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Abstract Determining short-lived intermediate structures in chemical reactions is challenging. Although ultrafast spectroscopic methods can detect the formation of transient intermediates, real-space structures cannot be determined directly from such studies. Time-resolved serial femtosecond crystallography (TR-SFX) has recently proven to be a powerful method for capturing molecular changes in proteins on femtosecond timescales. However, the methodology has been mostly applied to natural proteins/enzymes and limited to reactions promoted by synthetic molecules due to structure determination challenges. This work demonstrates the applicability of TR-SFX for investigations of chemical reaction mechanisms of synthetic metal complexes. We fix a light-induced CO-releasing Mn(CO)3 reaction center in porous hen egg white lysozyme (HEWL) microcrystals. By controlling light exposure and time, we capture the real-time formation of Mn-carbonyl intermediates during the CO release reaction. The asymmetric protein environment is found to influence the order of CO release. The experimentally-observed reaction path agrees with quantum mechanical calculations. Therefore, our demonstration offers a new approach to visualize atomic-level reactions of small molecules using TR-SFX with real-space structure determination. This advance holds the potential to facilitate design of artificial metalloenzymes with precise mechanisms, empowering design, control and development of innovative reactions.

Abstract Background We explore an optimized approach for increasing lesion size using a novel ablation catheter with a surface thermocouple and efficient irrigation in a temperature‐control setting. Methods We conducted radiofrequency applications at various power levels (35 W, 40 W, and 45 W), contact forces (CFs, 10 g/20 g), and durations (60 s/120 s/180 s) in perpendicular/parallel catheter orientations, with normal saline irrigation (NS‐irrigation) and Half NS‐irrigation (HNS‐irrigation) in an ex‐vivo model (Step 1). In addition, we performed applications (35 W/40 W/45 W for 60 s/120 s/180 s in NS‐irrigation and 35 W/40 W for 60 s/120 s/180 s in HNS‐irrigation) in four swine (Step 2), evaluating lesion characteristics and the occurrence of steam pops. Results In Step 1, out of 288 lesions, we observed 47 (16.3%) steam pops, with 13 in NS‐irrigation and 34 in HNS‐irrigation (p = .001). Although steam pops were mostly observed with the most aggressive setting (45 W/180 s, 54%) with NS‐irrigation, they happened in less aggressive settings with HNS irrigation. Lesion size significantly increased with longer‐duration ablation but not with HNS‐irrigation. The optimal %impedance‐drop cutoff to predict steam pops was 20% with a negative‐predictive‐value (NPV) = 95.1% including NS‐ and HNS‐irrigation groups, and 22% with an NPV = 96.1% in NS‐irrigation group. In Step 2, similar to the ex‐vivo model, lesion size significantly increased with longer‐duration ablation but not with HNS‐irrigation. Steam pops were absent with NS‐irrigation (0/35) even with the largest %impedance‐drop reaching 31% at 45 W/180 s. All steam pops were observed with HNS‐irrigation (6/21, 29%). The optimal %impedance‐drop cutoff predicting steam pops was 24% with an NPV = 96.3% including both NS‐ and HNS‐irrigation groups. Conclusions Rather than using HNS‐irrigation, very long‐duration of radiofrequency applications up to 45 W/180 s may be recommended to safely and effectively increase lesion dimensions using this catheter with NS‐irrigation.

Abstract DNA methylation is an epigenetic mechanism that introduces a methyl group at the C5 position of cytosine. This reaction is catalyzed by DNA methyltransferases (DNMTs) and is essential for the regulation of gene transcription. The DNMT1 and DNMT3A or -3B family proteins are known targets for the inhibition of DNA hypermethylation in cancer cells. A selective non-nucleoside DNMT3A inhibitor was developed that mimics S-adenosyl-l-methionine and deoxycytidine; however, the mechanism of selectivity is unclear because the inhibitor–protein complex structure determination is absent. Therefore, we performed docking and molecular dynamics simulations to predict the structure of the complex formed by the association between DNMT3A and the selective inhibitor. Our simulations, binding free energy decomposition analysis, structural isoform comparison, and residue scanning showed that Arg688 of DNMT3A is involved in the interaction with this inhibitor, as evidenced by its significant contribution to the binding free energy. The presence of Asn1192 at the corresponding residues in DNMT1 results in a loss of affinity for the inhibitor, suggesting that the interactions mediated by Arg688 in DNMT3A are essential for selectivity. Our findings can be applied in the design of DNMT-selective inhibitors and methylation-specific drug optimization procedures.

Abstract Background Atezolizumab, one of the immune checkpoint inhibitors, has been approved as an adjuvant treatment following resection and platinum‐based chemotherapy in patients with stage II–IIIA non‐small cell lung cancer with 1% or more programmed death ligand‐1 (PD‐L1) expression. The Food and Drug Administration (FDA) has approved SP263 as a companion diagnostic assay for adjuvant treatment with atezolizumab; however, in clinical practice, the 22C3 assay is most commonly used for advanced non‐small cell lung cancer. Therefore, our study aimed to compare two PD‐L1 assays, SP263 and 22C3, to evaluate whether 22C3 could replace SP263 when deciding whether to administer adjuvant atezolizumab. Methods We retrospectively and prospectively analyzed 98 patients who underwent surgical resection at Kanagawa Cancer Center (Japan). An immunohistochemistry assay was performed for all the cases with both SP263 and 22C3. We statistically analyzed the concordance of PD‐L1 expression between SP263 and 22C3 assays. Results The concordance between the two assays using Cohen's kappa was κ = 0.670 (95% CI: 0.522–0.818) at the 1% cutoff and κ = 0.796 (95% CI: 0.639–0.954) at the 50% cutoff. The Spearman correlation coefficient of 0.874 (p

Abstract Aim Numerous recent reports have highlighted the association between mental disorders and electrocardiographic findings. The early repolarization pattern (ERP) on electrocardiogram has been linked with a history of suicide attempts and attention deficit hyperactivity disorder, and associations with impulsivity have also been reported. It is known that suicidal intent is more common at night. Patients who have a mental disorder and ERP may have a higher likelihood of impulsivity, potentially increasing the risk of suicide at night. Methods The subjects were 43 patients with a history of suicide attempts who had undergone electrocardiographic examination at Jikei University School of Medicine Kashiwa Hospital and received intervention from our department. Due to the diurnal variation in electrocardiographic findings, only patients who underwent the examination during the daytime were included. Patients' clinical backgrounds were compared according to the presence or absence of ERP, and the association between nocturnal suicide attempts and ERP was examined using multivariate analysis. Results The frequency of nocturnal suicidal behavior was 76.2% in patients with ERP and 31.8% in those without ERP, but the difference was not significant after Bonferroni correction. In the multivariate analysis, there was a significant association of ERP with nocturnal suicide attempts (p = 0.018). Conclusion The finding of an association between ERP and nocturnal suicide attempts indicates that ERP is a biological indicator that can predict nocturnal suicide attempts.

Abstract Background Cognitive behavioral therapy for insomnia (CBT-I) is among the recommended non-pharmacological treatments for patients with insomnia. While there are multiple reports on the effects of CBT-I treatment, few studies evaluating the factors associated with the treatment response to CBT-I have been reported. The present study aimed to confirm the effects of CBT-I in patients with insomnia and to examine the clinico-demographic factors that can predict the outcomes of CBT-I in these patients. Methods Overall, 62 patients were included in the present study. To confirm the effectiveness of CBT-I, we compared the pre- and post-CBT-I therapy values of several sleep parameters. Furthermore, to identify the clinico-demographic factors that could be predictive of the treatment response to CBT-I, we performed generalized linear model (GLM) analysis. Results The values of several sleep parameters were significantly lower after treatment than at baseline. The results of the GLM analysis revealed that sex and occupation were significantly associated with the treatment response to CBT-I. Conclusions The present results suggest that several clinico-demographic factors should be considered in the treatment of patients with insomnia.

Characteristic dynamics in lava flows, such as the formation processes of lava levees, toe-like tips, and overlapped structures, were reproduced successfully through numerical simulation using the smoothed particle hydrodynamics (SPH) method. Since these specific phenomena have a great influence on the flow direction of lava flows, it is indispensable to elucidate them for accurate predictions of areas where lava strikes. At the first step of this study, lava was expressed using a molten metal with known physical properties. The computational results showed that levees and toe-like tips formed at the fringe of the molten metal flowing down on a slope, which appeared for actual lava flows as well. The dynamics of an overlapped structure formation were also simulated successfully; therein, molten metal flowed down, solidified, and changed the surface shape of the slope, and the second molten metal flowed over the changed surface shape. It was concluded that the computational model developed in this study using the SPH method is applicable for simulating and clarifying lava flow phenomena.

Abstract Background Lesion size is reported to become larger as contact force (CF) increases. However, this has not been systematically evaluated in temperature‐guided very high‐power short‐duration (vHPSD) ablation, which was therefore the purpose of this study. Methods Radiofrequency applications (90 W/4 s, temperature‐control mode) were performed in excised porcine myocardium with four different CFs of 5, 15, 25, and 35 g using QDOT‐MICRO™ catheter. Ten lesions for each combination of settings were created, and lesion metrics and steam‐pops were compared. Results A total of 320 lesions were analyzed. Lesion depth, surface area, and volume were smallest for CF of 5 g than for 15, 25, and 35 g (depth: 2.7 mm vs. 2.9 mm, 3.0 mm, 3.15 mm, p

Abstract Partial anomalous pulmonary venous return (PAPVR) is a rare congenital malformation where the pulmonary vein partially refluxes into the venous system. Here, we present the first robotic‐assisted right S3 segmentectomy in a 70‐year‐old male with early‐stage lung cancer and PAPVR in the right upper pulmonary vein. The patient, with suspected primary lung cancer (11 mm diameter, pure solid appearance in right S3 segment), exhibited clinical stage T1bN0M0 stage IA2. Preoperative computed tomography revealed severe lung emphysema, and right V1–3 returned directly to the superior vena cava. However, no signs of right‐sided heart failure were observed, and echocardiogram was normal with a pulmonary‐to‐systemic blood flow ratio of 1.4. Successful robot‐assisted right S3 segmentectomy with hilar nodal dissection was performed, and the patient was discharged on the sixth postoperative day without complications. One year postoperatively, there has been no recurrence of lung cancer or respiratory/right‐sided heart failure symptoms.

The effect of interpolation and super-resolution (SR) algorithms on quantitative and qualitative assessments of enlarged optical coherence tomography (OCT) images was investigated in this report. Spectral-domain OCT images from 30 eyes in 30 consecutive patients with diabetic macular edema (DME) and 20 healthy eyes in 20 consecutive volunteers were analyzed. Original image (OR) resolution was reduced by a factor of four. Images were then magnified by a factor of four with and without application of one of the following algorithms: bilinear (BL), bicubic (BC), Lanczos3 (LA), and SR. Differences in peak signal-to-noise ratio (PSNR), retinal nerve fiber layer (RNFL) thickness, photoreceptor layer status, and parallelism (reflects the complexity of photoreceptor layer alterations) were analyzed in each image type. The order of PSNRs from highest to lowest was SR > LA > BC > BL > non-processed enlarged images (NONE). The PSNR was statistically different in all groups. The NONE, BC, and LA images resulted in significantly thicker RNFL measurements than the OR image. In eyes with DME, the photoreceptor layer, which was hardly identifiable in NONE images, became detectable with algorithm application. However, OCT photoreceptor parameters were still assessed as more undetectable than in OR images. Parallelism was not statistically different in OR and NONE images, but other image groups had significantly higher parallelism than OR images. Our results indicated that interpolation and SR algorithms increased OCT image resolution. However, qualitative and quantitative assessments were influenced by algorithm use. Additionally, each algorithm affected the assessments differently.

PURPOSE: To characterize human parafoveal blood flow using adaptive optics scanning laser ophthalmoscopy (AO-SLO). METHODS: In 5 normal subjects, erythrocyte aggregate distributions were analyzed on 3 different days. Erythrocyte aggregates were described as a "dark tail" in AO-SLO. The characteristics of the pathways with dark tail flow in the parafovea were measured. Additionally, the tendency for dark tail flow before and after bifurcations was analyzed to study the blood flow in detail. RESULTS: Average velocity in parent vessels with dark tail flow was 1.30±0.27 mm/s. Average velocity in daughter vessels with dark tail flow was 1.12±0.25 mm/s, and the average velocity of plasma gaps in daughter vessels without dark tail flow was 0.64±0.11 mm/s. Downstream from the bifurcations, the velocity in vessels with dark tail flow was higher than that in those without it (p

Purpose: Although the treatment of nonsmall cell lung cancer (NSCLC) has rapidly progressed recently, there is little evidence of treatment for patients with symptomatic brain metastases (BM) and poor performance status (PS). However, in symptomatic BM patients, appropriate upfront intracranial treatment can often lead to rapid improvement in PS and effective systemic therapy. Thus, this study investigated the prognostic factors for the survival of poor PS NSCLC patients with synchronous BM. Methods: Data of patients with BM and Karnofsky PS (KPS) ≤70 at the first diagnosis of NSCLC who were treated in our hospital between January 2017 and December 2021 were reviewed. Patient survival was compared among patients stratified by type of first-line regimen of systemic treatment. Correlations between patient characteristics and survival were examined. Results: Fifty patients receiving aggressive treatment were enrolled. The median survival times for tyrosine kinase inhibitor (TKI), immune checkpoint inhibitor (ICI), and chemotherapy alone groups were 19 (95 % confidence interval [CI], 2.8–68.5), 19 (3.0–62.0), and 13 (1.2–24.8) months, respectively. Survival in the TKI and ICI groups was significantly longer than in the chemotherapy alone group (p = 0.046, TKI vs. chemo; p = 0.022, ICI vs. chemo; p = 0.023). Both sex and type of systemic treatment correlated to survival time on univariate analysis. Chemotherapy alone for systemic treatment [p = 0.034; hazard ratio (HR), 0.44 (0.20–0.94)] remained significant for predicting overall survival in the multivariate analysis. Conclusion: Even in patients with poor PS and BM at the initial diagnosis of NSCLC, the ICI group had a survival time comparable to that of the TKI group when combined with tailor-made intracranial treatment. There is a subgroup in the patient population that was previously considered unsuitable for ICI, whose PS improves with individualized intracranial treatment, and who may benefit from immunotherapy.

Gamma oscillation regularity (GOR) indicates the synchronization of inhibitory interneurons, while the reactivity of cortico-cortical evoked potentials (CCEPs) is supposed to reflect local cortical excitability. Under the assumption that the early response of CCEP near the stimulation site also indicates excitatory activity primarily mediated by pyramidal cells, we aimed to visualize the cortical inhibitory and excitatory activities using GOR and CCEP in combination and to use them to predict the epileptogenic zone (EZ) in mesial temporal lobe epilepsy (MTLE). In five patients who underwent intracranial electrode implantation, GOR and CCEP reactivity in the vicinity of the stimulation site was quantified. The interictal GOR was calculated using multiscale entropy (MSE), the decrease of which was related to the enhanced GOR. These parameters were compared on an electrode-and-electrode basis, and spatially visualized on the brain surface. As a result, elevated GOR and CCEP reactivities, indicative of enhanced inhibitory and excitatory activities, were observed in the epileptogenic regions. Elevated CCEP reactivity was found to be localized to a restricted area centered on the seizure onset region, whereas GOR elevation was observed in a broader region surrounding it. Although these parameters independently predicted the EZ with high specificity, we combined the two to introduce a novel parameter, the excitatory and inhibitory (EI) index. The EI index predicted EZ with increased specificity compared with GOR or CCEP reactivity alone. Our results demonstrate that GOR and CCEP reactivity provided a quantitative visualization of the distribution of cortical inhibitory and excitatory activities and highlighted the relationship between the two parameters. The combination of GOR and CCEP reactivities are expected to serve as biomarkers for localizing the epileptogenic zone in MTLE from interictal intracranial electroencephalograms.

Introduction: To elucidate factors associated with severe disease in patients with coronavirus disease 2019 (COVID-19) pneumonia complicated with diabetes mellitus. Methods: Among patients with COVID-19 pneumonia hospitalized from January to September 2021, 100 patients with diabetes were included in the study. Patients in the intensive care unit admission or in-hospital death category were defined as the severe group (26 patients), and the other patients as the moderate group (74 patients). Comparisons were made between the two groups. Medical histories were extracted from the medical records, and statistical analysis was performed. Results: Patients were 62.1 ± 13.0 years of age, 70 % male, 48 % aged 65 years and more, and HbA1c was 7.72 ± 1.51 %. The severe group had significantly higher blood glucose level, CRP, WBC, and LDH on admission. Serum albumin level was significantly lower in the severe group and was significantly negatively correlated with number of days on oxygen administration (r = 0.447) and maximal oxygen concentration (r = 0.561). Multiple logistic regression analysis with severity of illness as the objective variable showed that high CRP and low albumin levels on admission, and older age were independently associated. Conclusions: Low albumin levels on admission may be an indicator of severe disease in patients with diabetes.

Abstract Introduction Pharmacotherapy such as selective serotonin reuptake inhibitors (SSRIs) or serotonin‐noradrenaline reuptake inhibitors is recommended for the treatment of anxiety disorders. Although there are patients with persisted symptoms of anxiety disorders who are treated with monotherapy of benzodiazepine anxiolytics without SSRIs, the characteristics of these patients are unclear. In the present study, we investigated the characteristics of patients with persisted symptoms of anxiety disorder without SSRI prescription. Methods From a prescription dataset covering 2018 and 2020, the prescriptions of 243 patients with anxiety disorder were analyzed. Patients were classified into two groups: SSRI non‐prescription and prescription groups. Results The SSRI non‐prescription group had a higher ratio of females than did the SSRI prescription group (60.1% vs. 44.6%, respectively, p = 3.12 × 10−2), but statistically not significant after the Bonferroni correction. No significant differences in age, body mass index, or duration of outpatient visits were found between groups. Among the independent variables, sex (female) was the only variable identified that predicted SSRI non‐prescription. Conclusion The present study showed that among patients with anxiety disorders, sex (female) was the only variable that predicted SSRI non‐prescription.

Abstract Background Pulmonary arterial hypertension is a serious medical condition. However, the condition is often misdiagnosed or a rather long delay occurs from symptom onset to diagnosis, associated with decreased 5-year survival. In this study, we developed and tested a deep-learning algorithm to detect pulmonary arterial hypertension using chest X-ray (CXR) images. Methods From the image archive of Chiba University Hospital, 259 CXR images from 145 patients with pulmonary arterial hypertension and 260 CXR images from 260 control patients were identified; of which 418 were used for training and 101 were used for testing. Using the testing dataset for each image, the algorithm outputted a numerical value from 0 to 1 (the probability of the pulmonary arterial hypertension score). The training process employed a binary cross-entropy loss function with stochastic gradient descent optimization (learning rate parameter, α = 0.01). In addition, using the same testing dataset, the algorithm’s ability to identify pulmonary arterial hypertension was compared with that of experienced doctors. Results The area under the curve (AUC) of the receiver operating characteristic curve for the detection ability of the algorithm was 0.988. Using an AUC threshold of 0.69, the sensitivity and specificity of the algorithm were 0.933 and 0.982, respectively. The AUC of the algorithm’s detection ability was superior to that of the doctors. Conclusion The CXR image-derived deep-learning algorithm had superior pulmonary arterial hypertension detection capability compared with that of experienced doctors.

Abstract The prevalence of HIV-1 infection continues to pose a significant global public health issue, highlighting the need for antiretroviral drugs that target viral proteins to reduce viral replication. One such target is HIV-1 protease (PR), responsible for cleaving viral polyproteins, leading to the maturation of viral proteins. While darunavir (DRV) is a potent HIV-1 PR inhibitor, drug resistance can arise due to mutations in HIV-1 PR. To address this issue, we developed a novel approach using the fragment molecular orbital (FMO) method and structure-based drug design to create DRV analogs. Using combinatorial programming, we generated novel analogs freely accessible via an on-the-cloud mode implemented in Google Colab, Combined Analog generator Tool (CAT). The designed analogs underwent cascade screening through molecular docking with HIV-1 PR wild-type and major mutations at the active site. Molecular dynamics (MD) simulations confirmed the assess ligand binding and susceptibility of screened designed analogs. Our findings indicate that the three designed analogs guided by FMO, 19–0–14–3, 19–8–10–0, and 19–8–14–3, are superior to DRV and have the potential to serve as efficient PR inhibitors. These findings demonstrate the effectiveness of our approach and its potential to be used in further studies for developing new antiretroviral drugs.

Abstract Background The terminology for lung cancer diagnosis in small biopsies was adopted in the 2015 World Health Organization classification. If non‐small cell lung cancer (NSCLC) has no clear adenocarcinoma (AD) or squamous cell carcinoma morphology, the tumor is further classified based on mucin or immunohistochemical staining as NSCLC favor AD (NFAD), NSCLC favor squamous cell carcinoma, or NSCLC not otherwise specified. Since this new term was defined, the difference between AD and NFAD has not yet been fully explored. This study aimed to examine the differences in clinical background, gene alteration frequency, and programmed death ligand 1 (PD‐L1) expression. Methods We included patients diagnosed with AD or NFAD with small samples, and who underwent testing with the Oncomine Dx target test between August 2019 and April 2023 in Kanagawa Cancer Center. Results This study comprised 268 patients. A total of 96 patients underwent surgery after AD or NFAD diagnosis. The clinical stage was more advanced and pathological N0 was lower in NFAD than in AD. The pathology of the surgical specimens revealed that solid predominant AD was significantly more common in NFAD than in AD (p

PURPOSE: To investigate the effect of B-spline-based elastic image registration on adaptive optics scanning laser ophthalmoscopy (AO-SLO)-assisted capillary visualization. METHODS: AO-SLO videos were acquired from parafoveal areas in the eyes of healthy subjects and patients with various diseases. After nonlinear image registration, the image quality of capillary images constructed from AO-SLO videos using motion contrast enhancement was compared before and after B-spline-based elastic (nonlinear) image registration performed using ImageJ. For objective comparison of image quality, contrast-to-noise ratios (CNRS) for vessel images were calculated. For subjective comparison, experienced ophthalmologists ranked images on a 5-point scale. RESULTS: All AO-SLO videos were successfully stabilized by elastic image registration. CNR was significantly higher in capillary images stabilized by elastic image registration than in those stabilized without registration. The average ratio of CNR in images with elastic image registration to CNR in images without elastic image registration was 2.10 ± 1.73, with no significant difference in the ratio between patients and healthy subjects. Improvement of image quality was also supported by expert comparison. CONCLUSIONS: Use of B-spline-based elastic image registration in AO-SLO-assisted capillary visualization was effective for enhancing image quality both objectively and subjectively.