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Background: The fat attenuation index (FAI) measured using coronary computed tomography angiography (CCTA) enables the direct evaluation of pericoronary adipose tissue composition and vascular inflammation. We aimed to investigate the association of fractional flow reserve (FFR) and plaque vulnerability with coronary inflammation., Methods: Patients with suspected coronary artery disease (CAD) who underwent CCTA and invasive FFR measurements within 90-day were included. A cloud-based medical device, CaRi-Heart, serves as a surrogate tool for evaluating coronary inflammation based on FAI by analyzing CCTA images. The correlations between CCTA-defined plaque characteristics, invasive coronary angiographic and physiologic assessments, and CaRi-Heart risk were analyzed. The primary endpoint was the patient-oriented composite outcome (POCO) consisting of all-cause death, any myocardial infarction, and any revascularization., Results: A total of 564 patients (median age 67.0 years; 75.4 ​% men) were included. There were no significant differences in quantitative and qualitative plaque characteristics or FFR between the high- and low-CaRi-Heart risk groups (i.e., ≥5 ​% and <5 ​%). During the median follow-up of 3.2 years [1.13-4.73 years], CaRi-Heart risk ≥5 ​% was associated with a significantly higher rate of POCO compared to CaRi-Heart risk <5 ​% (0.9 ​% vs. 10.1 ​%, P ​= ​0.037). The CaRi-Heart risk was an independent predictor of POCO as a continuous (adjusted HR 1.016, 95 ​% CI 1.005-0.027, P ​= ​0.004) and categorical variable (CaRi-Heart risk ≥5 ​%, adjusted HR 2.949, 95 ​% CI 1.182-7.360, P ​= ​0.021), regardless of high-risk plaque characteristics and FFR., Conclusion: Coronary inflammation risk assessed using CaRi-Heart risk provides independent prognostic information regardless of plaque vulnerability and physiologic stenosis in patients with CAD., Competing Interests: Declaration of competing interest Dr Bon-Kwon Koo received an Institutional Research Grant from Abbott Vascular and Philips Volcano. Dr. Joon Hyung Doh received a Research Grant from Philips Volcano. All other authors declare that there is no conflict of interest relevant to the submitted work. Dr Tomlins is an employee of Caristo Diagnostics Ltd. Dr Antoniades is a founder, shareholder, and director of Caristo Diagnostics Ltd, a CT-image analysis company., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: HER2-low populations constitute a heterogeneous group, and the cytotoxic anticancer agent efficacy based on HER2 status remains unclear. This study evaluated the clinicopathological features and outcomes of patients with advanced breast cancer showing HER2-low expression treated with eribulin or capecitabine, two treatment options after anthracycline and taxane treatment., Methods: We retrospectively evaluated patients who were treated with eribulin or capecitabine between 2011 and 2015. HER2 status was evaluated according to the ASCO/CAP guidelines., Results: No significant difference was observed in overall survival (OS; eribulin: hazard ratio [HR], 0.66; 95% CI 0.40-1.10; capecitabine: HR, 0.76; 95% CI 0.45-1.30) or progression-free survival (PFS; eribulin: HR, 1.13; 95% CI 0.72-1.78; capecitabine: HR, 0.90; 95% CI 0.56-1.44) between patients receiving eribulin (HER2-null: 35, HER2-low: 44) and those receiving capecitabine (HER2-null: 41, HER2-low: 33). Subgroup analysis revealed no significant differences in OS between the two groups in the hormone-positive and -negative populations for eribulin and capecitabine. HER2-null and HER2-low patients showed objective response rates (ORRs) of 22.5% and 9.1% (p = 0.09) overall, and 32.0% and 10.5% (p = 0.03), respectively, in hormone-positive cases among eribulin-treated patients. No response was observed in hormone-negative patients. Capecitabine treatment in HER2-null and HER2-low patients had overall ORRs of 26.8% and 15.2% (p = 0.23), respectively, with 27.3% and 16.1% (p = 0.28) for hormone-positive cases; and 25.0% and 0% (p = 1.0), respectively, for hormone-negative cases., Conclusions: Eribulin and capecitabine sensitivity may vary based on HER2 expression in patients with HER2-low and HER2-null breast cancer. Prognosis was similar between the HER2-low and the HER2-null groups., (© 2024. The Author(s).)

Background: Recent studies suggest that the presence of calcified nodules (CN) is associated with worse prognosis in patients with acute coronary syndrome (ACS). We investigated clinical predictors of optical coherence tomography (OCT)-defined CN in ACS patients in a prospective multicenter registry., Methods and Results: We investigated 695 patients enrolled in the TACTICS registry who underwent OCT assessment of the culprit lesion during primary percutaneous coronary intervention. OCT-CN was defined as calcific nodules erupting into the lumen with disruption of the fibrous cap and an underlying calcified plate. Compared with patients without OCT-CN, patients with OCT-CN (n=28) were older (mean [±SD] age 75.0±11.3 vs. 65.7±12.7 years; P<0.001), had a higher prevalence of diabetes (50.0% vs. 29.4%; P=0.034), hemodialysis (21.4% vs. 1.6%; P<0.001), and Killip Class III/IV heart failure (21.4% vs. 5.7%; P=0.003), and a higher preprocedural SYNTAX score (median [interquartile range] score 15 [11-25] vs. 11 [7-19]; P=0.003). On multivariable analysis, age (odds ratio [OR] 1.072; P<0.001), hemodialysis (OR 16.571; P<0.001), and Killip Class III/IV (OR 4.466; P=0.004) were significantly associated with the presence of OCT-CN. In non-dialysis patients (n=678), age (OR 1.081; P<0.001), diabetes (OR 3.046; P=0.014), and Killip Class III/IV (OR 4.414; P=0.009) were significantly associated with the presence of OCT-CN., Conclusions: The TACTICS registry shows that OCT-CN is associated with lesion severity and poor clinical background, which may worsen prognosis.

Background: Myocardial bridge (MB) is a common coronary anomaly characterized by a tunneled course through the myocardium. Coronary computed tomography angiography (CCTA) can identify MB. The impact of MB detected by CCTA on coronary physiological parameters before and after percutaneous coronary intervention (PCI) is unknown., Methods and Results: We investigated 141 consecutive patients who underwent pre-PCI CCTA and fractional flow reserve (FFR)-guided elective PCI for de novo single proximal lesions in the left anterior descending artery (LAD). We compared clinical demographics and physiological parameters between patients with and without CCTA-defined MB. MB was identified in 46 (32.6%) patients using pre-PCI CCTA. The prevalence of diabetes was higher among patients with MB. Median post-PCI FFR values were significantly lower among patients with than without MB (0.82 [interquartile range 0.79-0.85] vs. 0.85 [interquartile range 0.82-0.89]; P=0.003), whereas pre-PCI FFR values were similar between the 2 groups. Multivariable linear regression analysis revealed that the presence of MB and greater left ventricular mass volume in the LAD territory were independently associated with lower post-PCI FFR values. Multivariable logistic regression analysis also revealed that the presence of MB and lower pre-PCI FFR values were independent predictors of post-PCI FFR values ≤0.80., Conclusions: CCTA-defined MB independently predicted both lower post-PCI FFR as a continuous variable and ischemic FFR as a categorical variable in patients undergoing elective PCI for LAD.

Sexual reproduction is widespread, but asexual lineages have repeatedly arisen from sexual ancestors across a wide range of eukaryotic taxa. The molecular changes underpinning the switch to asexuality remain elusive, particularly in organisms with haploid sexual systems. Here we explore independent events of loss of sex in the brown alga Scytosiphon, examine the proximate and evolutionary mechanisms involved, and test the importance of sexual conflict on gene expression changes following loss of sex. We find that asexual females ('Amazons') lose ability to produce sex pheromone and, consequently, are incapable of attracting males, whereas they gain rapid parthenogenic development from large, unfertilized eggs. These phenotypic changes are accompanied by convergent changes in gene expression. Decay of female functions, rather than relaxation of sexual antagonism, may be a dominant force at play during the emergence of asexuality in haploid sexual systems. Moreover, we show that haploid purifying selection plays a key role in limiting the accumulation of deleterious alleles in Amazons, and we identify an autosomal locus associated with the Amazon phenotype. The sex chromosome, together with this autosomal locus, may underlie the switch to obligate asexuality in the Amazon populations., (© 2024. The Author(s).)

Ferroelectric nematic liquid crystals (N F LCs) are distinguished by their remarkable polarization characteristics and diverse physical phenomena, sparking significant interest and excitement within the scientific community. To date, over 150 N F LC molecules are developed; however, there are no reports regarding straight linear polar molecules with a parallel alignment of the permanent dipole moment and the molecular axis. The straight polar mesogen nBOE exhibits an enantiotropic N F phase with a wide temperature window (up to 100 K) despite having a longer alkyl chain (up to n = 6) than the critical alkyl chain length of conventional models. Interestingly, nBOE with a medium-length alkyl chain displays an exotic phase sequence of N F - HC N F -SmX F during the elimination of positional displacement among adjacent molecules. Furthermore, the reflective color modulation of the HC N F LC over the entire VIS-NIR spectral regime by ultralow E-field (up to 0.14 V µm -1 ) is demonstrated., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Study Design: A retrospective cohort study., Objective: The study aimed to investigate the related factors affecting physical activity-related quality of life (QOL) after 2 years of cervical laminoplasty for degenerative cervical myelopathy (DCM), focusing on the degree of preoperative degeneration of the cervical multifidus muscles., Summary of Background Data: The association between paraspinal muscle degeneration and clinical outcomes after spinal surgery is being investigated. The effect of preoperative degeneration of the cervical multifidus muscles in patients undergoing cervical laminoplasty is ambiguous., Methods: Patients who underwent laminoplasty for DCM and followed up for more than 2 years were reviewed. To evaluate physical QOL, the physical component summary (PCS) of the 36-Item Short-Form Health Survey (SF-36) was recorded at 2 years postoperatively. The degree of preoperative degeneration in the multifidus muscles at the C4 and C7 levels on axial T2-weighted magnetic resonance imaging (MRI) was categorized according to the Goutallier grading system. The correlation between 2-year postoperative PCS and each preoperative clinical outcome, radiographic parameter, and MRI finding, including Goutallier classification, was analyzed. Variables with a P value <0.10 in univariate analysis were included in multiple linear regression analysis., Results: In total, 106 consecutive patients were included. The 2-year postoperative PCS demonstrated significant correlation with age ( R =-0.358, P =0.002), preoperative JOA score ( R =0.286, P =0.021), preoperative PCS ( R =0.603, P <0.001), C2-C7 lordotic angle ( R =-0.284, P =0.017), stenosis severity ( R =-0.271, P =0.019), and Goutallier classification at the C7 level ( R =-0.268, P =0.021). In multiple linear regression analysis, sex (β=-0.334, P =0.002), age (β=-0.299, P =0.013), preoperative PCS (β=0.356, P =0.009), and Goutallier classification at the C7 level (β=-0.280, P =0.018) were significantly related to 2-year postoperative PCS., Conclusions: Increased degeneration of the multifidus muscle at the C7 level negatively affected physical activity-related QOL postoperatively. These results may guide spine surgeons in predicting physical activity-related QOL in patients with DCM after laminoplasty., Level of Evidence: Level III., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess the incidence of postoperative shoulder imbalance (PSI) following posterior spinal fusion surgeries in adolescent idiopathic scoliosis (AIS) with Lenke2 and calculate the risk factors for PSI., Methods: Sixty patients who underwent surgery for Lenke2 AIS with more than 2-year follow-up were selected. Radiographic parameters were measured before and after surgery, and at the latest follow-up. The patients were divided into PSI and non-PSI groups, with PSI defined as a radiographic shoulder height >15 mm on postoperative radiography. The factors were compared between the PSI and non-PSI groups using the Mann-Whitney U test or chi-squared test. Finally, explanatory variables were chosen for multivariate analysis based on previous studies., Results: The PSI group comprised 17 patients. Most PSI cases spontaneously improved, and four patients (6.7%) showed PSI at the final follow-up. Univariate analysis indicated significant differences between postoperative T1 tilt (9.00 ± 5.17 vs. 5.67 ± 4.02, P = 0.029), UIV tilt (1.94 ± 4.49 vs. -1.00 ± 5.04, P = 0.039), and ΔT1 tilt (4.82 ± 3.99 vs. 2.12 ± 3.77, P = 0.026). Multivariate logistic regression analysis indicated that ΔT1 tilt had a significant positive relationship with PSI occurrence (coefficient = 0.2541, 95% confidence interval [CI]: 0.023 to 0.485, P = 0.0310). This study found no significant differences in the SRS-22 scores at the final follow-up., Conclusions: The incidence of PSI for Lenke2 AIS was 28.3% at 1 week postoperatively and 6.7% at the final follow-up. ΔT1 tilt was a risk factor for PSI. Adjustment of the T1 tilt during surgery was considered useful for the prevention of PSI., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Degenerative lumbar spondylolisthesis (DLS) is a degenerative condition that causes leg pain, numbness, and gait disturbances. Despite surgical treatment, reducing numbness is more challenging than reducing pain, and there is currently no established effective intervention method. Dysesthesia-matched transcutaneous electrical nerve stimulation (DM-TENS) is a novel technique that adjusts TENS settings to match the sensation of numbness, potentially improving it. We applied DM-TENS to a post-operative DLS patient with chronic lower limb numbness. As a result, the NRS for numbness was 8.00 before the intervention but improved to 6.67 ± 0.47 after HF-TENS and to 1.67 ± 0.47 after DM-TENS (mean ± SD), indicating that DM-TENS was more effective in reducing chronic lower limb numbness. This report highlights the promising potential of DM-TENS as an effective intervention for reducing numbness in DLS patients, who often experience lower limb numbness., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Homma et al.)

Background: Impaired global coronary flow reserve (G-CFR), evaluated through phase-contrast cine cardiovascular magnetic resonance (PC-CMR), has been linked to worse outcomes in patients with cardiovascular disease. This study aimed to investigate the prognostic value of G-CFR improvement, as evaluated using PC-CMR imaging pre- and post-percutaneous coronary intervention (PCI)., Methods: In this single-center study, 320 patients with chronic coronary syndrome (CCS) who underwent pre- and post-PCI PC-CMR measurements were followed-up to determine major adverse cardiac or cerebrovascular events (MACCE) predictors. MACCE was defined as a composite of cardiac death, nonfatal myocardial infarction, hospitalization due to heart failure, or ischemic stroke. The association between CMR parameters, including baseline data, G-CFR changes post-PCI and MACCE was investigated., Results: G-CFR improvement was observed in 165 (51.6%) patients, while MACCE occurred in 26 (8.1%) during a median follow-up period of 2.5 years. G-CFR improvement was significantly associated with a lower pre-PCI G-CFR. The log-rank test revealed a significant association between patients without G-CFR improvement post-PCI and a poor prognosis. Patients with lower pre-PCI G-CFR and lack of G-CFR improvement exhibited the highest incidence of MACCE. The multivariable Cox proportional hazard model revealed that lack of G-CFR improvement was an independently significant MACCE predictor from pre-PCI G-CFR and SYNTAX score., Conclusions: Besides the association between pre- and post-PCI lower G-CFR and worse prognosis, the presence or absence of G-CFR improvement post-PCI may provide novel insights into the prognosis following elective PCI in patients with CCS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Competing interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: Neuroinflammation is an important causal factor for a variety of psychiatric disorders. We previously reported increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and major depressive disorder. The present study aimed to examine the possible association of interleukin-6 levels with anxiety and frustration, negative valence symptoms shared in various psychiatric disorders., Methods: We included 129 patients with psychiatric disorders and 70 controls. CSF and plasma interleukin-6 levels were measured by immunoassay kits, and psychological symptoms were assessed with the State-Trait Anxiety Inventory, and the Basic Psychological Need Satisfaction and Frustration Scale. To examine regional cerebral blood flow, patients underwent arterial spin labeling analysis using magnetic resonance imaging., Results: Cerebrospinal fluid interleukin-6 levels were significantly correlated with State-Trait Anxiety Inventory-trait anxiety (r = 0.25, P = 0.046) and Basic Psychological Need Satisfaction and Frustration Scale-autonomy frustration scores (r = 0.29, P = 0.018). Patients with abnormally high cerebrospinal fluid interleukin-6 levels (defined >97.5 percentile of the controls) had higher scores for trait anxiety (P = 0.035) and autonomy frustration (P = 0.026), and significantly increased regional cerebral blood flow in the left superior temporal gyrus, bilateral nucleus accumbens, and cerebellum than the remaining patients., Conclusion: Patients with elevated cerebrospinal fluid interleukin-6 constitute a subpopulation of psychiatric disorders associated with anxiety and autonomy frustration, which may be related to altered functions in specific brain areas., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Triboluminescence is a phenomenon in which light is generated through mechanical stress; it has emerging applications in stress-sensing devices. Although the prevailing mechanistic model indicates that light emits from charge separation and recombination in fracture planes arising from polar structures, its application in designing triboluminescent materials remains limited owing to numerous exceptions. This study provides insights into the essential requirements for triboluminescence by investigating the structural and electrostatic properties of fractured crystals of copper thiocyanate complexes. The examined fracture plane indicated that charge pairs (which are essential for light emission) form when intermolecular interactions are disrupted during fracturing. On the basis of the nature of these charges, we successfully suppressed triboluminescence by inhibiting the formation of intermolecular interactions disrupted in the examined complexes. Furthermore, we induced its re-emergence by creating an alternative fracture plane through controlled manipulation of the molecular network. This demonstrative deactivation and reactivation of triboluminescence underscores the critical role of intermolecular disruption in generating charge pairs, a prerequisite for triboluminescence., (© 2024 Wiley-VCH GmbH.)

The cephalopod eye lens is unique because it has evolved as a compound structure with two physiologically distinct segments. However, the detailed ultrastructure of this lens and precise optical role of each segment are far from clear. To help elucidate structure-function relationships in the cephalopod lens, we conducted multiple structural investigations on squid. Synchrotron x-ray scattering and transmission electron microscopy disclose that an extensive network of structural features that resemble cell membrane complexes form a substantial component of both anterior and posterior lens segments. Optically, the segments are distinct, however, and Talbot interferometry indicates that the posterior segment possesses a noticeably higher refractive index gradient. We propose that the hitherto unrecognised network of membrane structures in the cephalopod lens has evolved to act as an essential conduit for the internal passage of ions and other metabolic agents through what is otherwise a highly dense structure owing to a very high protein concentration., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Objectives: The mechanisms behind the onset of acute aortic dissection have not been fully elucidated. We developed dynamic Synchrotron-based X-ray phase tomography to quantitatively study the dynamics of biological samples and applied it to the fresh aortic wall in acute type-A aortic dissection., Methods: Fresh, ring-shaped aortas undergoing aortic repair in acute type-A aortic dissection were measured in a container filled with normal cold saline within 24 hours of surgery. As a control, we obtained five formalin-fixed normal ascending aortas from autopsies (female : 2, 59.7 (SD : 5.5) years). To evaluate the quantitative morphological change, we estimated the density at five each step stretched by 2 mm per step. The fresh specimens were analyzed pathologically about the area ratio of elastic fibre., Results: Samples were obtained from five patients (1 man and 4 women, 59.4 (SD: 8.7) years) The overall density of the tunica media in the fresh aorta was 1.062(SD : 0.006) g/cm3 and differed significantly between the dissected and non-dissected portion (1.05(SD : 0.004) vs 1.066(SD : 0.004) g/cm3, respectively; p = 0.0122). When the fresh aortic wall was stretched and became thinner, the density of the tunica media remained unchanged. Compared with pathological findings, area ratio of the elastic fibre of the tunica media were lower in non-dissected portion than normal (48.6 (SD : 7.1) % v.s 60.5 (SD : 5.7) %, p < 0.001)., Conclusions: Dynamic-XPCT can trace the deformation process that occurs in situ in fresh aorta in acute type-A aortic dissection. We confirmed that densitometric property of the aortic wall in acute type-A aortic dissection was unchanged during the stretching process., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

The measurement of endogenous biomarkers in plasma and urine before and after administration of an investigational drug in a clinical study may provide an early indication of its drug-drug interaction (DDI) potential via a specific pathway. In the first international harmonized guideline on drug interaction studies, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M12, endogenous biomarkers have been recognized as an emerging approach in the transporter- and enzyme-based DDI risk assessment. Clinical Pharmacology Roundtable Conference 2024 held at Pharmaceuticals and Medical Devices Agency (PMDA) brought together experts from regulatory agencies, academia, and industries to discuss potential advantages and challenges of the biomarkers approach in drug development and regulatory decision making. This meeting report facilitates stakeholders involved in drug development in better understanding the utility of biomarker approaches and promotes early implementation of biomarker-informed DDI evaluation in regulatory use., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Normal cells coordinate proliferation and differentiation by precise tuning of gene expression based on the dynamic shifts of the epigenome throughout the developmental timeline. Although non-mutational epigenetic reprogramming is an emerging hallmark of cancer, the epigenomic shifts that occur during the transition from normal to malignant cells remain elusive. Here, we capture the epigenomic changes that occur during tumorigenesis in a prototypic embryonal brain tumor, medulloblastoma. By comparing the epigenomes of the different stages of transforming cells in mice, we identify nuclear factor I family of transcription factors, known to be cell fate determinants in development, as oncogenic regulators in the epigenomes of precancerous and cancerous cells. Furthermore, genetic and pharmacological inhibition of NFIB validated a crucial role of this transcription factor by disrupting the cancer epigenome in medulloblastoma. Thus, this study exemplifies how epigenomic changes contribute to tumorigenesis via non-mutational mechanisms involving developmental transcription factors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Alterations in the white matter have been implicated in schizophrenia. Myelin basic protein (MBP), a component of the myelin sheath, in the cerebrospinal fluid (CSF) has been suggested as a biomarker for white matter damage in demyelinating diseases. This prompted us to examine the CSF-MBP levels in patients with schizophrenia. We analyzed the CSF-MBP levels in 152 patients with schizophrenia and 117 age- and sex-matched controls. A significant positive correlation between age and CSF-MBP levels was observed both in the patients (p < 0.001) and controls (p = 0.014). No significant difference was observed in the CSF-MBP levels between the two groups. However, among a subsample of the patients (N = 32), a significantly negative correlation was observed between CSF-MBP and age-adjusted motor speed score of the brief assessment of cognition in schizophrenia (ρ = -0.59, p < 0.001). Further, among patients who underwent diffusional magnetic resonance imaging of the brain (N = 27), the CSF-MBP levels showed a significantly negative correlation with the mean kurtosis value in the right temporo-parietal region (p < 0.001). Our results suggest that the CSF-MBP level has limited utility as a diagnostic marker; however, higher CSF-MBP levels are associated with poorer motor speed, which may be associated with regional white matter damage in the brain in patients with schizophrenia., (© 2024 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

In the present work, we report an update and extension of the previous ion-pair formation study of Hubers, M.M.; Los, J. Chem. Phys. 1975 , 10 , 235-259, noting new fragment anions from time-of-flight mass spectrometry. The branching ratios obtained from the negative ions formed in K + SF 6 collisions, in a wide energy range from 10.7 up to 213.1 eV in the centre-of-mass frame, show that the main anion is assigned to SF 5 - and contributing to more than 70% of the total ion yield, followed by the non-dissociated parent anion SF 6 - and F - . Other less intense anions amounting to <20% are assigned to SF 3 - and F 2 - , while a trace contribution at 32u is tentatively assigned to S - formation, although the rather complex intramolecular energy redistribution within the temporary negative ion is formed during the collision. An energy loss spectrum of potassium cation post-collision is recorded showing features that have been assigned with the help of theoretical calculations. Quantum chemical calculations for the lowest-lying unoccupied molecular orbitals in the presence of a potassium atom are performed to support the experimental findings. Apart from the role of the different resonances participating in the formation of different anions, the role of higher-lying electronic-excited states of Rydberg character are noted.

Introduction: Occupational therapy (OT), a vital part of psychiatric rehabilitation, encourages participation in social activities, which is critical for the recovery of people with severe mental illnesses (SMI). However, the effects of OT on the subsequent social activities of patients with SMI have not been fully clarified. We aimed to identify the factors that encourage post-discharge social activity participation among patients with SMI who received OT., Method: Patients who underwent OT at the Kyorin University Hospital between April 2016 and March 2020 were retrospectively examined for baseline data during hospitalization and social activity status 1 year after discharge. Occupational support, group adaptation, artistic activities, and exercise programs were considered. Activities requiring social interaction were defined as social activities, including employment, schooling, sheltered work, and volunteer work. Multiple logistic regression analyses using demographic and medical data, prehospitalization social activity status, and OT participation rates as independent variables were used to examine the factors encouraging social activity participation after discharge. Decision tree analysis was conducted to identify patients who specifically needed to increase OT participation., Results: Of 524 eligible patients, 247 were included in the study. The number of patients who were socially active at admission and after discharge was 116 and 188, respectively. Multiple logistic regression analyses revealed that the following factors were likely to encourage social activity participation after discharge: higher rates of OT participation to facilitate group adaptation (OR = 1.015, 95% CI 1.003-1.027), being socially active at admission (OR = 4.557, 95% CI 2.155-9.637), and no marital history (OR = 0.293, 95% CI 0.130-0.661). Decision tree analysis showed that for patients who were socially inactive at admission and had a history of marriage, increasing OT participation to 52.6% or higher may ensure social activity participation after discharge., Conclusions: This study identified patients whose social participation after discharge could be boosted by OT that facilitates group adaptation. Our findings would facilitate the development of individualized add-on rehabilitation based on the effects of real-world OT practices., Competing Interests: Author MM received honorariums from Sumitomo Pharma and Yoshitomiyakuhin. Author YM received grants from the Japan Society for the Promotion of Science and honorariums from Sumitomo Pharma, Janssen Pharmaceutical, and Meiji Seika Pharma. Author TT received grants from the Japan Society for the Promotion of Science and honorariums from Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, Nippon Boehringer lngelheim, Mylan EPD, Mitsubishi Tanabe Pharma, Viatris, Mochida Pharmaceutical, Janssen Pharmaceutical, TEIJIN PHARMA, and Lundbeck Japan. Author KW is a consultant of Boehringer Ingelheim, Daiichi Sankyo, Eisai, Eli Lily, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Luye Pharma, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Pharmaceutical, and Takeda Pharmaceutical. Author HS received grants from the Japan Society for the Promotion of Science, Japan Research Foundation Clinical Pharmacology, and Takeda Science Foundation, and honorariums from Eisai, Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, Viatris, and Lundbeck Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships could be construed as a potential conflict of interest., (Copyright © 2024 Nagashima, Hayasaka, Teruya, Hoshino, Murao, Matumoto, Maruki, Katagiri, Imamura, Kurihara, Oe, Tsuboi, Watanabe and Sakurai.)

Background: Stress-transthoracic Doppler echocardiography (S-TDE) provides a noninvasive assessment of coronary flow parameters in the left anterior descending artery (LAD). However, the association between morphological characteristics and coronary flow changes after elective percutaneous coronary intervention (PCI) remains unclear. We aimed to evaluate the relationships between periprocedural coronary flow changes observed on S-TDE and lesion-specific plaque characteristics obtained by optical coherence tomography (OCT) in the interrogated vessels in patients with chronic coronary syndrome (CCS)., Methods and Results: Patients with CCS who underwent pre- and post-PCI S-TDE and elective fractional flow reserve (FFR)-guided PCI under OCT guidance for de novo single LAD lesions were included. S-TDE-derived hyperemic diastolic peak flow velocity (hDPV) was used as a surrogate for coronary flow. Lesions were categorized into two groups based on the %hDPV increase or decrease. The baseline clinical, physiological, and OCT findings were compared between the groups. In total, 103 LAD lesions were studied in 103 patients. After PCI, hDPV significantly increased from 55.6 cm/s to 69.5 cm/s (P<0.01), with a median %hDPV increase of 27.2 (6.32-59.1) %, while %hDPV decreased in 20 (19.4%) patients. The FFR improved in all patients. On OCT, layered plaques were more frequently present in the culprit vessels in the %hDPV-decrease group than in the %hDPV-increase group (85.0% vs. 50.6%, P = 0.01). Multivariable logistic regression analysis showed that the presence of layered plaques and high pre-PCI hDPV were independent predictors of %hDPV decrease., Conclusions: In patients who underwent successful uncomplicated elective PCI for de novo single LAD lesions, the presence of layered plaques was independently associated with hyperemic coronary flow decrease as assessed by S-TDE., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Usui et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background Context: Orthotic treatment is a common option for the conservative treatment of osteoporotic vertebral fractures (OVF). However, there is insufficient evidence of its clinical benefit., Purpose: To investigate the effectiveness of orthotic treatment for OVF., Study Design/setting: Retrospective cohort study with data from two prospective studies., Patient Sample: This study included 160 patients with fresh OVF enrolled in 2012 and 2020 prospective cohort studies., Outcome Measures: The visual analog scale (VAS) score for low back pain was used for clinical outcomes, and radiographic parameters included the percent height of the vertebra and angular change of the vertebral body. Moreover, the occurrence of secondary vertebral fractures was followed-up over time., Methods: The patients were divided into brace and no-brace groups and were matched according to propensity score for age, sex, anterior percent height at the initial examination, and presence of old OVFs. Hazard ratio for the cumulative incidence of secondary vertebral fractures with and without bracing were calculated and analyzed using the generalized Wilcoxon test. In addition, the brace group was divided into soft and rigid brace groups and compared with the no-brace group., Results: Each group had 61 cases after propensity score matching. There were no significant differences in the VAS improvement for low back pain and the change in percent height of the anterior and posterior walls from initial examination to 6 months after injury (p=.87, p=.39 and p=.14, respectively, mixed-effect models). Meanwhile, the mean angular change of fractured vertebrae was 4.3° / 3.2° initially and 1.2° / 2.5° at 6 months (the brace group / no-brace group, respectively; p=.007, mixed-effect models). A significant difference was also observed between the rigid brace group and the no-brace group (p=.008, mixed effect models). The incidence of secondary vertebral fractures was 1.6% / 11.4% at 1 month, indicating a significant difference (the brace group / no-brace group, respectively; p = .028). The hazard ratio for the cumulative incidence of secondary fractures due to orthotic treatment was 0.47 (95% confidence interval 0.20-1.09, p=.054)., Conclusions: Although orthotic treatment for fresh OVF did not relieve pain, it might contribute to the stabilization of the fractured vertebra, especially using a rigid brace. Moreover, it might influence a reduction of the imminent vertebral fracture risk immediately after the onset of OVF., Classifications: Clinical study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: Microvascular Resistance Reserve (MRR) has recently been introduced as a microvasculature-specific index and hypothesized to be independent of coronary stenosis. The aim of this study was to investigate the change of MRR after percutaneous coronary intervention (PCI)., Methods: In this post-hoc analysis from the PACIFC trials, symptomatic patients underwent [ 15 O]H 2 O positron emission tomography (PET) and invasive fractional flow reserve (FFR) before and after revascularization. Coronary flow reserve (CFR) from PET and invasive FFR were used to calculate MRR., Results: Among 52 patients (87 % male, age 59.4 ± 9.4 years), 61 vessels with a median FFR of 0.71 (95 % confidence interval: 0.55 to 0.74) and a mean MRR of 3.80 ± 1.23 were included. Following PCI, FFR, hyperemic myocardial blood flow (hMBF) and CFR increased significantly (all p-values ≤0.001). MRR remained unchanged after PCI (3.80 ± 1.23 before PCI versus 3.60 ± 0.97 after PCI; p=0.23). In vessels with a pre-PCI, FFR ≤0.70 pre- and post-PCI MRR were 3.90 ± 1.30 and 3.73 ± 1.14 (p=0.56), respectively. Similar findings were observed for vessels with a FFR between 0.71 and 0.80 (pre-PCI MRR 3.70 ± 1.17 vs. post PCI MRR 3.48 ± 0.76, p=0.19)., Conclusions: Our study indicates that MRR, assessed using a hybrid approach of PET and invasive FFR, is independent of the severity of epicardial stenosis. These findings suggest that MRR is a microvasculature-specific parameter., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that reduces postprandial glycemic excursions by enhancing insulin secretion. In this study, a new dimeric GLP-1 analogue (GLP-1cpGLP-1) was designed by inserting human insulin C-peptide (CP) in the middle of a dimer of [Gly8] GLP-1 (7-36). Then, the dimeric incretin (GLP-1cpGLP-1) was ligated to human αB-crystallin (αB-Cry) to create a hybrid protein, abbreviated as αB-GLP-1cpGLP-1. The constructed gene was well expressed in the bacterial host system. After specific chemical release from the hybrid protein, the dimeric incretin was purified by size exclusion chromatography (SEC). Finally, the RP-HPLC analysis indicated a purity of >99 % for the dimeric incretin. The secondary structure assessments by various spectroscopic methods, and in silico analysis suggested that the dimeric incretin has α-helical rich structure. The dynamic light scattering (DLS) analysis indicates that our dimeric incretin forms large oligomeric structures. This incretin analogue significantly reduced blood glucose levels in both healthy and diabetic mice while effectively triggering insulin release. The size exclusion HPLC also indicates the interaction of the new incretin analogue with human serum albumin, the main carrier protein in the bloodstream. Consistent with the results obtained from the biological activity assessments, this significant interaction indicates its potential as a viable therapeutic agent with a long-lasting effect. The results of our research represent a significant breakthrough in the successful design of an active incretin dimer capable of effectively controlling blood sugar levels and inducing insulin secretion in the realm of diabetes treatment., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Background: This study aimed to assess the prognosis of people with chronic kidney disease (CKD) in Japan using the Kidney Disease: Improving Global Outcomes (KDIGO) heatmap., Methods: The prognoses of individuals with estimated glomerular filtration rates (eGFR) <90 mL/min/1.73 m 2 were evaluated based on the KDIGO heatmap using an electronic medical record database in Japan. The primary outcome was major adverse cardiovascular events (MACE), a composite of myocardial infarction (MI), stroke, heart failure (HF) hospitalization and in-hospital death (referred to as MACE1). Additionally, ad hoc MACE2 (MI hospitalization, stroke hospitalization, HF hospitalization and in-hospital death) was examined. The secondary outcome was the renal outcome., Results: Of the 543 606 individuals included, the mean age was 61.6 ± 15.3 years, 50.1% were male and 40.9% lacked urine protein results. The risk of MACEs increased independently with both eGFR decline and increasing proteinuria from the early KDIGO stages: hazard ratios (95% confidence interval) of MACE1 and MACE2, compared with G2A1 were 1.16 (1.12-1.20) and 1.17 (1.11-1.23), respectively, for G3aA1, and 1.17 (1.12-1.21) and 1.35 (1.28-1.43), respectively, for G2A2. This increased up to 2.83 (2.54-3.15) and 3.43 (3.00-3.93), respectively, for G5A3. Risks of renal outcomes also increased with CKD progression., Conclusions: This study is the first to demonstrate the applicability of the KDIGO heatmap in assessing cardiovascular and renal risk in Japan. The risk increased from the early stages of CKD, indicating the importance of early diagnosis and intervention through appropriate testing., Competing Interests: The study was sponsored by AstraZeneca KK. H.A., M.H. and A.O. are employees of AstraZeneca KK. S.I., S.K. and K.S. are employees of Real World Data Co., Ltd, a healthcare analytics company that received funding for this research from AstraZeneca KK. S.M. and T.T. have received fees for lectures by AstraZeneca KK., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

To study plant organs, it is necessary to investigate the three-dimensional (3D) structures of plants. In recent years, non-destructive measurements through computed tomography (CT) have been used to understand the 3D structures of plants. In this study, we use the Chrysanthemum seticuspe capitulum inflorescence as an example and focus on contact points between the receptacles and florets within the 3D capitulum inflorescence bud structure to investigate the 3D arrangement of the florets on the receptacle. To determine the 3D order of the contact points, we constructed slice images from the CT volume data and detected the receptacles and florets in the image. However, because each CT sample comprises hundreds of slice images to be processed and each C. seticuspe capitulum inflorescence comprises several florets, manually detecting the receptacles and florets is labor-intensive. Therefore, we propose an automatic contact point detection method based on CT slice images using image recognition techniques. The proposed method improves the accuracy of contact point detection using prior knowledge that contact points exist only around the receptacle. In addition, the integration of the detection results enables the estimation of the 3D position of the contact points. According to the experimental results, we confirmed that the proposed method can detect contacts on slice images with high accuracy and estimate their 3D positions through clustering. Additionally, the sample-independent experiments showed that the proposed method achieved the same detection accuracy as sample-dependent experiments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Matsumoto, Utsumi, Kozuka, Iwamura, Nakai, Yamauchi, Karahara, Mineyuki, Hoshino, Uesugi and Kise.)

Objective: Unrecognized myocardial infarction (UMI) on delayed-enhancement cardiac magnetic resonance imaging (DE-CMR) and coronary computed tomography angiography (CCTA) derived high-risk features provide prognostic information in patients with chronic coronary syndrome (CCS). The study aimed to assess the prognostic value of UMI and predictors of UMI using CCTA in patients with CCS who underwent elective percutaneous coronary intervention (PCI)., Methods: This study enrolled 181 patients with CCS who underwent DE-CMR and CCTA before elective PCI. The CCTA-derived predictors of UMI and the association of baseline clinical characteristics, CCTA findings, and CMR-derived factors, including UMI, with MACEs, defined as death, nonfatal myocardial infarction, unplanned late revascularization, hospitalization for congestive heart failure, and stroke, were investigated., Results: UMI was detected in 57 (31.5%) patients. ROC analysis revealed that the optimal cut-off values of Agatston score and mean peri-coronary fat attenuation index (FAI) for predicting the presence of UMI were 397 and -69.8, respectively. The multivariable logistic regression analysis revealed that left ventricular mass, Agatston score >397, mean FAI >-69.8, positive remodeling of the target lesion, and CCTA-derived stenosis severity were independent predictors of UMI. Kaplan-Meier analysis revealed that patients with UMI were associated with increased risk of MACEs. The Cox proportional hazards analysis showed post-PCI minimum lumen diameter and the presence of UMI were independent predictors of MACEs. The risk of MACEs significantly increased according to the number of four preprocedural CCTA-relevant features of UMI., Conclusion: Preprocedural comprehensive CCTA analysis may help predict the presence of UMI and provide prognostic information in patients with CCS who underwent PCI., Competing Interests: Competing interests The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Hellenic Society of Cardiology. Published by Elsevier Inc. All rights reserved.)

Background: Systemic inflammatory response is significant prognostic indicator in patients with various diseases. The relationship between prognostic scoring systems based on the modified Glasgow Prognostic Score (mGPS) and achalasia in patients treated with laparoscopic Heller‑myotomy with Dor‑fundoplication (LHD) remains uninvestigated. This study aimed to examine the role of mGPS in patients with achalasia., Methods: 457 patients with achalasia who underwent LHD as the primary surgery between September 2005 and December 2020 were included. We divided patients into the mGPS 0 and mGPS 1 or 2 groups and compared the patients' background, pathophysiology, symptoms, surgical outcomes, and postoperative course., Results: mGPS was 0 in 379 patients and 1 or 2 in 78 patients. Preoperative vomiting and pneumonia were more common in patients with mGPS of 1 or 2. There were no differences in surgical outcomes. Postoperative upper gastrointestinal endoscopy revealed that severe esophagitis was more frequently observed in patients with mGPS of 1 or 2 (P < 0.01). The clinical success was 91% and 99% in the mGPS 0 and mGPS 1 or 2 groups, respectively (P < 0.01)., Conclusions: Although severe reflux esophagitis was more common in patients with achalasia with a high mGPS, good clinical success was obtained regardless of the preoperative mGPS., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

To date, several pathogenic mutations have been identified in the primary structure of human α-Crystallin, frequently involving the substitution of arginine with a different amino acid. These mutations can lead to the incidence of cataracts and myopathy. Recently, an important cataract-associated mutation has been reported in the functional α-Crystallin domain (ACD) of human αB-Crystallin protein, where arginine 107 (R107) is replaced by a leucine. In this study, we investigated the structure, chaperone function, stability, oligomerization, and amyloidogenic properties of the p.R107L human αB-Crystallin using a number of different techniques. Our results suggest that the p.R107L mutation can cause significant changes in the secondary, tertiary, and quaternary structures of αB-Crystallin. This cataractogenic mutation led to the formation of protein oligomers with larger sizes than the wild-type protein and reduced the chemical and thermal stability of the mutant chaperone. Both fluorescence and microscopic assessments indicated that this mutation significantly altered the amyloidogenic properties of human αB-Crystallin. Furthermore, the mutant protein indicated an attenuated in vitro chaperone activity. The molecular dynamics (MD) simulation confirmed the experimental results and indicated that p.R107L mutation could alter the proper conformation of human αB-Crystallin dimers. In summary, our results indicated that the p.R107L mutation could promote the formation of larger oligomers, diminish the stability and chaperone activity of human αB-Crystallin, and these changes, in turn, can play a crucial role in the development of cataract disorder., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Introduction: Mucormycosis presents a diagnostic challenge characterized by high morbidity and mortality rates due to its swift and pervasive nature, which leads to extensive tissue destruction and dissemination. Immunocompromised individuals, notably those with hematological malignancies, are at a heightened risk. First-line antifungal agents include liposomal amphotericin B (L-AMB), posaconazole, and isavuconazole (IVZ), which offer advantages, such as minimal drug interactions and a favorable safety profile. However, the necessity and efficacy of therapeutic drug monitoring (TDM) of IVZ remain unclear., Case Presentation: We report a successful case of IVZ therapy in a patient who was intolerant of L-AMB, highlighting the efficacy and pharmacokinetics of IVZ in treating pulmonary mucormycosis. Pharmacokinetic analysis revealed steady plasma IVZ concentrations, emphasizing the importance of monitoring IVZ levels, particularly in patients undergoing renal replacement therapy., Conclusion: This case highlights the efficacy of IVZ therapy for mucormycosis and the potential utility of TDM in a specific patient population. Further research is needed to elucidate the optimal IVZ dosing and monitoring strategies to ensure safe and efficacious treatment., (© 2024 S. Karger AG, Basel.)

Background: This study investigated the prognostic value of cardiovascular magnetic resonance (CMR)-derived global coronary flow reserve (G-CFR) in addition to cardiopulmonary exercise testing (CPET) variables in patients with acute myocardial infarction (AMI). Methods and Results: We investigated 127 patients with AMI who underwent primary or urgent percutaneous coronary intervention (PCI) and post-intervention CMR and CPET. The incidence of major cardiac and cerebrovascular events (MACCE), defined as all-cause death, recurrent non-fatal myocardial infarction, re-hospitalization due to congestive heart failure, and stroke, was evaluated (median follow-up, 2.8 years). Patients with MACCE (n=14) had lower ejection fraction (EF) (50 [43-59] vs. 58 [51-63]%; P=0.014), lower G-CFR (1.74 [1.19-2.20] vs. 2.40 [1.61-3.66]; P=0.008), and lower peak oxygen consumption (V̇O 2 ) (15.16±2.64 vs. 17.19±3.70 mL/kg/min; P=0.049) than patients without MACCE. G-CFR<2.33 and peak V̇O 2 <15.65 mL/kg/min (cut-off values derived from receiver operating characteristic curve analyses) were significantly associated with the incidence of MACCE (log-rank test, P=0.01). The combination of low G-CFR and low peak V̇O 2 improved risk discrimination for MACCE when added to the reference clinical model including age, male sex, post-PCI peak creatine kinase, EF, and left anterior descending artery culprit lesion. Conclusions: G-CFR and peak V̇O 2 showed incremental prognostic information compared with the reference model using historically important clinical risk factors, indicating that this approach may help identify high-risk patients who suffer subsequent adverse events., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Background: The hyperaemic stenosis resistance (HSR) index was introduced to provide a more comprehensive indicator of the haemodynamic severity of a coronary lesion. HSR combines both the pressure drop across a lesion and the flow through it. As such, HSR overcomes the limitations of the more traditional fractional flow reserve (FFR) or coronary flow reserve (CFR) indices., Aims: We aimed to identify the diagnostic and prognostic value of HSR and evaluate the clinical implications., Methods: Patients with chronic coronary syndromes (CCS) and obstructive coronary artery disease were selected from the multicentre ILIAS Registry. For this study, only patients with combined Doppler flow and pressure measurements were included., Results: A total of 853 patients with 1,107 vessels were included. HSR more accurately identified the presence of inducible ischaemia compared to FFR and CFR (area under the curve 0.71 vs 0.66 and 0.62, respectively; p<0.005 for both). An abnormal HSR measurement was an independent and important predictor of target vessel failure at 5-year follow-up (hazard ratio 3.80, 95% confidence interval: 2.12-6.73; p<0.005). In vessels deferred from revascularisation, HSR seems to identify more accurately those vessels that may benefit from revascularisation rather than FFR and/or CFR., Conclusions: The present study affirms the theoretical advantages of the HSR index for the detection of ischaemia-Âinducing coronary lesions in a large CCS population. (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry [ILIAS Registry], ClinicalTrials.gov: NCT04485234).

Importance: The associations between angiographic findings and post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) and their clinical relevance according to residual functional disease burden have not been thoroughly investigated., Objectives: To evaluate the association of angiographic and physiologic parameters according to residual functional disease burden after drug-eluting stent implantation., Design, Setting, and Participants: This cohort study population was from the International Post-PCI FFR registry, which incorporated 4 registries from Korea, China, and Japan. Patients who underwent angiographically successful second-generation drug-eluting stent implantation and post-PCI FFR measurement were included in the analysis. The patients were divided into 3 groups according to the residual disease burden (post-PCI FFR ≤0.80 [residual ischemia], 0.81-0.86 [suboptimal], and >0.86 [optimal]). The data were collected from August 23, 2018, to June 11, 2019, and the current analysis was performed from January 11, 2022, to October 7, 2023., Exposures: Angiographic parameters and post-PCI FFR., Main Outcomes and Measures: The primary outcome was target vessel failure (TVF), defined as a composite of cardiac death, target vessel-related myocardial infarction, and target vessel revascularization (TVR) at 2 years., Results: In this cohort of 2147 patients, the mean (SD) age was 64.3 (10.0) years, and 1644 patients (76.6%) were men. Based on the post-PCI physiologic status, 269 patients (12.5%) had residual ischemia, 551 (25.7%) had suboptimal results, and 1327 (61.8%) had optimal results. Angiographic parameters had poor correlations with post-PCI FFR (r < 0.20). Post-PCI FFR was isolated from all angiographic parameters in the unsupervised hierarchical cluster analysis. Post-PCI FFR was associated with the occurrence of TVF (adjusted hazard ratio [AHR] per post-PCI FFR 0.01 increase, 0.94 [95% CI, 0.92-0.97]; P < .001), but angiographic parameters were not. The residual ischemia group had a significantly higher rate of TVF than the suboptimal group (AHR, 1.75 [95% CI, 1.08-2.83]; P = .02) and the optimal group (AHR, 2.94 [95% CI, 1.82-4.73]; P < .001). The TVR in the residual ischemia group was predominantly associated with TVR in the nonstented segment (14 [53.8%]), unlike the other 2 groups (3 [10.0%] in the suboptimal group and 13 [30.2%] in the optimal group)., Conclusions and Relevance: In this cohort study of the International Post-PCI FFR registry, a low degree of associations were observed between angiographic and physiologic parameters after PCI. Post-PCI FFR, unlike angiographic parameters, was associated with clinical events and the distribution of clinical events. The current study supports the use of post-PCI FFR as a procedural quality metric and further prospective study is warranted.

Purpose: Nusinersen is an antisense oligonucleotide for the treatment of spinal muscular atrophy (SMA). A post-marketing surveillance (PMS) has been ongoing (August 2017-August 2025) in all patients in Japan who received intrathecal nusinersen in real-world clinical settings. We report the interim analysis results of safety and effectiveness. Methods: This interim analysis was conducted using data collected from 401 patients whose case report forms were obtained at least once by 30 May 2020. Collected data included patient demographics and adverse events (AEs) for safety, and motor function assessments and Clinical Global Impressions of Improvement (CGI-I) for effectiveness. Results: All 401 patients were diagnosed with SMA and were included in the safety and effectiveness analysis (infantile-onset SMA [ n  = 126, 31.4%], later-onset SMA [ n  = 275, 68.6%]). The median duration of treatment was 330 days (range 1-823 days). The incidence proportion of AEs was 31.7% (37.3% in infantile-onset SMA and 29.1% in later-onset SMA). The most common AEs were headache (4.5%), pyrexia (4.2%), and pneumonia (3.7%). The incidence proportion of serious AEs was 11.5%. Nusinersen improved motor function scores and was assessed as 'effective' based on CGI-I in 99.7-100% of patients. Conclusions: This interim analysis of the PMS in Japanese patients treated with nusinersen found no new safety concerns, with the type of AEs consistent with the expected safety profile. The benefit-risk balance of nusinersen treatment remains favorable.

Study Design: Retrospective single-center study., Purpose: This study aimed to examine the factors associated with the self-image domain of the Scoliosis Research Society-22 revised (SRS-22r) in patients who underwent corrective surgery for adult idiopathic scoliosis (AdIS)., Overview of Literature: Adult spinal deformity (ASD) can be classified into AdIS and de novo scoliosis. However, no studies have investigated the effect of different ASD pathologies on self-image., Methods: This study enrolled 60 patients who underwent corrective surgery and were followed up for >2 years postoperatively. AdIS was defined as adolescent idiopathic scoliosis in patients who had no history of corrective surgery, had a primary thoracolumbar/lumbar (TL/L) curve, and were ≥30 years old at the time of surgery., Results: The AdIS (n=23; mean age, 53.1 years) and de novo (n=37; mean age, 70.0 years) groups were significantly different in terms of the main thoracic and TL/L curves, sagittal vertical axis, thoracic kyphosis, and thoracolumbar kyphosis preoperatively. The scores in the self-image domain of the SRS-22r (before surgery/2 years after surgery [PO2Y]) were 2.2/4.4 and 2.3/3.7 in the AdIS and de novo groups, respectively, and PO2Y was significantly different between the two groups (p<0.001). Multivariate regression analysis revealed that AdIS was an independent factor associated with self-image at PO2Y (p=0.039)., Conclusions: AdIS, a spinal deformity pathology, was identified as a significant factor associated with the self-image domain of SRS-22r in patients who underwent corrective surgery. AdIS is not solely classified based on pathology but also differs in terms of the clinical aspect of self-image improvement following corrective surgery.

Background: Fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) provides prognostic information, but limited data are available regarding prognostication using post-PCI coronary flow reserve (CFR). In this study we aimed to assess the prognostic value of post-procedural FFR and CFR for target vessel failure (TVF) after PCI., Methods and results: This lesion-based post-hoc pooled analysis of previously published registry data involved 466 patients with chronic coronary syndrome with single-vessel disease who underwent pre- and post-PCI FFR and CFR measurements, and were followed-up to determine the predictors of TVF. The prognostic value of post-PCI CFR and FFR was compared with that of FFR or CFR alone. Post-PCI FFR/CFR discordant results were observed in 42.5%, and 10.3% of patients had documented TVF. Receiver-operating characteristic curve analysis revealed that the optimal cutoff values of post-PCI FFR and CFR to predict the occurrence of TVF were 0.85 and 2.26, respectively. Significant differences in TVF were detected according to post-PCI FFR (≤0.85 vs. >0.85, P=0.007) and post-PCI CFR (<2.26 vs. ≥2.26, P<0.001). Post-PCI FFR ≤0.85 and post-PCI CFR <2.26 were independent prognostic predictors., Conclusions: After PCI completion, discordant results between FFR and CFR were not uncommon. Post-PCI CFR categorization showed incremental prognostic value for predicting TVF independent of post-PCI FFR risk stratification.

Study Design: Retrospective cohort study., Objective: To assess the utility of preoperative vertebral bone quality (VBQ) scores in predicting the 5-year clinical outcomes following lumbar spine surgery., Summary of Background Data: Osteoporosis poses a significant concern in older adults undergoing spinal surgery. The VBQ score, assessed through preoperative magnetic resonance imaging (MRI), is associated with subsequent osteoporotic fractures and postoperative complications. However, previous report on the impact of VBQ score on mid-term clinical outcomes after lumbar spine surgery remains lacking., Methods: A total of 189 patients who underwent lumbar surgery (≤3-disc levels) for lumbar spinal stenosis between 2010 and 2016 were enrolled. Patients were classified into high (>3.35), middle (2.75 to 3.35), and low (<2.73) VBQ score groups based on tertiles. Clinical scores, including Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ) and Short Form-36 (SF-36), were recorded preoperatively and 1, 2, and 5 years postoperatively., Results: Comparative analysis showed significant differences among the VBQ groups throughout the study period in low back pain (P=0.013), walking ability (P=0.005), social life function (P=0.010) of JOABPEQ, and physical component summary of the SF-36 (P=0.018) following lumbar spine surgery. A higher VBQ score was significantly correlated with worse 5-year postoperative outcomes for all domains except for lumbar function of the JOABPEQ using multiple linear regression analysis, adjusting for age, sex, BMI, hyperlipidemia, surgical procedures, and each preoperative score., Conclusion: A high preoperative VBQ score is a risk factor for poor 5-year clinical outcomes after lumbar spine surgery. Evaluation of the VBQ score through routine preoperative MRI facilitates osteoporotic screening in lumbar patients without radiation exposure and healthcare costs, while also demonstrating its potential as a prognostic indicator of postoperative clinical outcomes., Level of Evidence: 3., Competing Interests: Conflicts of Interest and Source of Funding: None declared, (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Vessel-level physiological data derived from pressure wire measurements are one of the important determinant factors in the optimal revascularisation strategy for patients with multivessel disease (MVD). However, these may result in complications and a prolonged procedure time., Aims: The feasibility of using the quantitative flow ratio (QFR), an angiography-derived fractional flow reserve (FFR), in Heart Team discussions to determine the optimal revascularisation strategy for patients with MVD was investigated., Methods: Two Heart Teams were randomly assigned either QFR- or FFR-based data of the included patients. They then discussed the optimal revascularisation mode (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) for each patient and made treatment recommendations. The primary endpoint of the trial was the level of agreement between the treatment recommendations of both teams as assessed using Cohen's kappa., Results: The trial included 248 patients with MVD from 10 study sites. Cohen's kappa in the recommended revascularisation modes between the QFR and FFR approaches was 0.73 [95% confidence interval {CI} : 0.62-0.83]. As for the revascularisation planning, agreements in the target vessels for PCI and CABG were substantial for both revascularisation modes (Cohen's kappa=0.72 [95% CI: 0.66-0.78] and 0.72 [95% CI: 0.66-0.78], respectively). The team assigned to the QFR approach provided consistent recommended revascularisation modes even after being made aware of the FFR data (Cohen's kappa=0.95 [95% CI:0.90-1.00])., Conclusions: QFR provided feasible physiological data in Heart Team discussions to determine the optimal revascularisation strategy for MVD. The QFR and FFR approaches agreed substantially in terms of treatment recommendations.

Schizophrenia is a syndrome with multiple etiologies, one of which is the potential for an autoimmune disease of the brain such as N-methyl-d-aspartate receptor (NMDAR) encephalitis, which can induce psychosis resembling schizophrenia. Here, we examined anti-neuronal autoantibodies related to psychosis using both cell- (CBA) and tissue-based assays (TBA) in the cerebrospinal fluid (CSF) of patients with chronic schizophrenia and control participants. First, we screened for the antibodies against leucine-rich glioma-inactivated 1 (LGI1), γ-aminobutyric acid B receptor (GABABR), dipeptidyl aminopeptidase-like protein 6 (DPPX), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR1/R2), and contactin-associated protein-like 2 (CASPR2) in 148 patients with schizophrenia. No antibodies were detected. Next, we performed CBA for NMDAR antibodies in 148 patients with schizophrenia and 151 age- and sex-matched controls. Although we detected relatively weak immunoreactivity for NMDAR in the CSFs of two patients with schizophrenia and three controls, no samples were positive when strict criteria were applied. For TBA in the rat hippocampus and cerebellum, we detected positive signals in the CSFs of 13 patients with schizophrenia and eight controls. Positive samples were analyzed for paraneoplastic syndrome and antinuclear antibodies using immunoblotting. The CSFs of nine patients and six controls were positive for dense fine speckle 70 (DFS70) antibodies. Additionally, antibodies against centromere protein (CENP)-A and CENP-B were detected in patients with schizophrenia. Our results suggest that autoantibodies against NMDAR, LG1, GABABR, DPPX, AMPAR1/R2, and CASPR2 are not associated with the pathogenesis of chronic schizophrenia. Moreover, we emphasize the importance of considering the effect of anti-DFS70 antibodies when analyzing autoantibodies in CSF samples. Conclusively, we obtained no evidence suggesting that the most frequent neuronal autoantibodies in the CSF play a role in the pathogenesis of schizophrenia, even in our sample., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The microvascular resistance reserve (MRR) is an innovative index to assess the vasodilatory capacity of the coronary circulation while accounting for the presence of concomitant epicardial disease. The MRR has shown to be a valuable diagnostic and prognostic tool in the general coronary artery disease (CAD) population. However, considering the fundamental aspects of its assessment and the unique hemodynamic characteristics of women, it is crucial to provide additional considerations for evaluating the MRR specifically in women., Aim: The aim of this study was to assess the diagnostic and prognostic applicability of the MRR in women and assess the potential differences across different sexes., Methods: From the ILIAS Registry, we enrolled all patients with a stable indication for invasive coronary angiography, ensuring complete physiological and follow-up data. We analyzed the diagnostic value by comparing differences between sexes and evaluated the prognostic value of the MRR specifically in women, comparing it to that in men., Results: A total of 1494 patients were included of which 26% were women. The correlation between MRR and CFR was good and similar between women (r = 0.80, p < 0.005) and men (r = 0.81, p < 0.005). The MRR was an independent and important predictor of MACE in both women (HR 0.67, 0.47-0.96, p = 0.027) and men (HR 0.84, 0.74-0.95, p = 0.007). The optimal cut-off value for MRR in women was 2.8 and 3.2 in men. An abnormal MRR similarly predicted MACE at 5-year follow-up in both women and men., Conclusion: The MRR seems to be equally applicable in both women and men with stable coronary artery disease., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Sarcopenia and osteoporosis substantially influence health and lifespan. However, the variables affecting skeletal muscle mass (SMM) or bone mineral density (BMD) remain unknown., Design and Methods: From August 1, 2018 to July 31, 2019, we conducted a single-center, observational cohort study with 291 Japanese adult patients on maintenance hemodialysis due to end-stage kidney disease, who had their femoral neck BMD measured using dual-energy X-ray absorptiometry. After 1-year follow-up, we measured annual changes of BMD (ΔBMD) and SMM (ΔSMM), which were calculated through a modified creatinine index (mg/kg/day) using age, sex, serum creatinine, and single-pooled Kt/V for urea. The factors associated with ΔSMM/ΔBMD or progressive loss of SMM/BMD, defined as ΔSMM/ΔBMD < 0 per year, respectively, were analyzed with multivariable, linear regression or logistic regression models., Results: The median age of the patients was 66 years and 33% were female. Dialysis vintage and β-blocker-use were inversely correlated to ΔSMM. In comparison to nonusers, β-blockers users had 2.5-fold higher SMM loss odd ratios [95% confidence interval, 1.3-4.8]. The risk for SMM loss caused by β-blockers was not increased in users of renin-angiotensin system inhibitors. The ΔBMD was negatively correlated to the usage of calcium channel blockers. The risk of developing osteosarcopenia, which was defined as annual loss of both SMM and BMD, increased in calcium channel blockers users., Conclusions: The use of β-blockers is associated with an elevated risk of developing sarcopenia, whereas renin-angiotensin system inhibitors may minimize this effect in patients with end-stage kidney disease. Use of calcium channel blocker therapy was associated with a faster decline of BMD., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Few studies have assessed the minimum clinically important difference (MCID) of each Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) domain. This study assessed MCIDs of JOABPEQ in patients with lumbar spine disease by generation., Methods: We evaluated the JOABPEQ score of 805 consecutive patients with lumbar spine disease undergoing posterior surgery preoperatively and 1 year postoperatively. MCIDs of each JOABPEQ domain were determined using anchor- and distribution-based methods according to age. A question based on the concept of a health transition item was used as the anchor for the MCID decision., Results: Overall, MCIDs of the JOABPEQ were 28.6 and 27.3 points for pain-related disorder and gait disturbance, respectively. The MCID for the lumbar spine dysfunction domain did not reach 0.6 over the area under the curve. Regarding the differences among generations, MCIDs of pain-related disorder and gait disturbance domains differed slightly between the elderly and middle-aged. The psychological disorder domain did not reflect clinically meaningful changes in the elderly. MCIDs of the social life disturbance domain decreased with age., Conclusions: Focusing on achieving the ideal responsiveness of patient-reported outcomes across generations, MCIDs of the pain-related disorder and gait disturbance domains may be valuable for patients, regardless of age, when adopting the JOABPEQ for patients with lumbar spine disease undergoing surgery. This study only evaluated cases that underwent posterior lumbar surgery. Future research will necessitate conducting surveys concerning the outcomes of various treatments for lumbar spine disease., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2024 The Japanese Society for Spine Surgery and Related Research.)

The eye lens is responsible for focusing objects at various distances onto the retina and its refractive power is determined by its surface curvature as well as its internal gradient refractive index (GRIN). The lens continues to grow with age resulting in changes to the shape and to the GRIN profile. The present study aims to investigate how the ageing process may influence lens optical development. Murine lenses of accelerated senescence-prone strain (SAMP8) aged from 4 to 50 weeks; senescence-resistant strain (SAMR1) aged from 5 to 52 weeks as well as AKR strain (served as control) aged from 6 to 70 weeks were measured using the X-ray interferometer at the SPring-8 synchrotron Japan within three consecutive years from 2020 to 2022. Three dimensional distributions of the lens GRIN were reconstructed using the measured data and the lens shapes were determined using image segmentation in MatLab. Variations in the parameters describing the lens shape and the GRIN profile with age were compared amongst three mouse strains. With advancing age, both the lens anterior and posterior surface flattens and the lens sagittal thickness increase in all three mouse strains (Anterior radius of curvature increase at 0.008 mm/week, 0.007 mm/week and 0.002 mm/week while posterior radius of curvature increase at 0.002 mm/week, 0.007 mm/week and 0.003 mm/week respectively in AKR, SAMP8 and SAMR1 lenses). Compared with the AKR strain, the SAMP8 samples demonstrate a higher rate of increase in the posterior curvature radius (0.007 mm/week) and the thickness (0.015 mm/week), whilst the SAMR1 samples show slower increases in the anterior curvature radius (0.002 mm/week) and its thickness (0.013 mm/week). There are similar age-related trends in GRIN shape in the radial direction (in all three types of murine lenses nr2 and nr6 increase with age while nr4 decrease with age consistently) but not in the axial direction amongst three mouse strains (nz1 of AKR lens decrease while of SAMP8 and SAMR1 increase with age; nz2 of all three models increase with age; nz3 of AKR lens increase while of SAMP8 and SAMR1 decrease with age). The ageing process can influence the speed of lens shape change and affect the GRIN profile mainly in the axial direction, contributing to an accelerated decline rate of the optical power in the senescence-prone strain (3.5 D/week compared to 2.3 D/week in the AKR control model) but a retardatory decrease in the senescence-resistant strain (2.1 D/week compared to the 2.3D/week in the AKR control model)., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Coronary flow velocity reserve (CFVR) can be measured noninvasively using stress transthoracic Doppler echocardiography (S-TDE). The prognostic significance of S-TDE-derived CFVR after percutaneous coronary intervention (PCI) remains unknown. The aim of this study was to investigate the prognostic value of post-PCI CFVR and its additional efficacy to fractional flow reserve (FFR) in patients undergoing elective PCI., Methods: A retrospective study was conducted involving 187 consecutive patients with chronic coronary syndrome who underwent elective PCI guided by FFR for the left anterior descending coronary artery. Pre- and post-PCI wire-based FFR and CFVR assessments of the left anterior descending coronary artery using S-TDE were performed in all patients. The association between post-PCI clinical and physiologic parameters and major adverse cardiac events (MACE), defined as a composite of cardiac death, myocardial infarction, heart failure, and unplanned remote target vessel revascularization, was evaluated., Results: Three-quarters of patients exhibited CFVR increase after PCI, while all patients showed FFR improvement. During a median follow-up period of 1.5 years, MACE occurred in 21 patients (11.2%). Among clinical demographics, patients with MACE had higher levels of N-terminal pro-brain natriuretic peptide compared with those without MACE (median, 615 pg/mL [interquartile range, 245-1,500 pg/mL] vs 180 pg/mL [interquartile range, 70-559 pg/mL]; P = .010). Post-PCI S-TDE-derived CFVR was lower in patients with MACE, while post-PCI FFR showed a nonsignificant tendency to be lower in patients with MACE. In a multivariable analysis, higher NT-proBNP (adjusted hazard ratio, 1.33; 95% CI, 1.02-1.74; P = .038), post-PCI CFVR ≤ 2.0 (adjusted hazard ratio, 2.93; 95% CI, 1.16-7.40; P = .023), and post-PCI FFR ≤ 0.82 (adjusted hazard ratio, 3.93; 95% CI, 1.52-10.18; P = .005) were independently associated with MACE., Conclusions: In patients with chronic coronary syndrome who underwent successful elective PCI for left anterior descending coronary artery, the combined assessment of S-TDE-derived post-PCI CFVR and post-PCI FFR provided a significant association with the occurrence of MACE., Competing Interests: Conflicts of Interest None., (Copyright © 2023 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Insulin fibrillation poses a significant challenge in the development and treatment of diabetes. Current efforts to unravel its mechanisms have thus far remained incomplete. To shed light on the intricate processes behind insulin fibrillation, we employed mutagenesis techniques to introduce additional positive charge residues into the C-terminal region of the insulin B chain which plays an important role in insulin dimerization. We employed our investigation with various spectroscopic methods, electron microscopy, and molecular dynamics simulations. These methods allowed us to explore the structure and fibrillation behavior of the engineered B chains following their expression in a bacterial host and successful purification. This manipulation had a pronounced impact on the oligomerization behavior of the insulin B chain. It appears that these mutations delay the formation of the dimeric state in the process of transitioning to larger oligomers, consequently, leading to an alteration in the kinetics of fibrillation. Our findings also indicated that the mutant insulin B chains (Di-R, Di-K, and Di-H) displayed resistance to the initiation of fibrillation. This resistance can be attributed to the repulsive forces generated by the introduced positive charges, which disrupt the attractive interactions favoring nucleation. Notably, the mutant B chains formed shorter and less abundant oligomers and fibrils, which can be ascribed to the alterations induced by repulsion. Our engineered mutant B chains exhibited enhanced stability against stress-induced fibrillation, hinting at their potential utility in the development of new insulin analogs. This study underscores the significance of the C-terminal region in the initial stages of insulin B chain fibrillation, providing valuable insights into the intricate mechanisms involved and their potential pharmaceutical applications., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024. Published by Elsevier B.V.)

αB-crystallin, a member of the small heat shock protein (sHSP) family, is expressed in diverse tissues, including the eyes, brain, muscles, and heart. This protein plays a crucial role in maintaining eye lens transparency and exhibits holdase chaperone and anti-apoptotic activities. Therefore, structural and functional changes caused by genetic mutations in this protein may contribute to the development of disorders like cataract and cardiomyopathy. Recently, the substitution of arginine 123 with tryptophan (p.R123W mutation) in human αB-crystallin has been reported to trigger cardiomyopathy. In this study, human αB-crystallin was expressed in Escherichia coli (E. coli), and the missense mutation p.R123W was created using site-directed mutagenesis. Following purification via anion exchange chromatography, the structural and functional properties of both proteins were investigated and compared using a wide range of spectroscopic and microscopic methods. The p.R123W mutation induced significant alterations in the secondary, tertiary, and quaternary structures of human αB-crystallin. This pathogenic mutation resulted in an increased β-sheet structure and formation of protein oligomers with larger sizes compared to the wild-type protein. The mutant protein also exhibited reduced chaperone activity and lower thermal stability. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) demonstrated that the p.R123W mutant protein is more prone to forming amyloid aggregates. The structural and functional changes observed in the p.R123W mutant protein, along with its increased propensity for aggregation, could impact its proper functional interaction with the target proteins in the cardiac muscle, such as calcineurin. Our results provide an explanation for the pathogenic intervention of p.R123W mutant protein in the occurrence of hypertrophic cardiomyopathy (HCM)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Reza Yousefi reports financial support was provided by Iran National Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The substitution of leucine to proline at position 39 (p.P39L) in human αB-crystallin (αB-Cry) has been associated with conflicting interpretations of pathogenicity in cataracts and cardiomyopathy. This study aimed to investigate the effects of the p.P39L mutation on the structural and functional features of human αB-Cry. The mutant protein was expressed in Escherichia coli (E. coli) and purified using anion exchange chromatography. We employed a wide range of spectroscopic analyses, gel electrophoresis, transmission electron microscopy (TEM), and atomic force microscopy (AFM) techniques to investigate the structure, function, stability, and fibrillation propensity of the mutant protein. The p.P39L mutation caused significant changes in the secondary, tertiary, and quaternary structures of human αB-Cry and increased the thermal stability of the protein. The mutant αB-Cry exhibited an increased chaperone activity and an altered oligomeric size distribution, along with an increased propensity to form amyloid aggregates. It is worth mentioning, increased chaperone activity has important positive and negative effects on damaged cells related to cataracts and cardiomyopathy, particularly by interfering in the process of apoptosis. Despite the apparent positive nature of the increased chaperone activity, it is also linked to adverse consequences. This study provides important insights into the effect of proline substitution by leucine at the N-terminal region on the dual nature of chaperone activity in human αB-Cry, which can act as a double-edged sword., (© 2024. The Author(s).)

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature., Competing Interests: HH, HS, SH, GS, YT, MT, MI, MS, IH, KH, MH, AN, YM, SO, MM, AU, YK, AM, KN, SK, TS, TI, HN, YG, MR, TT, KY, NT, HK, JI, IN, TK, TT, MD, HN, KT, KS, KN, TT, HF, YS, KY, LR, NH, HM, TY, SW, TA, KT, TN, HK, FH, AH, HH, KT, TT, TK, TK, IG, GC, NA, HH, SK, TK, MH, YH, RM, KO, AH, LB, IY, YH, HK, YM, KI, HK, BK, HO, YY, AT, NK, SG, MI, MN, KM, EO, IO, TS, KY, HA, KT, KI, TS, AK, MF, NU, TK, TT, YY, MI, TH, KI, KN, SH, KE, KH, YT, SN, NS, TY, NU, TY, YK, RO, NS, KS, SH, KO, HM, TF, MT, HS, DS, YI, TI, YK, TY, KS, TM No competing interests declared, SY, NN Employee of Takeda Pharmaceutical Company, Ltd

Background: Balloon kyphoplasty (BKP) is a method for the management of osteoporotic vertebral body fracture (OVF). However, improvement in back pain (BP) is poor in some patients, also previous reports have not elucidated the exact incidence and risk factors for residual BP after BKP. We clarified the characteristics of residual BP after BKP in patients with OVF., Hypothesis: In this study, we hypothesize that some risk factors may exist for residual BP 2 years after the treatment of OVF with BKP., Patients and Methods: A multicenter cohort study was performed where patients who received BKP within 2 months of OVF injury were followed-up for 2 years. BP at 6 months after surgery and final observation was evaluated by Visual Analog Scale (VAS) score. Patients with a score of 40 mm or more were allocated to the residual BP group, and comparisons between the residual back pain group and the improved group were made for bone density, kyphosis, mobility of the fractured vertebral body, total spinal column alignment, and fracture type (fracture of the posterior element, pedicle fracture, presence or absence of posterior wall damage, etc.). Also, Short Form 36 (SF-36) for physical component summary (PCS) and mental component summary (MCS) at the final follow-up was evaluated in each radiological finding., Results: Of 116 cases, 79 (68%) were followed-up for 2 years. Two years after the BKP, 26 patients (33%) experienced residual BP. Neither age nor sex differed between the groups. In addition, there was no difference in bone mineral density, BKP intervention period (period from onset to BKP), and osteoporosis drug use. However, the preoperative height ratio of the vertebral body was significantly worse in the residual BP group (39.8% vs. 52.1%; p  = 0.007). Two years after the operation, the vertebral body wedge angle was significantly greater in the residual BP group (15.7° vs. 11.9°; p  = 0.042). In the multiple logistic regression model with a preoperative vertebral body height ratio of 50% or less [calculated by receiver operating characteristic (ROC) curve], the adjusted odds ratio for residual BP was 6.58 (95% confidence interval 1.64-26.30; p  = 0.007); similarly, patients with vertebral body height ratio less than 50% had a lower score of SF-36 PCS 24.6 vs. 32.2 p  = 0.08., Conclusion: The incidence of residual BP 2 years after BKP was 33% in the current study. The risk factor for residual BP after BKP was a preoperative vertebral body height ratio of 50% or less, which should be attentively assessed for the selection of a proper treatment scheme and to provide adequate stabilization., Level of Evidence: III., Competing Interests: Conflict of InterestThe authors declare that they have no competing interests., (© Indian Orthopaedics Association 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)