Discovery of Novel Bicyclic Pyrazoles as Potent PIP5K1C Inhibitors.

Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) is generated by phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) from phosphatidylinositol 4-phosphate (PI4P). Structurally diverse and selective inhibitors against PIP5Ks are required to further elucidate the therapeutic potential for PIP5K inhibition, although the effects of PIP5K inhibition on various diseases and their symptoms, such as cancer and chronic pain, have been reported. Our medicinal chemistry efforts led to novel and potent PIP5K1C inhibitors. Compounds 30 and 33 not only showed potent activity but also demonstrated low total clearance in mice and high levels of kinase selectivity. These compounds might serve as tools to further elucidate the complex biology and therapeutic potential of PIP5K inhibition.

Discrimination between healthy participants and people with panic disorder based on polygenic scores for psychiatric disorders and for intermediate phenotypes using machine learning.

OBJECTIVE: Panic disorder is a modestly heritable condition. Currently, diagnosis is based only on clinical symptoms; identifying objective biomarkers and a more reliable diagnostic procedure is desirable. We investigated whether people with panic disorder can be reliably diagnosed utilizing combinations of multiple polygenic scores for psychiatric disorders and their intermediate phenotypes, compared with single polygenic score approaches, by applying specific machine learning techniques. METHODS: Polygenic scores for 48 psychiatric disorders and intermediate phenotypes based on large-scale genome-wide association studies (n = 7556-1,131,881) were calculated for people with panic disorder (n = 718) and healthy controls (n = 1717). Discrimination between people with panic disorder and healthy controls was based on the 48 polygenic scores using five methods for classification: logistic regression, neural networks, quadratic discriminant analysis, random forests and a support vector machine. Differences in discrimination accuracy (area under the curve) due to an increased number of polygenic score combinations and differences in the accuracy across five classifiers were investigated. RESULTS: All five classifiers performed relatively well for distinguishing people with panic disorder from healthy controls by increasing the number of polygenic scores. Of the 48 polygenic scores, the polygenic score for anxiety UK Biobank was the most useful for discrimination by the classifiers. In combinations of two or three polygenic scores, the polygenic score for anxiety UK Biobank was included as one of polygenic scores in all classifiers. When all 48 polygenic scores were used in combination, the greatest areas under the curve significantly differed among the five classifiers. Support vector machine and logistic regression had higher accuracy than quadratic discriminant analysis and random forests. For each classifier, the greatest area under the curve was 0.600 ± 0.030 for logistic regression (polygenic score combinations N = 14), 0.591 ± 0.039 for neural networks (N = 9), 0.603 ± 0.033 for quadratic discriminant analysis (N = 10), 0.572 ± 0.039 for random forests (N = 25) and 0.617 ± 0.041 for support vector machine (N = 11). The greatest areas under the curve at the best polygenic score combination significantly differed among the five classifiers. Random forests had the lowest accuracy among classifiers. Support vector machine had higher accuracy than neural networks. CONCLUSIONS: These findings suggest that increasing the number of polygenic score combinations up to approximately 10 effectively improved the discrimination accuracy and that support vector machine exhibited greater accuracy among classifiers. However, the discrimination accuracy for panic disorder, when based solely on polygenic score combinations, was found to be modest.

Assessing ulnar neuropathy at the elbow using magnetoneurography.

OBJECTIVE: To measure neuromagnetic fields of ulnar neuropathy patients at the elbow after electrical stimulation and evaluate ulnar nerve function at the elbow with high spatial resolution. METHODS: A superconducting quantum interference device magnetometer system recorded neuromagnetic fields of the ulnar nerve at the elbow after electrical stimulation at the wrist in 16 limbs of 16 healthy volunteers and 21 limbs of 20 patients with ulnar neuropathy at the elbow. After artifact removal, neuromagnetic field signals were processed into current distributions, which were superimposed onto X-ray images for visualization. RESULTS: Based on the results in healthy volunteers, conduction velocity of 30 m/s or 50% attenuation in current amplitude was set as the reference value for conduction disturbance. Of the 21 patient limbs, 15 were measurable and lesion sites were detected, whereas 6 limbs were unmeasurable due to weak neuromagnetic field signals. Seven limbs were deemed normal by nerve conduction study, but 5 showed conduction disturbances on magnetoneurography. CONCLUSIONS: Measuring the magnetic field after nerve stimulation enabled visualization of neurophysiological activity in patients with ulnar neuropathy at the elbow and evaluation of conduction disturbances. SIGNIFICANCE: Magnetoneurography may be useful for assessing lesion sites in patients with ulnar neuropathy at the elbow.

Development of quality indicators for palliative care in intensive care units and pilot testing them via electronic medical record review.

BACKGROUND: Patients in intensive care units (ICUs) often require quality palliative care for relief from various types of suffering. To achieve quality palliative care, specific goals need to be identified, measured, and reported. The present study aimed to develop quality indicators (QIs) for palliative care in ICUs, based on a systematic review and modified Delphi method, and test their feasibility by reviewing electronic medical record (EMR) data. METHODS: The current study was performed in two phases: the development of QIs using the modified Delphi method, and pilot-testing the quality of palliative care in ICUs based on EMR review. The pilot test included 262 patients admitted to the general or emergency ICU at a university hospital from January 1, 2019, to June 30, 2019. RESULTS: A 28-item QI set for palliative care in ICUs was developed based on the consensus of 16 experts. The Delphi process resulted in low measurability ratings for two items: "Assessment of the patient's psychological distress" and "Assessment of the patient's spiritual and cultural practices." However, these items were determined to be important for quality care from the perspective of holistic assessment of distress and were adopted in the final version of the QI set. While the pilot test results indicated the feasibility of the developed QIs, they suggested that the frequency of care performance varied, and certain aspects of palliative care in ICUs needed to be improved, namely (1) regular pain assessment, (2) identification of the patient's advance directive and advance care planning for treatment, (3) conducting an interdisciplinary family conference on palliative care, and (4) assessment of psychological distress of family members. CONCLUSIONS: The QI set, developed using the modified Delphi method and tested using EMR data, provided a tool for assessing the quality of palliative care in ICUs. In the two ICUs considered in this study, aspects of the palliative care process with a low performance frequency were identified, and further national surveys were recommended. It is necessary to conduct ongoing surveys at more facilities to improve the quality of palliative care in ICUs.

Optical manipulation and fusion of aqueous droplets containing inorganic and organic solutes in air using the dual-beam laser trapping technique.

The comparative evaluation of two aerosol droplets of different chemical compositions using the dual-beam laser trapping technique can be employed for highly sensitive and accurate measurements of the water activities of such droplets. However, it is technically difficult to load droplets of different chemical compositions into adjacent optical traps that are only a few tens of micrometers apart. To overcome this challenge, a chamber with an overhanging roof was created. This roof prevented the initially trapped droplets from being contaminated by aerosol droplets that were subsequently introduced into the chamber. Herein, we report the simultaneous laser trapping of an aqueous ammonium sulfate (AS) droplet and an aqueous succinic acid (SA) droplet in air using the dual-beam laser trapping technique. Two droplets were successfully fused through optical manipulation to form a mixed inorganic/organic droplet in air. This experimental approach is advantageous because it forms mixed inorganic/organic droplets under constant relative humidity (RH) conditions. However, in previous studies, it was necessary to compensate for changes in RH prior to and after droplet fusion. To assess the validity of theoretical predictions of the water activity of droplets containing AS and SA, the equilibrium radii of the droplet were compared with those calculated using certain theoretical models.

Association between immune checkpoint inhibitor-induced myocarditis and concomitant use of thiazide diuretics.

Although an association has been reported between diuretics and myocarditis, it is unclear whether the risk of immune checkpoint inhibitor (ICI)-induced myocarditis is affected by concomitant diuretics. Thus, the aim of this work was to evaluate the impact of concomitant diuretics on ICI-induced myocarditis. This cross-sectional study used disproportionality analysis and a pharmacovigilance database to assess the risk of myocarditis with various diuretics in patients receiving ICIs via the analysis of data entered into the VigiBase database through December 2022. Multiple logistic regression analysis was performed to identify risk factors for myocarditis in patients who received ICIs. A total of 90 611 patients who received ICIs, including 975 cases of myocarditis, were included as the eligible dataset. A disproportionality in myocarditis was observed for loop diuretic use (reporting odds ratio 1.47, 95% confidence interval [CI] 1.02-2.04, P = .03) and thiazide use (reporting odds ratio 1.76, 95% CI 1.20-2.50, P < .01) in patients who received ICIs. The results of the multiple logistic regression analysis showed that the use of thiazides (odds ratio 1.67, 95% CI 1.15-2.34, P < .01) was associated with an increased risk of myocarditis in patients who received ICIs. Our findings may help to predict the risk of myocarditis in patients receiving ICIs.

Quality indicators for palliative care in intensive care units: a systematic review.

BACKGROUND: Establishing appropriate quality assessment indicators for palliative care in intensive care units (ICUs) is vital. This systematic review summarizes the existing quality indicators (QIs) for palliative care in ICUs. It assesses the methodological quality of QI development to pave the way for more valid QIs. METHODS: A literature search was conducted using MEDLINE, PsycINFO, CINAHL, Cochrane databases, and the Ichushi-web database for Japanese literature for all studies published until November 2021. The included QIs were drawn from the National Consensus Project for Quality Palliative Care (NCP) and the Donabedian model of quality. Methodological quality was assessed based on the appraisal of indicators through the research and evaluation tool. RESULTS: Five studies were included, from which 109 indicators were extracted: 78% were process indicators, 5% were outcome indicators, and 17% were structure indicators. The most common indicators addressed the palliative care domain of "ethical and legal aspects of care" (n=38, 30%). Another distinctive feature of some indicators was a focus on supporting ICU staff. Regarding methodological quality, the "scientific evidence" varied (11-89%). Most of the data on QI measures and data sources were obtained from a review of electronic medical records (EMRs). Administrative data also provided a few measurable indicators. CONCLUSIONS: Out of all the QIs covered in this review, most were process indicators, and only a few were outcome indicators. Ethical and legal aspects of care and support for the ICU staff emerged as unique to palliative care. Although the existing QIs can be used for palliative care in ICUs, more specific indicators are urgently needed. Continuous quality assessment and improvement, as well as the addition of more palliative care practices in ICUs, would provide further evidence and help develop valid QIs.

Content-based image retrieval for the diagnosis of myocardial perfusion imaging using a deep convolutional autoencoder.

BACKGROUND: Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) plays a crucial role in the optimal treatment strategy for patients with coronary heart disease. We tested the feasibility of feature extraction from MPI using a deep convolutional autoencoder (CAE) model. METHODS: Eight hundred and forty-three pairs of stress and rest myocardial perfusion images were collected from consecutive patients who underwent cardiac scintigraphy in our hospital between December 2019 and February 2022. We trained a CAE model to reproduce the input paired image data, so as the encoder to output a 256-dimensional feature vector. The extracted feature vectors were further dimensionally reduced via principal component analysis (PCA) for data visualization. Content-based image retrieval (CBIR) was performed based on the cosine similarity of the feature vectors between the query and reference images. The agreement of the radiologist's finding between the query and retrieved MPI was evaluated using binary accuracy, precision, recall, and F1-score. RESULTS: A three-dimensional scatter plot with PCA revealed that feature vectors retained clinical information such as percent summed difference score, presence of ischemia, and the location of scar reported by radiologists. When CBIR was used as a similarity-based diagnostic tool, the binary accuracy was 81.0%. CONCLUSION: The results indicated the utility of unsupervised feature learning for CBIR in MPI.

Photoredox-based late-stage functionalization in SAR study for in vivo potent glucosylceramide synthase inhibitor.

Glucosylceramide synthase (GCS) has drawn much attention as an attractive protein target in the disease pathways of Parkinson's Disease (PD) and lysosomal storage disorders, such as Gaucher's Disease (GD). In previous our study, T-036 and its analogue, 2a, were discovered as novel GCS inhibitors. To further improve activity of this chemical series, SAR was investigated on the fused pyridyl ring core of 2a by employing a photoredox reaction that significantly reduced synthetic demand. Herein, we successfully applied the decarboxylation C-H alkylation photoredox reaction to introduce a wide variety of substituents at the 6-position of the fused pyridine core scaffold. This quick SAR acquisition facilitated the swift identification of the potent GCS inhibitors 2b (IC50 = 5.9 nM) and 2g (IC50 = 3.6 nM). Moreover, 2b exhibited superior in vivo potency to that of our previously reported lead compound, T-036.

Bepridil monotherapy failed to prevent coronary vasospasm in a Brugada syndrome patient.

Coronary vasospasm sometimes coexists with Brugada syndrome (BrS) and is reportedly associated with poor prognosis. Although calcium channel blockers are considered first-line drugs to prevent coronary vasospasm, they also have the potential to induce ST elevation and ventricular fibrillation (VF) in BrS. Therefore, the optimal medication for such a complicated case is still underdetermined. We report a male patient who presented with VF due to BrS, which was later found to have coexisted with coronary vasospasm. He was treated with low-dose bepridil expecting both its anti-arrhythmic and vasodilatory effects, but a later acetylcholine provocation test showed no suppression of vasospasm. Based on these results, we decided to add nitrates to the medication. This case report illustrates that drug selection needs caution in BrS when complicated with vasospastic angina and that bepridil monotherapy may not be sufficient to suppress coronary vasospasm in such cases.

Current status of palliative care delivery and self-reported practice in ICUs in Japan: a nationwide cross-sectional survey of physician directors.

BACKGROUND: It is currently unknown how widespread is the practice of palliative care in intensive care units (ICUs) in Japan. This study aimed to determine evaluate the delivery and self-reported practice of palliative care in ICUs in Japan. METHODS: A self-administered questionnaire was sent to the physician directors of all 873 ICUs in Japan in August 2020. RESULTS: Of the 873 institutions, 439 responded the questionnaire (response rate: 50%) and 413 responses were included in the analysis. The responding physicians thought palliative care was appropriate for physical symptoms (36%, 95% Confidence Interval [CI] 32-41), the provision of information (32%, 95% CI: 28-37), psychological distress (25%, 95% CI: 21-29) and in Post Intensive Care Syndrome (PICS) prevention (20%, 95% CI: 17-24). Only 4% (95% CI: 2-6) of participants indicated that they always provided palliative care screening for the patients admitted to the ICU. The most common method to determine eligibility for palliative care was the "prediction of prognosis by clinician's experience" (54%, 95% CI: 50-59). Thirty-one percent (95% CI: 27-36) of participants responded that there was no clear method used to decide which patients need palliative care. Fifty-four percent of the participants answered they had no standardized protocols for symptom management at all. Less than 5% answered they had standardized protocols for end-of-life symptom management or terminal weaning off mechanical ventilation including extubation of endotracheal tubes. CONCLUSIONS: In Japan, the dissemination of palliative care and its integration into ICU care appears insufficient. To improve the quality of life of patients who are admitted to ICU, it may be useful to implement palliative care screening and multidisciplinary conferences, to develop standardized protocols for symptom management and withholding or withdrawing of life-sustaining treatment, and to educate primary palliative care for all ICU physicians.

Moderately Oxidizing Thioxanthylium Organophotoredox Catalysts for Radical-Cation Diels-Alder Reactions.

Moderately oxidizing thioxanthylium photoredox catalysts that operate under irradiation with green light have been developed. These catalysts exhibit relatively moderate excited-state reduction potentials [E1/2(C*/C•-) = 1.75-1.94 V vs saturated calomel electrode (SCE)] and can efficiently promote radical-cation Diels-Alder reactions under irradiation with green light. Interestingly, ß-halogenostyrenes (Ep/2 = 1.57-1.61 V vs SCE) are well tolerated, affording synthetically useful halocyclohexenes.

Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore.

Inhibition of glucosylceramide synthase (GCS) is a major therapeutic strategy for Gaucher's disease and has been suggested as a potential target for treating Parkinson's disease. Herein, we report the discovery of novel brain-penetrant GCS inhibitors. Assessment of the structure-activity relationship revealed a unique pharmacophore in this series. The lipophilic ortho-substituent of aromatic ring A and the appropriate directionality of aromatic ring B were key for potency. Optimization of the absorption, distribution, metabolism, elimination, toxicity (ADMETox) profile resulted in the discovery of T-036, a potent GCS inhibitor in vivo. Pharmacophore-based scaffold hopping was performed to mitigate safety concerns associated with T-036. The ring opening of T-036 resulted in another potent GCS inhibitor with a lower toxicological risk, T-690, which reduced glucosylceramide in a dose-dependent manner in the plasma and cortex of mice. Finally, we discuss the structural aspects of the compounds that impart a unique inhibition mode and lower the cardiovascular risk.

Development of the temperature-dependent interatomic potential for molecular dynamics simulation of metal irradiated with an ultrashort pulse laser.

Laser ablation is often explained by a two-temperature model (TTM) with different electron and lattice temperatures. To realize a classical molecular dynamics simulation of the TTM, we propose an extension of the embedded atom method to construct an interatomic potential that is dependent on the electron temperature. This method is applied to copper, and its validity is demonstrated by comparison of several physical properties, such as the energy-volume curve, phonon dispersion, electronic heat capacity, ablation threshold, and mean square displacement of atoms, with those of finite-temperature density functional theory.

Association between on-road driving performance test and usual walking speed or sustainable attention in the elderly; Preliminary survey.

OBJECTIVE: An increase in older drivers has been widely recognized in Japan; accordingly, screening to prevent traffic accidents is a crucial issue for safe driving. As a preliminary study, we examined the association between on-road driving performance and cognition or physical performance in older individuals. METHODS: The survey was conducted in 2020, and the participants were recruited in Katagami City, Akita, Japan. The Road Test was used to assess on-road driving performance. The physical assessment comprised the usual walking speed (UWS) and grip strength (GS), and the cognitive evaluation consisted of the National Center for Geriatrics and Gerontology Functional Assessment Tool (NCGG-FAT) and the Japanese version of Stroke Drivers' Screening Assessment (J-SDSA). A multiple regression model was also applied to examine the association between on-road driving performance and the physical items or cognitive domains of the NCGG-FAT and the J-SDSA in older individuals. RESULTS: Twenty-one participants (mean age ± standard deviation [SD], 77.0 ± 5.5 years) were included in this study. A correlation analysis showed that the on-road test score was correlated with performances on the UWS (r = 0.53, p = .002), the word list memory (WM) test (r = 0.44, p = .046), the trail-making test-A (TMT-A) (r = -0.44, p = .048), the SDSA dot cancelation (DC) test (r = -0.63, p = .002), and the SDSA squares matrix compass test (SM) (r = 0.54, p = .048). According to a stepwise linear regression, the on-road test score was associated with the UWS (ß = -0.01, p = .003) and the SDSA DC (ß = 4.89, p = .01), with an adjusted R2 = 0.54. CONCLUSIONS: The results of the study suggested that the UWS and sustainable attention might be potential factors influencing on-road driving performance. Our preliminary findings warrant further investigation.

Attitudes of Physicians toward Palliative Care in Intensive Care Units: A Nationwide Cross-Sectional Survey in Japan.

CONTEXT: Palliative care is an essential component of comprehensive care for patients with critical illnesses. In Japan, little is known about palliative care in intensive care units (ICUs), and palliative care approaches are not widespread. OBJECTIVE: This study aimed to better understand the attitudes of physicians toward palliative care and the utilization and needs of specialized palliative care consultations in ICUs in Japan. METHODS: A nationwide, self-administered questionnaire was distributed ICU physician directors in all hospitals with ICUs. RESULTS: Questionnaires were distributed to 873 ICU physician directors; valid responses were received from 436 ICU physician director (50% response rate). Among the respondents, 94% (n = 411) felt that primary palliative care should be strengthened in ICUs; 89% (n = 386) wanted ICU physicians to collaborate with specialists, such as palliative care teams (PCTs); and 71% (n = 311) indicated the need for specialized palliative care consultations; however, only 38% (n = 166) actually consulted, and only 6% (n = 28) consulted more than 10 patients in the past year. Physicians most commonly consulted PCT for patients with serious end-of-life illness (24%) (n = 107), intractable pain (21%) (n = 92), and providing psychological support to family members (43%, n = 187). The potential barriers in providing primary and specialized palliative care included being unable to understand the patients' intentions (54%, n = 235), lack of knowledge and skills in palliative care (53%, n = 230), and inability to consult with PCTs in a timely manner (46%, n = 201). CONCLUSIONS: These data suggest a need for primary palliative care education in ICUs and improved access to specialized palliative care consultations.

Cumulative Adverse Event Reporting of Anaphylaxis After mRNA COVID-19 Vaccine (Pfizer-BioNTech) Injections in Japan: The First-Month Report.

INTRODUCTION: In mid-February, the nationwide immunization plan for the prevention of coronavirus disease 2019 (COVID-19) started in Japan (at first primarily focused on health professionals) using an mRNA-based vaccine (Pfizer/BioNTech). During the phase-in period from February to March, attention was focused on post-vaccination anaphylaxis and anaphylactoid symptoms from the viewpoint of ensuring the safety of the vaccination program. OBJECTIVE: The aim of this report was to provide an update on the status of anaphylaxis and anaphylactoid symptoms occurring after vaccination for COVID-19, as reported under the Adverse Event Following Immunization (AEFI) reporting system in Japan. METHODS: The Pharmaceutical and Medical Devices Agency (PMDA) received AEFI reports from health professionals and manufacturers under the reporting system for AEFI after vaccination for COVID-19, which has been in operation since mid-February 2021. Reported AEFIs of anaphylaxis and anaphylactoid symptoms were assessed using the Brighton Collaboration Criteria to assess diagnostic certainty. RESULTS: 1-month since Japan started the vaccination program for COVID-19 in February 2021, 578,835 doses have been administered to health professionals, with the PMDA receiving 181 suspected event reports of anaphylaxis and anaphylactoid symptoms. In 171 of these 181 cases, women developed these symptoms. Among 181 cases evaluated according to the Brighton Collaboration Criteria, 47 cases (26%) were classified as level 1-3 (reporting rate: 8.1/100,000 doses). CONCLUSION: The results appear similar to reported AEFIs in foreign studies of coronavirus vaccine administration to health professionals, although the reporting rate was higher. Further work is needed to examine the causal relationship of anaphylaxis reactions to coronavirus vaccine administration. Issues of multiple reporting and possible sex/age bias also remain to be analyzed.

A new brain-penetrant glucosylceramide synthase inhibitor as potential Therapeutics for Gaucher disease.

Gaucher disease (GD), the most common lysosomal storage disorders, is caused by GBA gene mutations resulting in glycosphingolipids accumulations in various tissues, such as the brain. While suppressing glycosphingolipid accumulation is the central strategy for treating peripheral symptoms of GD, there is no effective treatment for the central nervous system symptoms. As glycosphingolipid biosynthesis starts from ceramide glycosylation by glucosylceramide synthase (GCS), inhibiting GCS in the brain is a promising strategy for neurological GD. Herein, we discovered T-036, a potent and brain-penetrant GCS inhibitor with a unique chemical structure and binding property. T-036 does not harbor an aliphatic amine moiety and has a noncompetitive inhibition mode to the substrates, unlike other known inhibitors. T-036 exhibited sufficient exposure and a significant reduction of glucosylsphingolipids in the plasma and brain of the GD mouse model. Therefore, T-036 could be a promising lead molecule for treating central nervous system symptoms of GD.