Search

Competing Interests: Funding Support and Author Disclosures The Section of Arrhythmia is supported by an endowment from Abbott Japan, Boston Scientific Japan, and Medtronic Japan. Dr Hirata chairs the section, and Drs Fukuzawa and Imamura belong to the section. Dr Fukuzawa has received a scholarship donation from Biotronik Japan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Using numerical indices and visual evaluation, we evaluated the dependence of coronary-artery depictability on the denoising parameter in compressed sensing magnetic resonance angiography (CS-MRA). This study was conducted to clarify the acceleration factor (AF) and denoising factor (DF) dependence of CS-MRA image quality. Vascular phantoms and clinical images were acquired using three-dimensional CS-MRA on a clinical 1.5 T system. For the phantom measurements, we compared the full width at half maximum (FWHM), sharpness, and contrast ratio of the vascular profile curves for various AFs and DFs. In the clinical cases, the FWHM, sharpness, contrast ratio, signal-to-noise ratio, noise level values, and visual evaluation results were compared for various DFs. Phantom image analyses demonstrated that the respective measurements of the FWHM, sharpness, and contrast ratios did not significantly change with an increase in AF. The FWHM and sharpness measurements slightly changed with the DF level. However, the contrast ratio tended to increase with an increase in the DF level. In the clinical cases, the FWHM and sharpness showed no significant differences, even when the DF level was changed. However, the contrast ratio tended to decrease as the DF level increased. When the DF levels of the clinical cases increased, the background signals of the myocardium, fat, and noise levels decreased. We investigated the dependence of the coronary-artery depictability on AF and DF using CS-MRA. Analysis of the coronary-artery profile curves indicated that a better image quality was achieved with a stronger DF on coronary CS-MRA., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Our previous findings indicated that many respiratory syncytial virus (RSV) isolates are unstable at 4 °C compared to 20 °C. Some of the strains completely lose infectivity after 24 h at 4 °C. This study analyzed the inactivation process at 4 °C using a representative strain, RSV/Sendai/851/13. After 24 h of storage at 4 °C, the virus was completely inactivated but retained its ability to attach to and to be taken into host cells. It suggested a reduced fusion ability between the viral and cellular membranes. During storage at 4 °C, the RSV fusion (F) protein underwent a conformational change and was no longer recognized by pre-fusion form-specific antibodies. When the RSV/Sendai/851/13 strain was passaged at 4 °C, a variant with an amino acid substitution, I148T, in the F protein fusion peptide was selected. Also, an amino acid change in G protein demonstrating stability at low temperatures was obtained. These results show that the inactivation of RSV at 4 °C is due to the loss of membrane fusion activity in the F protein, which cannot maintain its pre-fusion state at 4 °C., (© 2024. The Author(s).)

A novel in silico drug design procedure is described targeting the Main protease (Mpro) of the SARS-CoV-2 virus. The procedure combines molecular docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations. The binding structure and properties of Mpro were predicted for Nelfinavir (NFV), which had been identified as a candidate compound through drug repositioning, targeting Mpro. Several poses of the Mpro and NFV complexes were generated by docking, from which four docking poses were selected by scoring with FMO energy. Then, each pose was subjected to MD simulation, 100 snapshot structures were sampled from each of the generated MD trajectories, and the structures were evaluated by FMO calculations to rank the pose based on binding energy. Several residues were found to be important in ligand recognition, including Glu47, Asp48, Glu166, Asp187, and Gln189, all of which interacted strongly with NFV. Asn142 is presumably regarded to form hydrogen bonds or CH/π interaction with NFV; however, in the present calculation, their interactions were transient. Moreover, the tert -butyl group of NFV had no interaction with Mpro. Identifying such strong and weak interactions provides candidates for maintaining and substituting ligand functional groups and important suggestions for drug discovery using drug repositioning. Besides the interaction between NFV and the amino acid residues of Mpro, the desolvation effect of the binding pocket also affected the ranking order. A similar procedure of drug design was applied to Lopinavir, and the calculated interaction energy and experimental inhibitory activity value trends were consistent. Our approach provides a new guideline for structure-based drug design starting from a candidate compound whose complex crystal structure has not been obtained.

The formulation of active pharmaceutical ingredients involves discovering stable crystal packing arrangements or polymorphs, each of which has distinct pharmaceutically relevant properties. Traditional experimental screening techniques utilizing various conditions are commonly supplemented with in silico crystal structure prediction (CSP) to inform the crystallization process and mitigate risk. Predictions are often based on advanced classical force fields or quantum mechanical calculations that model the crystal potential energy landscape but do not fully incorporate temperature, pressure, or solution conditions during the search procedure. This study proposes an innovative alchemical path that utilizes an advanced polarizable atomic multipole force field to predict crystal structures based on direct sampling of the NPT ensemble. The use of alchemical (i.e., nonphysical) intermediates, a novel Monte Carlo barostat, and an orthogonal space tempering bias combine to enhance the sampling efficiency of the deposition/sublimation phase transition. The proposed algorithm was applied to 2-((4-(2-(3,4-dichlorophenyl)ethyl)phenyl)amino)benzoic acid (Cambridge Crystallography Database Centre ID: XAFPAY) as a case study to showcase the algorithm. Each experimentally determined polymorph with one molecule in the asymmetric unit was successfully reproduced via approximately 1000 short 1 ns simulations per space group where each simulation was initiated from random rigid body coordinates and unit cell parameters. Utilizing two threads of a recent Intel CPU (a Xeon Gold 6330 CPU at 2.00 GHz), 1 ns of sampling using the polarizable AMOEBA force field can be acquired in 4 h (equating to more than 300 ns/day using all 112 threads/56 cores of a dual CPU node) within the Force Field X software (https://ffx.biochem.uiowa.edu). These results demonstrate a step forward in the rigorous use of the NPT ensemble during the CSP search process and open the door to future algorithms that incorporate solution conditions using continuum solvation methods., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Purpose: Magnetic resonance elastography (MRE) is used to measure liver stiffness with gradient-recalled echo (GRE)-based and spin-echo echo planar imaging (SE-EPI)-based sequences. We compared the liver stiffness (LS) values of the two sequences on a 1.5-T MR imaging scanner., Methods: This is a retrospective study. An MRE imaging section was obtained from a horizontal section of the liver. Region of interest was drawn on the elastogram, and the mean LS and pixel values were measured and compared. The correlations between proton density fat fraction, R2* values, and biochemical data from electronic medical records were confirmed, and multivariate analysis was performed., Results: The mean LS values were 3.01 ± 1.78 kPa for GRE and 3.13 ± 1.57 kPa for SE-EPI, showing excellent agreement and a strong correlation between the two sequences (correlation coefficient r = 0.96). The mean pixel values were 369.5 ± 142.7 pixels for GRE and 490.1 ± 197.9 pixels for SE-EPI, showing a significant difference by the Wilcoxon rank sum test (p < 0.01). There were no LS unmeasurable cases in SE-EPI, but seven (2.5%) were unmeasurable in GRE, and multivariate analysis showed a significant difference with p < 0.001 in R2* values (mean, 92.7 Hz) for the GRE method., Conclusion: The GRE and SE-EPI methods were comparable for LS measurements in 1.5-T liver MRE, indicating that SE-EPI MRE is more useful because GRE MRE may not measure cases with high R2* values and the region of interest tends to be smaller., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this study, we synthesized a family of novel ionic liquids (ILs) with meglumine (MGM) as cations and tartaric acid (TA), azelaic acid (AA), geranic acid (GA), and capric acid (CPA) as anions, using pharmaceutical additives via simple acid-base neutralization reactions. The successful synthesis was validated by attenuated total reflection-Fourier transform infrared (ATR-FTIR) and powder X-ray diffraction (PXRD). Thermal analysis using differential scanning calorimetry confirmed the glass transition temperature of MGM-ILs to be within the range of -43.4 °C--13.8 °C. We investigated the solubilization of 15 drugs with varying pKa and partition coefficient (log P) values using these ILs and performed a comparative analysis. Furthermore, we present MGM-IL as a new skin permeation enhancer for the drug model flurbiprofen (FRP). We confirmed that AA/MGM-IL improves the skin permeation of FRP through hairless mouse skin. Moreover, AA/MGM-IL enhanced drug skin permeability by affecting keratin rather than stratum corneum lipids, as confirmed by ATR-FTIR. To conclude, MGM-ILs exhibited potential as drug solubilizer and skin permeation enhancers of drugs.

Hypothesis: A hydrated 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer brush exhibits exceptional lubricity. This lubrication mechanism has traditionally been attributed to either the inherent fluidity of the brush or the water film that forms owing to its hydrophilic nature. Given previous findings that the frictional properties of the MPC polymer brush film show load dependence, we hypothesize that the lubrication mechanism can be elucidated by examining the shear gap (varies owing to the load) dependence of the brush's viscoelastic response., Experiments: MPC polymer brush films with different thicknesses were prepared. Their viscoelastic responses were evaluated across different shear gap widths, and the frictional properties were subsequently compared across states with distinct viscoelastic behaviors., Findings: The observed shear viscoelasticity demonstrated a clear gap dependence that correlated with frictional attributes. Our data suggests that the lubrication mechanism shifts based on the shear gap. Specifically, two states exhibited low coefficients of friction: one where the osmotic pressure supports the load while allowing flexible deformation of the brush film, and the other where the brush film undergoes compression and transitions to a fully elastic state., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Shintaro Itoh reports financial support was provided by Japan Science and Technology Agency. Shintaro Itoh reports financial support was provided by Japan Society for the Promotion of Science. Shintaro Itoh reports financial support was provided by CCI Corporation research foundation. Fengchang Lin reports financial support was provided by JST SPRING. Shintaro Itoh reports equipment, drugs, or supplies was provided by J-Parc Center.]., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures The Section of Arrhythmia (Kobe University Graduate School of Medicine) is supported by an endowment from Abbott Japan, Boston Scientific Japan, and Medtronic Japan. Dr Fukuzawa belongs to the Section and has received a scholarship donation from Biotronik Japan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Competing Interests: Funding Support and Author Disclosures This work was made possible by support from National Institutes of Health grant OT2OD023848 to Dr Shivkumar. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Interest in small molecules that target RNA is flourishing, and the expectation set on them to treat diseases with unmet medical needs is high. However, several challenges remain, including difficulties in selecting suitable tools and establishing workflows for their discovery. In this context, we optimized experimental and computational approaches that were previously employed for the protein targets. Here, we demonstrate that a fluorescence-based assay can be effectively used to screen small molecule libraries for their ability to bind and stabilize an RNA stem-loop. Our screen identified several fluoroquinolones that bind to the target stem-loop. We further probed their interactions with the target using biolayer interferometry, isothermal titration calorimetry (ITC), and nuclear magnetic resonance spectroscopy. The results of these biophysical assays suggest that the fluoroquinolones bind the target in a similar manner. Armed with this knowledge, we built models for the complexes of the fluoroquinolones and the RNA target. Then, we performed fragment molecular orbital (FMO) calculations to dissect the interactions between the fluoroquinolones and the RNA. We found that the binding free energies obtained from the ITC experiments correlated strongly with the interaction energies calculated by FMO. Finally, we designed fluoroquinolone analogues and performed FMO calculations to predict their binding free energies. Taken together, the results of this study support the importance of conducting orthogonal assays in binding confirmation and compound selection and demonstrate the usefulness of FMO calculations in the rational design of RNA-targeted small molecules.

Background: Six-month adjuvant chemotherapy with S-1 is standard care for resected pancreatic cancer in Japan; however, the optimal duration has not been established. We aimed to evaluate the impact of duration of adjuvant chemotherapy with S-1., Methods: We performed a multicenter, randomized, open-label, phase II study. Patients with histologically proven invasive pancreatic ductal carcinoma, pathological stage I-III, and no local residual or microscopic residual tumor were eligible. Patients were randomized 1:1 to receive 6- or 12-month adjuvant chemotherapy with S-1. The primary endpoint was 2-year overall survival (OS). Secondary endpoints were disease-free survival (DFS) and feasibility., Results: A total of 170 patients were randomized (85 per group); the full analysis set was 82 in both groups. Completion rates were 64.7% (6-month group) and 44.0% (12-month group). Two-year OS was 71.5% (6-month group) and 65.4% (12-month group) (hazard ratio (HR): 1.143; 80% confidence interval CI 0.841-1.553; P  =  0.5758). Two-year DFS was 46.4% (6-month group) and 44.9% (12-month group) (HR: 1.069; 95% CI 0.727-1.572; P = 0.6448). In patients who completed the regimen, 2-year DFS was 56.5% (6-month group) and 75.0% (12-month group) (HR: 0.586; 95% CI 0.310-1.105; P  = 0.0944). Frequent (≥ 5%) grade ≥ 3 adverse events comprised anorexia (10.5% in the 6-month group) and diarrhea (5.3% vs. 5.1%; 6- vs. 12-month group, respectively)., Conclusions: In patients with resected pancreatic cancer, 12-month adjuvant chemotherapy with S-1 was not superior to 6-month therapy regarding OS and DFS., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: There is a strong demand for remote monitoring systems to gather health data. This study investigated the safety, usefulness, and patient satisfaction in outpatient care using telehealth with real-time electrocardiogram (ECG) monitoring after catheter ablation. Methods and Results: In all, 38 patients who underwent catheter ablation were followed up using telehealth. At the 3- and 6-month follow-up, a self-fitted Duranta ECG monitoring device was sent to the patient's home before the online consultation. Patients attached the devices themselves, and the doctors viewed the patients by video chat and performed real-time ECG monitoring. The frequency of hospital visits and the ECG monitoring duration were compared with conventional in-person follow-up data (n=102). The completion rate for telehealth follow-up was 32 of 38 patients (84%). The number of hospital visits during the 6 months was significantly lower with telehealth follow-up than with conventional follow-up (median [interquartile range] 1 [1-1] vs. 5 [3-5]; P<0.0001). However, the ECG monitoring duration was approximately 4-fold longer for the telehealth follow-up (median [interquartile range] 89 [64-117] vs. 24 [0.1-24] h; P<0.0001). No major adverse events were observed during the telehealth follow-up. Patient surveys showed high satisfaction with telehealth follow-up due to reduced hospital visits. Conclusions: A combination of telehealth follow-up with real-time ECG monitoring increased the ECG monitoring duration and patient satisfaction without any adverse events., Competing Interests: The Section of Arrhythmia is supported by endowments from Abbott JAPAN, Medtronic JAPAN, and Boston Scientific JAPAN. The Section of Arrhythmia has received a scholarship fund from Biotronik JAPAN. K.H. chairs the Section, and K.F. and K.I. belong to the Section. However, none of the authors declare any conflicts of interest regarding this manuscript’s contents., (Copyright © 2023, THE JAPANESE CIRCULATION SOCIETY.)

Competing Interests: Funding Support and Author Disclosures The Section of Arrhythmia is supported by an endowment from Abbott Japan, Boston Scientific Japan, and Medtronic Japan. Dr Hirata chairs the Section, and Drs Fukuzawa and Takami belong to the Section. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Over 4 billion years of evolution, multiple mutations, including nucleotide substitutions, gene and genome duplications and recombination, have established de novo genes that translate into proteins with novel properties essential for high-order cellular functions. However, molecular processes through which a protein evolutionarily acquires a novel function are mostly speculative. Recently, we have provided evidence for a potential evolutionary mechanism underlying how, in mammalian cells, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) evolved into a GTP sensor from ATP-utilizing kinase. Mechanistically, PI5P4Kβ has acquired the guanine efficient association (GEA) motif by mutating its nucleotide base recognition sequence, enabling the evolutionary transition from an ATP-dependent kinase to a distinct GTP/ATP dual kinase with its K M for GTP falling into physiological GTP concentrations-the genesis of GTP sensing activity. Importantly, the GTP sensing activity of PI5P4Kβ is critical for the manifestation of cellular metabolism and tumourigenic activity in the multicellular organism. The combination of structural, biochemical and biophysical analyses used in our study provides a novel framework for analysing how a protein can evolutionarily acquire a novel activity, which potentially introduces a critical function to the cell., (© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Although the ergogenic effects of 3-6 mg/kg caffeine are widely accepted, the efficacy of low doses of caffeine has been discussed. However, it is unclear whether the ergogenic effects of caffeine on jump performance are dose responsive in a wide range of doses. This study aimed to examine the effect of very low (1 mg/kg) to moderate doses of caffeine, including commonly utilized ergogenic doses (i.e., 3 and 6 mg/kg), on vertical jump performance. A total of 32 well-trained collegiate sprinters and jumpers performed countermovement jumps and squat jumps three times each in a double-blind, counterbalanced, randomized, crossover design. Participants ingested a placebo or 1, 3, or 6 mg/kg caffeine 60 min before jumping. Compared with the placebo, 6 mg/kg caffeine significantly enhanced countermovement jump (p < .001) and squat jump (p = .012) heights; furthermore, 1 and 3 mg/kg of caffeine also significantly increased countermovement jump height (1 mg/kg: p = .002, 3 mg/kg: p < .001) but not squat jump height (1 mg/kg: p = .436, 3 mg/kg: p = .054). There were no significant differences among all caffeine doses in both jumps (all p > .05). In conclusion, even at a dose as low as 1 mg/kg, caffeine improved vertical jump performance in a dose-independent manner. This study provides new insight into the applicability and feasibility of 1 mg/kg caffeine as a safe and effective ergogenic strategy for jump performance.

A third-generation inhibitor of catechol O -methyltransferase (COMT), opicapone ( 1 ), has the 3-nitrocatechol scaffold as do the second-generation inhibitors such as entacapone ( 2 ) and tolcapone ( 3 ), but only 1 can sustainably inhibit COMT activity making it suitable for a once-daily regimen. These improvements should be attributed to the optimized sidechain moiety (oxidopyridyloxadiazolyl group) of 1 substituted at the 5-position of the 3-nitrocatechol ring. We analyzed the role of the sidechain moiety by solving the crystal structures of COMT/ S -adenosylmethionine (SAM)/Mg/ 1 and COMT/ S -adenosylhomocysteine (SAH)/Mg/ 1 complexes. Fragment molecular orbital (FMO) calculations elucidated that the dispersion interaction between the sidechains of Leu 198 and Met 201 on the β6β7-loop and the oxidopyridine ring of 1 were unique and important in both complexes. In contrast, the catechol binding site made a remarkable difference in the sidechain conformation of Lys 144. The ε-amino group of Lys 144 was outside of the catalytic pocket and was replaced by a water molecule in the COMT/SAH/Mg/ 1 complex. No nitrocatechol inhibitor has ever been reported to make a complex with COMT and SAH. Thus, the conformational change of Lys 144 found in the COMT/SAH/Mg/ 1 complex is the first crystallographic evidence that supports the role of Lys 144 as a catalytic base to take out a proton ion from the reaction site to the outside of the enzyme. The fact that 1 generated a complex with SAH and COMT also suggests that 1 could inhibit COMT twofold, as a typical substrate mimic competitive inhibitor and as a product-inhibition enhancer.

Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Section of Arrhythmia is supported by an endowment from Abbott JAPAN, Medtronic JAPAN, and Boston Scientific JAPAN. Ken-ichi Hirata chairs the Section, and Koji Fukuzawa and Mitsuru Takami belong to the Section. However, all authors report no conflict of interest for this manuscript's content.

Introduction: Intermuscular implantations of subcutaneous implantable cardioverter-defibrillators (S-ICD) have been recommended, but the position of the anterior border of the latissimus dorsi muscle (LDM) has not previously been evaluated in establishing an incision line to facilitate the intermuscular approach. The objective of this study is to evalua the position and trend of the anterior border of the LDM in patients who are candidates for implantable cardioverter-defibrillators., Methods: The distance from the back to the anterior border of the LDM (A) and the anterior-posterior width of the chest wall (B) were measured on computed tomography retrospectively, and the ratio (=A/B) was used as the position of the anterior border of the LDM. In addition, the variability and factors affecting the values were evaluated., Results: An analysis was performed on 78 patients, and the position of the anterior border of the LDM (=A/B) exhibited a normal distribution, with a mean value of 0.53 ± 0.062 (0.41-0.69). The position of the anterior border of the LDM tended to be more anterior in younger, taller, male, primary prevention, nonheart failure, low brain natriuretic peptide level, and nondiabetic patients., Conclusion: The position of the anterior border of the LDM varied from case to case with variable results. Conventional incisions on the midaxillary line may be inappropriate for intermuscular implantations, and the position of the anterior border of the LDM should be evaluated in each individual case to establish the incision line., (© 2023 Wiley Periodicals LLC.)

Background: Pancreatic metastases from other primary malignancies are rare. There is no clear evidence for a treatment strategy for this condition. The purpose of this study was to assess the clinical outcomes, including prognostic factors for pancreatic resection of metastatic tumors in the pancreas, through a retrospective review., Methods: Data of 35 patients who underwent pancreatic resection for pancreatic metastasis between 2005 and 2020 in eight Japanese institutions were included in this study. Survival analyses were performed using the Kaplan-Meier method, and comparisons were made using the Cox proportional hazards model., Results: The median follow-up period was 35 months (range, 5-102 months). Median duration from resection for primary tumor to resection for metastatic pancreatic tumor was 10.6 years (range, 0.6-29.2 years). The 3- and 5-year survival rates after resection for metastatic tumors in the pancreas were 89% and 69%, respectively. In contrast, the 3- and 5-year disease-free survival rates after resection for metastatic tumors in the pancreas were 48% and 21%, respectively. Performance status ≥1 at the time of resection for metastatic tumors in the pancreas (HR: 7.56, p = 0.036) and pancreatic metastasis tumor diameter >42 mm (HR: 6.39, p = 0.02) were significant poor prognostic factors only in the overall survival., Conclusions: The prognosis of pancreatic resection for metastatic tumors in the pancreas is relatively good for selected patients. However, because it is prone to recurrence after radical surgery, it should only be considered in patients with good PS., Competing Interests: Declaration of competing interest We have no COI., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A non-covalent oral drug targeting SARS-CoV-2 main protease (M pro ), ensitrelvir (Xocova), has been developed using structure-based drug design (SBDD). To elucidate the factors responsible for enhanced inhibitory activities from an in silico screening hit compound to ensitrelvir, we analyzed the interaction energies of the inhibitors with each residue of M pro using fragment molecular orbital (FMO) calculations. This analysis reveals that functional group conversion for P1' and P1 parts in the inhibitors increases the strength of existing interactions with M pro and also provides novel interactions for ensitrelvir; the associated changes in the conformation of M pro induce further interactions for ensitrelvir in other parts, including hydrogen bonds, a halogen bond, and π-orbital interactions. Thus, we illuminate the promising strategies of SBDD for leading ensitrelvir to get higher activity against M pro by elucidating microscopic interactions through FMO-based analysis. These detailed mechanism findings, including water cross-linkings, will help to design novel inhibitors in SBDD.

The aim of this study was to enhance the solubility and stability of the water-insoluble drug carvedilol (CAR) with maleic acid (MLE) to create a co-amorphous system by a solvent evaporation method. Phase diagrams of co-amorphous CAR-MLE, constructed from peak height in the Fourier-transform infrared (FTIR) spectra and the glass transition temperature ( T g) from differential scanning calorimetry (DSC) measurements, revealed that the optimal molar ratio of CAR to MLE was 2:1. The FTIR spectra indicated that the secondary amine-derived peak of CAR and the carboxy group-derived peak of MLE disappeared in the CAR:MLE (2:1) co-amorphous system. DSC measurements showed that the endothermic peaks associated with the melting of CAR and MLE disappeared and a T g at 43 °C was apparent. Furthermore, the solubility of CAR tested using the shaking flask method for 24 h at 37 °C was 1.2 μg/mL, whereas that of the co-amorphous system was approximately three times higher, at 3.5 μg/mL. Finally, the stability was evaluated by powder- X-ray diffraction at 40 °C; no clear diffraction peaks originating from crystals were observed in the amorphous state until after approximately three months of storage. These results indicate that co-amorphization of CAR with MLE improved the solubility of CAR while maintaining its stability in an amorphous form.

The left ventricular summit corresponds to the epicardial side of the basal superior free wall, extending from the base of the left coronary aortic sinus. The summit composes the floor of the compartment surrounded by the aortic root, infundibulum, pulmonary root, and left atrial appendage. The compartment is filled with thick adipose tissue, carrying the coronary vessels. Thus, the treatment of ventricular tachycardia originating from the summit is challenging, and three-dimensional understanding of this complicated region is fundamental. We revisit the clinical anatomy of the left ventricular summit with original images from the Wallace A. McAlpine collection., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Lesion gaps assessed by late-gadolinium enhancement magnetic resonance imaging (LGE-MRI) are associated with the atrial fibrillation (AF) recurrence after pulmonary vein isolation. Animal studies have demonstrated that the catheter-contact force (CF), stability, and orientation are strongly associated with lesion formation. However, the impact of those procedural factors on the lesion characteristics associated with AF recurrence has not been well discussed., Methods: A total of 30 patients with paroxysmal AF who underwent catheter ablation were retrospectively enrolled. Radiofrequency (RF) applications were performed with 35 W for 30 s in a point-by-point fashion under esophageal temperature monitoring. The inter-lesion distance was 4 mm. The lesions were visualized by LGE-MRI 3 months postprocedure and assessed by the LGE volume (ml), gap number (GN), and average gap length (AGL [mm]). The gaps were defined as nonenhancement sites of >4 mm. The procedural factors including the catheter-CF, stability, and orientation were calculated on the NavX system., Results: Six (20%) of 30 patients had AF recurrences 12 months postablation. A univariate analysis demonstrated that the AGL was associated with AF recurrence (hazard ratio [HR]: 1.20, confidence interval [CI]: 1.03-1.42, p = .02). All AF recurrence were found in patients with an AGL of >7 mm. The catheter-CF and stability were associated with an AGL of >7 mm, but not the orientation (CF-HR: 0.62, CI: 0.39-0.97, p = .038; stability-HR: 0.8, CI: 0.66-0.98, p = .027)., Conclusions: RF ablation with a low CF and poor catheter stability has a potential risk of creating large lesion gaps associated with AF recurrence., (© 2023 Wiley Periodicals LLC.)

Coarse-graining, which models molecules with coarse-grained (CG) beads, allows molecular dynamics simulations to be applied to systems with large length and time scales while preserving the essential molecular structure. However, CG models generally have insufficient representability and transferability. A commonly used method to resolve this problem is multi-state iterative Boltzmann inversion (MS-IBI) with pressure correction, which matches both the structural properties and pressures at different thermodynamic states between CG and all-atom (AA) simulations. Nevertheless, this method is usually effective only in a narrow pressure range. In this paper, we propose a modified CG scheme to overcome this limitation. We find that the fundamental reason for this limitation is that CG beads at close distances are ellipsoids rather than isotropically compressed spheres, as described in conventional CG models. Hence, we propose a method to compensate for such differences by slightly modifying the radial distribution functions (RDFs) derived from AA simulations and using the modified RDFs as references for pressure-corrected MS-IBI. We also propose a method to determine the initial non-bonded potential using both the target RDF and pressure. Using n -dodecane as a case study, we demonstrate that the CG model developed using our scheme reproduces the RDFs and pressures over a wide range of pressure states, including three reference low-pressure states and two test high-pressure states. The proposed scheme allows for accurate CG simulations of systems in which pressure or density varies with time and/or position.

Amorphous drug formulations exploiting drug-drug interactions have been extensively studied. This study aims to develop a transdermal system containing an amorphous complex of the nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen (FLU) and lidocaine (LDC) for alleviating chronic pain. The high-viscosity complex between FLU and LDC (Complex) was obtained by heating in ethanol. For the complex, attenuated total reflection-Fourier transform infrared spectroscopy showed a shift in the carboxy-group-derived peak of FLU, and differential scanning calorimetry indicated the endothermic peaks associated with the melting of FLU and LDC disappeared. 13 C dipolar decoupling and 15 N cross-polarization magic-angle spinning nuclear magnetic resonance measurement suggested the interaction between the carboxyl group of FLU and the secondary amine of LDC. The interaction between the aromatic rings of FLU and LDC contributed to the molecular complex formation. The solubility of FLU from the complex was about 100 times greater than FLU alone. The skin permeation flux of FLU from the complex through the hairless mouse skin was 3.8 times higher than FLU alone in hypromellose gel. Thus, adding LDC to the formulation can be an effective method for enhancing the skin permeation of NSAIDs, which can prove useful for treating chronic pain and inflammatory diseases.

Famotidine (FMT) is a competitive histamine-2 (H2) receptor antagonist that inhibits gastric acid secretion for the treatment of Gastroesophageal reflux disease. To study the promoting effect and mechanism of terpenes, including l-menthol, borneol, and geraniol, as chemical enhancers, FMT was used as a model drug. Attenuated total reflectance-Fourier transform IR spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC) were used to explore the effects of terpenes on the skin. Hairless mouse skin was mounted on Franz-type diffusion cell, and skin permeation experiment of FMT hydrogel was carried out. The results suggested that the thermodynamic activity influenced the permeability of the drug, and the main mechanism of terpenes to enhance skin permeation of the drug was based on increasing the fluidity of the intercellular lipids. Moreover, it was revealed that l-menthol simultaneously relaxed the packing structure and lamellar structure, whereas geraniol had a great influence on the lamellar structure only. Collectively, all terpenes had a promoting effect on skin permeation of FMT, indicating their potential as chemical enhancers to change the microstructure of stratum corneum and improve the permeation of FMT through the skin, and it has great potential to be used in transdermal formulations of FMT.

Background: The mechanism underlying the sex differences in atrial fibrillation (AF) recurrence following pulmonary vein (PV) isolation is not fully understood. We hypothesized that non-PV foci and epicardial adipose tissue (EAT) play a key role., Methods and results: Data from 304 consecutive patients (75% males) who underwent contrast-enhanced computed tomography and catheter ablation of AF were reviewed. The EAT around the atrium was measured separately in 4 parts of the atrium. All patients underwent high-dose isoproterenol infusions to assess the non-PV foci. Significantly more non-PV foci and less EAT around the atrium were observed in female patients than in male patients. In males, those with non-PV foci on the left atrial (LA) anterior wall had significantly greater EAT for the same lesions than those without non-PV foci. During a median follow-up of 27 months, the predictors of AF recurrence after first catheter ablation were female sex, presence of non-PV foci, LA diameter, and septal EAT index. A sex-specific analysis revealed that LA diameter was a predictor only in males and that the presence of non-PV foci in the septal region was a strong predictor in males (hazard ratio [HR]: 2.24) and females (HR: 3.65)., Conclusions: Sex-specific differences were observed in non-PV foci sites and local EAT and in regard to the predictors of AF recurrence.

Background: Ventricular tachycardia (VT) non-inducibility at the end of ablation is associated with a less likely VT recurrence. However, it is not clear whether we should use VT non-inducibility as a routine end point of VT ablation. The aim of this study was to evaluate VT recurrence in patients in whom VT non-inducibility was not achieved at the end of the radiofrequency (RF) ablation and the factors attributing to the VT recurrence., Methods: We analyzed that 62 patients in whom VT non-inducibility was not achieved at the end of the RF ablation were studied., Results: Over 2 years, 22 (35%) of the cases had VT recurrences. A multivariate analysis showed that an LVEF ≥35% (HR: 0.19; 95% CI: 0.06-0.49; p  < .01) and elimination of the clinical VT as an acute ablation efficacy (HR: 0.23; 95% CI: 0.04-0.81; p  = .02) were independent predictors of fewer VT recurrences. RF ablation was associated with a 91.1% reduction in VT episodes., Conclusion: Even if VT non-inducibility was not achieved, patients with an LVEF ≥35% or in whom the clinical VT could be eliminated might be prevented from having VT recurrences. The validity of the VT non-inducibility of any VT should be evaluated considering each patient's background and the results of the procedure., Competing Interests: The Section of Arrhythmia is supported by an endowment from Abbott JAPAN and Medtronic JAPAN and has received a scholarship fund from Biotronik JAPAN. Ken‐ichi Hirata chairs the Section, and Koji Fukuzawa and Kunihiko Kiuchi belong to the Section. However, all authors report no conflict of interest for this manuscript's contents., (© 2022 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Background: It is uncertain whether cardiac resynchronization therapy with a defibrillator (CRT-D) provides better survival benefits than a CRT-pacemaker (CRT-P) in heart failure patients with a reduced ejection fraction (≦35%, HFrEF) treated with contemporary HF therapy., Methods: We retrospectively analyzed the ventricular arrhythmia (VAs; sustained ventricular tachycardia/fibrillation) events in HFrEF patients who underwent CRT without a prior history of VAs or aborted sudden cardiac death before the CRT implantation. Between January/2010 and December/2020, a CRT device was implanted in 79 HFrEF patients (mean age: 69 ± 12 years, male: 57, ischemic cardiomyopathy: 16). CRT-D and CRT-P devices were implanted in 50 and 29 patients, respectively, at each physician's discretion. CRT-Ds were indicated in younger patients than were CRT-Ps (66 ± 12 vs. 73 ± 12 years, p  = 0.03), but the gender distribution did not differ (female, 24% [12 of 50] vs. 35% [10 of 29], p  = 0.44). The VA events during a median follow-up of 3.5-years (interquartile range [IQR]:1.6-5.5) and their predictors were analyzed., Results: VA events occurred in 9 patients with CRT-Ds (18%) and one with a CRT-P (3%, p  = 0.08). The VA event rate was significantly lower in patients without a prior non-sustained ventricular tachycardia (NSVT: ≥3 beats; rate, ≥120 bpm; lasting <30 s, HR 0.05; 95% CI 0.01-0.30; p  < 0.01) and females (HR 0.11; 95% CI 0.01-0.93; p  = 0.04). Of note, no female patients without a prior history of NSVT experienced VA events., Conclusion: HFrEF CRT candidates without a prior history of NSVT and females may obtain less benefit from a primary preventive defibrillator indication., Competing Interests: The Section of Arrhythmia is supported by an endowment from Abbott JAPAN, Medtronic JAPAN, and Boston Scientific JAPAN. Ken‐ichi Hirata chairs the Section, and Koji Fukuzawa and Mitsuru Takami belong to the Section. However, the authors have no competing interests to declare that are relevant to the content of this article., (© 2022 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

This study sought to assess the left atrial (LA) functional recovery after radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) and to evaluate the determining factor of procedural success of RFCA, using a novel preload stress echocardiography. A total of 111 patients with AF were prospectively recruited. The echocardiographic parameters were obtained during the leg-positive pressure (LPP) maneuver, both at baseline and midterm after RFCA. As an index of LA distensibility, the LA expansion index was calculated as (LAV max - LAV min ) × 100 / LAV min . During a median follow-up period of 14.2 months, AF recurrence was observed in 23 patients (20.7%). In LA functional parameters at baseline, only the Δ LA expansion index was significantly larger in the success group (16 ± 11% vs 4 ± 9%, p <0.05). At midterm follow-up, the Δ LA expansion index significantly increased to 32 ± 19% (p <0.05), together with structural LA reverse remodeling only in the success group. Moreover, the Δ stroke volume index during the LPP stress test significantly increased only in the success group (from 2.3 ± 1.3 ml/m 2 to 3.1 ± 4.8 ml/m 2 , p <0.05). In a multivariate analysis, left ventricular ejection fraction (hazard ratio 0.911, p <0.05) and baseline Δ LA expansion index (hazard ratio 0.827, p <0.001) were independent predictors of AF recurrence. In conclusion, the baseline Δ LA expansion index during LPP stress is a reliable marker for predicting procedural success after RFCA. Moreover, maintenance of sinus rhythm resulted in an improvement of the preload reserve after RFCA., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors, but are the most common mesenchymal tumors of the gastrointestinal tract. The risk classification of GISTs is based on the tumor size, mitotic index, tumor site, and presence of tumor rupture. Recurrence in the very-low-risk group is extremely rare. We herein report a case of liver metastases 2 years after resection of a very-low-risk duodenal GIST., Case Presentation: A 57-year-old woman presented to the hospital for evaluation of melena. Esophagogastroduodenoscopy showed bleeding from the exposed blood vessels at the top of a submucosal tumor approximately 20 mm in size located in the second (descending) part of the duodenum, and the bleeding was controlled with electrocoagulation. A GIST was suspected, and the patient underwent wedge resection of the duodenum. The resected specimen contained a 16- × 12-mm (< 20-mm) white submucosal tumor composed of spindle cells with a mitotic count of 4 per 50 high-power fields, and a histologically negative margin was achieved. Immunochemical analysis revealed positive tumor staining for c-kit protein and alpha-smooth muscle actin and negative staining for CD34, desmin, and S-100 protein. Therefore, the tumor was diagnosed as a very-low-risk duodenal GIST based on the Fletcher classification and modified Fletcher classification (Joensuu classification). The postoperative course was uneventful, and the patient was discharged on postoperative day 11. At the follow-up visit 2 years postoperatively, contrast-enhanced computed tomography revealed liver tumors in S8 and S6 measuring 26 × 24 and 10 × 10 mm, respectively. Both lesions showed peripheral dominant hyperenhancement with hypoenhancement inside, indicating tissue degeneration within the tumors. These imaging findings closely resembled those of the duodenal GIST. Hence, the patient was diagnosed with liver metastases of GIST 2 years postoperatively. She was subsequently started on treatment with 400 mg of imatinib. At the time of this writing (2 months after diagnosis), the patient was clinically well and asymptomatic and was continuing imatinib therapy., Conclusions: Recurrence of very-low-risk GISTs is extremely rare. Even a small GIST with low mitotic activity can never be considered completely benign, and long-term follow-up is necessary., (© 2022. The Author(s).)

Estrogen receptors (ERs) are ligand-activated transcription factors, with two subtypes ERα and ERβ. The endogenous ligand of ERs is the common 17β-estradiol, and the ligand-binding pocket of ERα and ERβ is very similar. Nevertheless, some ERβ-selective agonist ligands have been reported. DPN (diarylpropionitrile) is a widely used ERβ-selective agonist; however, the structure of the ERβ-DPN complex has not been solved. Therefore, the bound-state conformation of DPN and its enantioselectivity remain unresolved. In this report, we present the structures of the complexes of ERβ with DPN or its derivatives that include a chlorine atom by the X-ray crystallography. Additionally, we measured the binding affinity between ERβ and DPN or derivatives by isothermal titration calorimetry (ITC) and estimated the binding affinity by fragment molecular orbital (FMO) calculations. We also examined the correlation between the ITC data and results from the FMO calculations. FMO calculations showed that S-DPN interacts strongly with three amino acids (Glu305, Phe356, and His475) of ERβ, and ITC measurements confirmed that the chlorine atom of the DPN derivatives enhances binding affinity. The enthalpy change by ITC correlated strongly with the interaction energy (total IFIEs; inter-fragment interaction energies) calculated by FMO (R = 0.870). We propose that FMO calculations are a valuable approach for enhancing enthalpy contributions in drug design, and its scope of applications includes halogen atoms such as chlorine. This study is the first quantitative comparison of thermodynamic parameters obtained from ITC measurements and FMO calculations, providing new insights for future precise drug design., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Moisture-activated dry granulation (MADG) is an eco-friendly granulation method that uses a small amount of water and insoluble excipients to absorb moisture. MADG is expected to improve productivity and reduce costs. Erythritol, an excipient used for preparing orally disintegrating tablets (ODTs), has poor tabletability and is difficult to form into tablets by conventional methods, such as high-shear granulation (HSG) and direct compression. In this study, we optimized the manufacturing conditions for ODTs to improve the tabletability of erythritol using MADG. The disintegration time of tablets made using the MADG method was approximately one-tenth that of those made using the HSG method, and the hardness was approximately 1.4 times higher. Moreover, MADG could delay disintegration and improve tabletability. We further attempted to optimize the manufacturing conditions using MADG, particularly in terms of the amount of water used. The disintegration time increased as the amount of added water increased. Moreover, water absorption tests revealed that capillary wetting decreased as the amount of water added increased, but the initial wetting did not change. These results suggested that the disintegration time was prolonged because of the increase in granule density and decrease in capillary wetting with the increase in the amount of added water. The hardness of the tablets increased because of the easy deformation of the granules after the addition of up to 3% water; however, when more than 3% water was added, the hardness decreased because of the aggregation of the granules with the excess water. Finally, two-dimensional maps of the effect of the amount of added water and water activity indicated that tablets with a hardness of ≥80 N and a disintegration time of ≤15 s could be produced by adjusting the amount of added water to within the range of 2.2-3.3% and water activity to 0.3-0.53. These results indicate that MADG can improve the tabletability of erythritol and be used for the granulation of ODTs. Tablets with appropriate hardness and disintegration properties can be produced by adjusting the water content to approximately 2.7% and the water activity to approximately 0.4 when producing ODTs with MADG.

Introduction: The skin overlying cardiovascular implantable electronic devices (CIEDs) sometimes becomes very thin after implantations, which could cause a device erosion. The factors related to the skin thickness of device pockets have not been elucidated. This study aimed to evaluate the skin thickness of CIED pockets and search for the factors associated with the thickness., Methods: Seventeen skin thickness points around the CIED pocket were measured through ultrasonography in each patient., Results: A total of 101 patients (76 ± 11 years, 26 female) were enrolled. The median duration from the implantation to the examination was 95 months (quartile: 52.5-147.5). The median skin thickness overlying the device was 4.1 mm (3.3-5.9). Patients with heart failure and malignancy had thinner skin overlying the CIED than those without. A significant correlation existed between skin thickness and body mass index (BMI), hemoglobin, serum creatinine, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction. In contrast, age, gender, and device size did not exhibit a significant correlation with skin thickness. A multivariate logistic regression analysis revealed that chronic heart failure and a decrease in the eGFR and BMI were independent predictive factors of "very thin (≦3.3 mm)" skin of the CIED pocket late after an implantation., Conclusion: Aside from a low BMI, the comorbidities (low hemoglobin, heart failure, and renal dysfunction) had a stronger impact on the skin thickness overlying the device than the device size. A careful observation of the device pocket should be performed in patients with those risk factors., (© 2022 Wiley Periodicals LLC.)

Fragment molecular orbital (FMO) method is a powerful computational tool for structure-based drug design, in which protein-ligand interactions can be described by the inter-fragment interaction energy (IFIE) and its pair interaction energy decomposition analysis (PIEDA). Here, we introduced a dynamically averaged (DA) FMO-based approach in which molecular dynamics simulations were used to generate multiple protein-ligand complex structures for FMO calculations. To assess this approach, we examined the correlation between the experimental binding free energies and DA-IFIEs of six CDK2 inhibitors whose net charges are zero. The correlation between the experimental binding free energies and snapshot IFIEs for X-ray crystal structures was R 2  = 0.75. Using the DA-IFIEs, the correlation significantly improved to 0.99. When an additional CDK2 inhibitor with net charge of -1 was added, the DA FMO-based scheme with the dispersion energies still achieved R 2  = 0.99, whereas R 2 decreased to 0.32 employing all the energy terms of PIEDA., (© 2022 Wiley Periodicals LLC.)

Background: Several algorithms have been proposed for differentiating the right and left outflow tracts (RVOT/LVOT) arrhythmia origins from 12-lead electrocardiograms (ECGs); however, the procedure is complicated. A deep learning (DL) model, a form of artificial intelligence, can directly use ECGs and depict the importance of the leads and waveforms. This study aimed to create a visualized DL model that could classify arrhythmia origins more accurately., Methods and results: This study enrolled 80 patients who underwent catheter ablation. A convolutional neural network-based model that could classify arrhythmia origins with 12-lead ECGs and visualize the leads that contributed to the diagnosis using a gradient-weighted class activation mapping method was developed. The average prediction results of the origins by the DL model were 89.4% (88.2-90.6) for accuracy and 95.2% (94.3-96.2) for recall, which were significantly better than when a conventional algorithm is used. The ratio of the contribution to the prediction differed between RVOT and LVOT origins. Although leads V1 to V3 and the limb leads had a focused balance in the LVOT group, the contribution ratio of leads aVR, aVL, and aVF was higher in the RVOT group., Conclusions: This study diagnosed the arrhythmia origins more accurately than the conventional algorithm, and clarified which part of the 12-lead waveforms contributed to the diagnosis. The visualized DL model was convincing and may play a role in understanding the pathogenesis of arrhythmias.

Unlike most kinases, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) utilizes GTP as a physiological phosphate donor and regulates cell growth under stress (i.e., GTP-dependent stress resilience). However, the genesis and evolution of its GTP responsiveness remain unknown. Here, we reveal that PI5P4Kβ has acquired GTP preference by generating a short dual-nucleotide-recognizing motif called the guanine efficient association (GEA) motif. Comparison of nucleobase recognition with 660 kinases and 128 G proteins has uncovered that most kinases and PI5P4Kβ use their main-chain atoms for adenine recognition, while the side-chain atoms are required for guanine recognition. Mutational analysis of the GEA motif revealed that the acquisition of GTP reactivity is accompanied by an extended activity toward inosine triphosphate (ITP) and xanthosine triphosphate (XTP). Along with the evolutionary analysis data that point to strong negative selection of the GEA motif, these results suggest that the GTP responsiveness of PI5P4Kβ has evolved from a compromised trade-off between activity and specificity, underpinning the development of the GTP-dependent stress resilience., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)