyr (Y370:5-HT2B, Y374:5-HT7) and aromatic residue (W131:5-HT2B, F158:5-HT7). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT2B (Ki=4.3 nM) and 5-HT7 receptor (Ki=4.3 nM) with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects.

Discovery of N-[2-hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (darexaban, YM150) as a potent and orally available factor Xa inhibitor.

Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound 1a that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of 1a without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 14i is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.

Pharmacological profile of AS1670542, a novel orally-active human thrombopoietin receptor agonist.

Eltrombopag, an orally-active small molecule thrombopoietin (TPO) receptor agonist, was used for the first time in 2008 to treat patients with chronic idiopathic thrombocytopenic purpura. Here, we investigated the pharmacological effect of a new orally-active small molecule TPO receptor agonist which may be effective in treating these patients. 50% effective concentration values for cell proliferation with AS1670542 or eltrombopag were 1.9 and 13nM, respectively, while those for megakaryocyte colony formation from human cord blood CD34(+) cells with AS1670542 or eltrombopag were 260 and 950nM, respectively. On Day 14 after the start of administration, AS1670542 significantly increased the number of human platelets in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice with transplanted human hematopoietic stem cells at 0.3 (P<0.05); in contrast, while administration of eltrombopag also increased the numbers of these platelets at 30mg/kg/day (P=0.058), no statistical significance was noted in the increase. Here, we identified AS1670542, a novel orally-active TPO receptor agonist which mimics the biological activity of TPO and may demonstrate greater in vitro and in vivo pharmacologically efficacy than eltrombopag.

A new aspect of nickel-catalyzed Grignard cross-coupling reactions: selective synthesis, structure, and catalytic behavior of a T-shape three-coordinate nickel(I) chloride bearing a bulky NHC ligand.

Novel T-shape three-coordinate nickel(I) chlorides bearing an N-heterocyclic carbene ligand, NiCl(IPr)(2) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene), were isolated by a reaction of Ni(0)(NHC)(2) with aryl chlorides. This Ni(I) complex was shown to act as a catalyst in a cross-coupling reaction of aryl halides with phenylmagnesium chloride.

C-F bond-cleavage reactions of fluoroalkanes with magnesium reagents and without metal catalysts.

An unexpected C-F bond-cleavage reaction of unactivated fluoroalkanes with the well-known Grignard reagents without using metal catalysts has been discovered. For example, a reaction between 1-fluorooctane and phenyl magnesium chloride gave n-octylbenzene in moderate yield. This coupling reaction via the activation of an unactivated alkyl carbon-fluorine bond proceeds with phenylmagnesium chloride, whereas methylmagnesium chloride did not give the C-C cross-coupling product but rather a halogen exchange product.

Nickel-NHC-catalyzed alpha-arylation of acyclic ketones and amination of haloarenes and unexpected preferential N-arylation of 4-aminopropiophenone.

Arylation of both acyclic ketones and primary and secondary amines was achieved using a new, simple, stable, and easy-to-access nickel(II)-halide complex bearing mixed PPh3/N-heterocyclic carbene ligands as a catalyst precursor. Acyclic ketones were first arylated at the alpha-position with the nickel catalyst. On the other hand, less basic amines, such as diphenylamine and 4-aminobenzophenone, were more favorable in the catalytic amination of haloarenes than basic amines, contrary to previous reports. N-Arylation of 4-aminopropiophenone was found to proceed selectively without causing alpha-arylation of the ketone group.