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In odontoblasts, intracellular Ca 2+ signaling plays key roles in reactionary dentin formation and generation of dentinal pain. Odontoblasts also express several G s protein-coupled receptors that promote production of cyclic AMP (cAMP). However, the crosstalk between intracellular cAMP and Ca 2+ signaling, as well as the role of cAMP in the cellular functions of odontoblasts, remains unclear. In this study, we measured intracellular cAMP levels and intracellular free Ca 2+ concentration ([Ca 2+ ] i ). We also investigated the effect of intracellular cAMP on mineralization by the odontoblasts. In the presence of extracellular Ca 2+ , the application of forskolin (adenylyl cyclase activator) or isoproterenol (G s protein-coupled beta-2 adrenergic receptor agonist) increased intracellular cAMP levels and [Ca 2+ ] i in odontoblasts. The [Ca 2+ ] i increases could not be observed by removing extracellular Ca 2+ , indicating that cAMP is capable to activate Ca 2+ entry. Forskolin-induced [Ca 2+ ] i increase was inhibited by a protein kinase A inhibitor in odontoblasts. The [Ca 2+ ] i increase was sensitive to Gd 3+ , 2APB, or Zn 2+ but not verapamil, ML218, or La 3+ . In immunofluorescence analyses, odontoblasts were immunopositive for calcium homeostasis modulator 1 (CALHM1), which was found close to ionotropic ATP receptor subtype, P2X 3 receptors. When CALHM1 was knocked down, forskolin-induced [Ca 2+ ] i increase was suppressed. Alizarin red and von Kossa staining showed that forskolin decreased mineralization. These findings suggest that activation of adenylyl cyclase elicited increases in the intracellular cAMP level and Ca 2+ influx via protein kinase A activation in odontoblasts. Subsequent cAMP-dependent Ca 2+ influx was mediated by CALHM1 in odontoblasts. In addition, the intracellular cAMP signaling pathway in odontoblasts negatively mediated dentinogenesis., Competing Interests: Declarations Ethical approval Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: To investigate the effectiveness and safety of thoracic endovascular aortic repair (TEVAR) for infectious aortic diseases., Materials and Methods: Patients who underwent TEVAR for infectious aortic diseases including infected thoracic aortic aneurysm, aortobronchial fistula (ABF), and aortoenteric fistula from December 2011 to October 2022 at 4 institutions were retrospectively studied. The primary outcome of the study was overall survival, whereas the secondary outcome was comprehensive adverse events. Comprehensive adverse events were defined as a combination of deaths, aortic events, and infectious adverse events., Results: A total of 28 patients were included in the analysis, with 13 patients having infected thoracic aortic aneurysms, 12 ABFs, and 3 aortoenteric fistulae. Seven patients (25%) underwent additional procedures (abscess drainage, 6 cases; total esophagectomy, 1 case). The mean follow-up period was 30.0 months (SD ± 33.9). The 1-year and 5-year survival rates were 85.7% and 67.9%, respectively. The 1-year and 5-year aorta-related complication-free survival rates were 64.3% and 42.9%, respectively. On univariate analysis, the presence of an ABF was associated with a higher risk of comprehensive adverse events (odds ratio = 11; P = .04)., Conclusions: TEVAR might be a promising treatment for infectious thoracic aortic diseases. Among the infectious pathologies, ABF was considered ominous in terms of late outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Background: Cutis laxa constitutes a diverse group of connective tissue diseases, both inherited and acquired, characterized by loose skin and varying systemic involvement, including pulmonary lesions. While cutis laxa has been linked to conditions like emphysema, asthma, and bronchiectasis, the specific pathological and radiological characteristics underlying pulmonary complications related to cutis laxa remain unclear., Case Presentation: A 36-year-old woman, diagnosed with cutis laxa at birth, presented to our outpatient clinic with severe obstructive ventilatory impairment, evident in pulmonary function tests (expiratory volume in one second (FEV 1 )/forced vital capacity (FVC): 34.85%; %residual volume [RV]: 186.5%; %total lung capacity [TLC]: 129.2%). Pulmonary function tests also indicated small airway disease (%FEF50%, 7.9%; %FEF75%, 5.7%; and %FEF25-75%, 6.8%). Computed tomography (CT) revealed the lack of normal increase in lung attenuation on expiratory CT scan, with no discernible emphysematous changes. Exome sequencing was performed to confirm the association between the pulmonary lesions and cutis laxa, revealing a frameshift variant in exon 30 of the elastin gene (ELN). Further analysis employing a parametric response map revealed a longitudinal increase in the percentage of functional small airway disease (fSAD) from 37.84% to 46.61% over the 8-year follow-up, despite the absence of overt changes in CT findings, specifically the lack of normal increase in lung attenuation on expiratory CT scan. Over the same follow-up interval, there was a modest reduction of 25.6 mL/year in FEV 1 coupled with a significant increase in %RV. Pulmonary function test metrics, reflective of small airway disease, exhibited a continual decline; specifically, %FEF50%, %FEF75%, and %FEF25-75% diminished from 7.9% to 7.0%, 5.7% to 4.6%, and 6.8% to 5.4%, respectively., Conclusions: This case highlighted an instance of autosomal dominant cutis laxa arising from a frameshift variant in exon 30 of ELN, accompanied by small airway disease. Comprehensive investigation, utilizing quantitative CT analysis, revealed a longitudinal increase in fSAD percentage with a mild reduction in FEV 1 . These findings indicate that elastin deficiency may not only diminish elastic fibers in the skin but also be implicated in small airway disease by impacting components of the extracellular matrix in the lungs., (© 2024. The Author(s).)

Aim: This study aimed to investigate the utility of low-energy virtual monochromatic imaging (VMI) combined with deep-learning image reconstruction (DLIR) in improving the delineation of endoleaks (ELs) after endovascular aortic repair (EVAR) in contrast-enhanced dual-energy CT (DECT)., Methods: A total of 61 consecutive patients (mean age, 77 years; 46 men) after EVAR who underwent contrast-enhanced DECT were enrolled. Virtual monochromatic 40- and 70-keV images were reconstructed using DLIR (TrueFidelity-H) and conventional hybrid iterative reconstruction (IR). Contrast-to-noise ratio (CNR) of the EL on the venous-phase CT was calculated. Four different reconstructed image series (hybrid IR and DLIR at two energy levels, 40- and 70-keV) were displayed side-by-side and visually assessed for EL conspicuity on a 5-point comparative scale from 0 (best) to -4 (significantly inferior). Two experienced radiologists independently conducted a qualitative evaluation of the CT images., Results: A total of 30 out of 61 patients presented with an EL. On both 40- and 70-keV images, the CNR of the EL was significantly higher in DLIR than in hybrid IR (40-keV, 14.5 ± 7.3 vs 8.6 ± 4.2, P<0.001; 70-keV, 8.7 ± 4.5 vs 5.5 ± 2.6, P<0.001). The comparative scale of EL conspicuity in the 40-keV DLIR images (Observer1, -0.2 ± 0.4; Observer2, 0.0 ± 0.0) was significantly higher than 40-keV hybrid IR (Observer1, -0.5 ± 0.5; Observer2, -1.0 ± 0.0; P<0.05), 70-keV DLIR (Observer1, -1.8 ± 0.4; Observer2, -2.0 ± 0.0; P<0.001) and 70-keV hybrid IR images (Observer1, -1.8 ± 0.4; Observer2, -2.4 ± 0.5; P<0.001), respectively., Conclusions: Using 40-keV VMI in combination with DLIR improves EL delineation after EVAR compared with the 70-keV VMI with hybrid IR or DLIR., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study aims to investigate the efficacy of thoracic endovascular aortic repair (TEVAR) for type B aortic dissection (TBAD) complicated by malperfusion. Methods: This retrospective study included patients who underwent TEVAR for the treatment of TBAD complicated by malperfusion from June 1998 to June 2022 in four institutions. In addition to the common outcomes, including short- and medium-term mortality and morbidity, the preservation of each organ was investigated. Results: A total of 23 patients were included in this analysis. The 30-day mortality was 4% (1/23) of the patients. The overall survival rate was 87% at 1 year. The preservation rate of each organ was 33% (4/12) for the visceral organs, 85% (17/20) for the kidneys, and 100% (18/18) for the legs. Fisher's exact test showed a significant difference in the preservation rate between the viscera and the other organs ( P = 0.018 vs. kidneys, P = 0.0025 vs. legs). It was shown that the survival rate of patients with visceral malperfusion was significantly lower than that of patients with non-visceral malperfusion ( P = 0.006). Conclusion: In terms of mortality, TEVAR showed satisfactory results. The preservation of visceral organs was still challenging even with TEVAR and adjunctive measures., (@ 2024 The Editorial Committee of Annals of Vascular Diseases.)

The craniofacial bone, crucial for protecting brain tissue and supporting facial structure, undergoes continuous remodeling through mesenchymal (MSCs) or skeletal stem cells (SSCs) in their niches. Gli1 is an ideal marker for labeling MSCs and osteoprogenitors in this region, and Gli1-lineage cells are identified as pivotal for bone growth, development, repair, and regeneration. Despite its significance, the distribution of Gli1-lineage cells across the dental, oral, and craniofacial (DOC) regions remains to be systematically explored. Utilizing tissue-clearing and light sheet fluorescence microscopy (LSFM) with a Gli1CreER; tdTomatoAi14 mouse model, we mapped the spatial distribution of Gli1-lineage cells throughout the skull, focusing on calvarial bones, sutures, bone marrow, teeth, periodontium, jaw bones, and the temporomandibular joint (TMJ). We found Gli1-lineage cells widespread in these areas, underscoring their significance in DOC regions. Additionally, we observed their role in repairing calvarial bone defects, providing novel insights into craniofacial biology and stem cell niches and enhancing our understanding of stem cells and their progeny's behavior in vivo., (© The Author(s) [2024]. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD., Methods: In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period., Results: All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated., Conclusion: The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073)., (© The Author(s) 2024. Published by Oxford University Press.)

Objective: To develop and validate a scoring system to predict mid-term adverse events after elective thoracic endovascular aortic repair (TEVAR)., Methods: In this multicenter retrospective observational cohort study, 350 patients who underwent elective TEVAR for thoracic aortic disease between January 2008 and December 2021 were analyzed. The primary outcome was the first adverse event occurring within 5 years of the initial TEVAR, which included death during the initial hospitalization, perioperative neurologic complication, stent graft-induced new entry, dissection, rupture, graft infection, and reintervention related to the initial TEVAR. The scoring system was developed using the regression coefficients of the Fine-Gray subdistribution hazard model. Its performance was evaluated using the area under the receiver operating characteristic curve (AUC) for competing risk analysis and internally validated by cross-validation., Results: Eighty-two patients experienced at least 1 adverse event within 5 years of the initial TEVAR. The 5-year cumulative incidence of adverse events was 26% (95% confidence interval, 21%-31%). Female sex, comorbidity score, use of anticoagulants, preoperative aortic diameter at the diaphragm level, proximal oversizing ratio, aortic coverage length, and hybrid procedure were included in the scoring system. The AUC of the scoring system in the internal validation was 0.748 (standard error, 0.009). When the scoring system was validated in patients with intact thoracic aortic aneurysm only, the AUC was 0.780 (standard error, 0.012)., Conclusions: Although external validation is needed, our scoring system may be useful for decision making, especially in patients with an intact thoracic aortic aneurysm., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Goal-directed reaches give rise to dynamic neural activity across the brain as we move our eyes and arms, and process outcomes. High spatiotemporal resolution mapping of multiple cortical areas will improve our understanding of how these neural computations are spatially and temporally distributed across the brain. In this study, we used micro-electrocorticography (μECoG) recordings in two male monkeys performing visually guided reaches to map information related to eye movements, arm movements, and receiving rewards over a 1.37 cm 2 area of frontal motor cortices (primary motor cortex, premotor cortex, frontal eye field, and dorsolateral pre-frontal cortex). Time-frequency and decoding analyses revealed that eye and arm movement information shifts across brain regions during a reach, likely reflecting shifts from planning to execution. We then used phase-based analyses to reveal potential overlaps of eye and arm information. We found that arm movement decoding performance was impacted by task-irrelevant eye movements, consistent with the presence of intermixed eye and arm information across much of motor cortices. Phase-based analyses also identified reward-related activity primarily around the principal sulcus in the pre-frontal cortex as well as near the arcuate sulcus in the premotor cortex. Our results demonstrate μECoG's strengths for functional mapping and provide further detail on the spatial distribution of eye, arm, and reward information processing distributed across frontal cortices during reaching. These insights advance our understanding of the overlapping neural computations underlying coordinated movements and reveal opportunities to leverage these signals to enhance future brain-computer interfaces., Competing Interests: Conflict of interest: A.L.O. is a scientific advisor for Meta Reality Labs

Introduction Oxidative stress, an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, plays an important role in various dental diseases. Local anesthetics are frequently used in dentistry. The potential antioxidant activity of dental local anesthetics can contribute to dental practice. Therefore, this study aimed to investigate the ROS-scavenging activities of three commonly used dental local anesthetics, lidocaine, prilocaine, and articaine, focusing on their effects on hydroxyl radicals (HO • ) and superoxide anions (O 2 •- ). Materials and methods The electron spin resonance (ESR) spin-trapping technique was employed to specifically measure the ROS-scavenging activities of these local anesthetics at varying concentrations. Results Lidocaine, prilocaine, and articaine exhibited concentration-dependent HO • -scavenging activities, with IC 50 values of 0.029%, 0.019%, and 0.014%, respectively. Lidocaine and prilocaine showed concentration-dependent O 2 •- -scavenging activity, with IC 50 values of 0.033% and 0.057%, respectively. However, articaine did not scavenge O 2 •- . Conclusions The proactive use of dental local anesthetics may mitigate oxidative injury and inflammatory damage through direct ROS scavenging. However, further research is needed to elucidate the specific mechanisms underlying the antioxidant effects of these dental local anesthetics and their potential impact on the dental diseases associated with oxidative stress., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. 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, Kuroda et al.)

Introduction: Space is a unique environment characterized by isolation from community life and exposure to circadian misalignment, microgravity, and space radiation. These multiple differences from those experienced on the earth may cause systemic and local tissue stress. Autonomic nerves, including sympathetic and parasympathetic nerves, regulate functions in multiple organs. Saliva is secreted from the salivary gland, which is regulated by autonomic nerves, and plays several important roles in the oral cavity and digestive processes. The balance of the autonomic nervous system in the seromucous glands, such as the submandibular glands, precisely controls serous and mucous saliva. Psychological stress, radiation damage, and other triggers can cause an imbalance in salivary secretion systems. A previous study reported that amylase is a stress marker in behavioral medicine and space flight crews; however, the detailed mechanisms underlying amylase regulation in the space environment are still unknown. Methods: In this study, we aimed to elucidate how lunar gravity (1/6  g ) changes mRNA expression patterns in the salivary gland. Using a multiple artificial gravity research system during space flight in the International Space Station, we studied the effects of two different gravitational levels, lunar and Earth gravity, on the submandibular glands of mice. All mice survived, returned to Earth from space, and their submandibular glands were collected 2 days after landing. Results: We found that lunar gravity induced the expression of the salivary amylase gene Amy1 ; however, no increase in Aqp5 and Ano1 , which regulate water secretion, was observed. In addition, genes involved in the exocrine system, such as vesicle-associated membrane protein 8 ( Vamp8 ) and small G proteins, including Rap1 and Rab families, were upregulated under lunar gravity. Conclusion: These results imply that lunar gravity upregulates salivary amylase secretion via Rap / Rab signaling and exocytosis via Vamp8 . Our study highlights Amy1 as a potential candidate marker for stress regulation in salivary glands in the lunar gravity environment., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ouchi, Kono, Satou, Kurashima, Yamaguchi, Kimura and Shibukawa.)

Titanium (Ti) is an attractive material, abundant in nature and possessing superior mechanical and chemical properties. However, its widespread use is significantly hampered by the strong affinity between titanium and oxygen (O), resulting in elevated manufacturing costs during the refining, melting, and casting processes. The current work introduces a high-throughput technique that effectively reduces the oxygen content in molten titanium to a level suitable for structural material applications (1000 mass ppm, equivalent to 0.1 mass%). This technique aspires to streamline the mass production of titanium by seamlessly integrating the refining, melting, and casting processes. The developed method leverages the high affinity of rare-earth metals, such as yttrium (Y), for oxygen. This method utilizes the formation reaction of their oxyhalides (YOF) to directly remove oxygen from liquid titanium, resulting in titanium with a significantly reduced oxygen content of 200 mass ppm. This technique enables the direct conversion of titanium oxide feeds into low-oxygen titanium without requiring conversion into intermediate compounds. Additionally, this process offers a pathway for the upgrade recycling of high-oxygen-content titanium scrap directly into low-oxygen titanium. Consequently, this technology holds the potential to dramatically lower titanium production costs, thereby facilitating its more widespread utilization., (© 2024. The Author(s).)

Competing Interests: Funding Support and Author Disclosures Dr Naganuma is a clinical proctor of TAVI for Edwards Lifesciences and Medtronic. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Polymers that release small molecules in response to mechanical force are promising candidates as next-generation on-demand delivery systems. Despite advancements in the development of mechanophores for releasing diverse payloads through careful molecular design, the availability of scaffolds capable of discharging biomedically significant cargos in substantial quantities remains scarce. In this report, we detail a nonscissile mechanophore built from an 8-thiabicyclo[3.2.1]octane 8,8-dioxide ( TBO ) motif that releases one equivalent of sulfur dioxide (SO 2 ) from each repeat unit. The TBO mechanophore exhibits high thermal stability but is activated mechanochemically using solution ultrasonication in either organic solvent or aqueous media with up to 63% efficiency, equating to 206 molecules of SO 2 released per 143.3 kDa chain. We quantified the mechanochemical reactivity of TBO by single-molecule force spectroscopy and resolved its single-event activation. The force-coupled rate constant for TBO opening reaches ∼9.0 s -1 at ∼1520 pN, and each reaction of a single TBO domain releases a stored length of ∼0.68 nm. We investigated the mechanism of TBO activation using ab initio steered molecular dynamic simulations and rationalized the observed stereoselectivity. These comprehensive studies of the TBO mechanophore provide a mechanically coupled mechanism of multi-SO 2 release from one polymer chain, facilitating the translation of polymer mechanochemistry to potential biomedical applications.

Biological aging profoundly impairs the homeostasis of the skeletal system. Cellular senescence, a hallmark of biological aging, plays an instrumental role in bone disease. The underlying mechanisms of cellular senescence, triggered by both intracellular and extracellular stimuli, are multifaceted and yet to be uncovered. Recent research indicates that acute cellular senescence often serves beneficial roles, such as contributing to growth, development, and tissue regeneration. By contrast, chronic cellular senescence, primarily driven by the accumulation of senescent cells (SnCs) and the release of senescence-associated secretory phenotypes (SASP), has detrimental effects on the skeletal system by irreversibly disrupting bone homeostasis and promoting age-related disorders. Furthermore, the bone marrow is rich in immune cells and their exposure to SASP often leads to immune dysfunction, resulting in unresolved chronic inflammation and compromised adaptive immunity. Until now, the impact of SnCs and SASP on the skeleton has remained elusive. Meanwhile, extensive efforts are being made to combat age-related diseases through various strategies. Among them, SnCs and SASP are the primary targets for antiaging therapeutic clearance, resulting in the development of "senolytics" and "senomorphics," respectively. In this review, we summarize and highlight the role of SnCs and SASP in skeletal pathophysiology, the mechanism of cellular senescence in affecting bone metabolism, and potential therapeutic approaches, particularly senolytics and senomorphics, in treating cellular senescence-related bone diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A 66-year-old man presented with hemolytic anemia, which required frequent blood transfusion, 6 months after surgical repair of an ascending aortic pseudoaneurysm. Hemolysis was attributed to luminal stenosis caused by graft kinking by laboratory test, CT and four-dimensional magnetic resonance imaging. First, an Excluder cuff was placed at the stenotic site under rapid pacing, but it migrated distally. Thereafter a Palmaz XL stent was placed at the stenotic site, which led to resolution of anemia. In this case, a Palmaz XL stent was successfully used to treat hemolytic anemia caused by graft kinking following ascending aortic surgery., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Many virus-like particles (VLPs) have good chemical, thermal, and mechanical stabilities compared to those of other biologics. However, their stability needs to be improved for the commercialization and use in translation of VLP-based materials. We developed an endoskeleton-armored strategy for enhancing VLP stability. Specifically, the VLPs of physalis mottle virus (PhMV) and Qβ were used to demonstrate this concept. We built an internal polymer "backbone" using a maleimide-PEG 15 -maleimide cross-linker to covalently interlink viral coat proteins inside the capsid cavity, while the native VLPs are held together by only noncovalent bonding between subunits. Endoskeleton-armored VLPs exhibited significantly improved thermal stability (95 °C for 15 min), increased resistance to denaturants (i.e., surfactants, pHs, chemical denaturants, and organic solvents), and enhanced mechanical performance. Single-molecule force spectroscopy demonstrated a 6-fold increase in rupture distance and a 1.9-fold increase in rupture force of endoskeleton-armored PhMV. Overall, this endoskeleton-armored strategy provides more opportunities for the development and applications of materials.

Background: Severe peripheral nerve damage always requires surgical treatment. Autologous nerve transplantation is a standard treatment, but it is not sufficient due to length limitations and extended surgical time. Even with the available artificial nerves, there is still large room for improvement in their therapeutic effects. Novel treatments for peripheral nerve injury are greatly expected., Methods: Using a specialized microfluidic device, we generated artificial neurite bundles from human iPSC-derived motor and sensory nerve organoids. We developed a new technology to isolate cell-free neurite bundles from spheroids. Transplantation therapy was carried out for large nerve defects in rat sciatic nerve with novel artificial nerve conduit filled with lineally assembled sets of human neurite bundles. Quantitative comparisons were performed over time to search for the artificial nerve with the therapeutic effect, evaluating the recovery of motor and sensory functions and histological regeneration. In addition, a multidimensional unbiased gene expression profiling was carried out by using next-generation sequencing., Result: After transplantation, the neurite bundle-derived artificial nerves exerted significant therapeutic effects, both functionally and histologically. Remarkably, therapeutic efficacy was achieved without immunosuppression, even in xenotransplantation. Transplanted neurite bundles fully dissolved after several weeks, with no tumor formation or cell proliferation, confirming their biosafety. Posttransplant gene expression analysis highlighted the immune system's role in recovery., Conclusion: The combination of newly developed microfluidic devices and iPSC technology enables the preparation of artificial nerves from organoid-derived neurite bundles in advance for future treatment of peripheral nerve injury patients. A promising, safe, and effective peripheral nerve treatment is now ready for clinical application., (© 2024. The Author(s).)

Background: Vertical run-length nonuniformity (VRLN) is a texture feature representing heterogeneity within native T1 images and reflects the extent of cardiac fibrosis. In uremic cardiomyopathy, interstitial fibrosis was the major histological alteration. The prognostic value of VRLN in patients with end-stage renal disease (ESRD) remains unclear., Purpose: To evaluate the prognostic value of VRLN MRI in patients with ESRD., Study Type: Prospective., Population: A total of 127 ESRD patients (30 participants in the major adverse cardiac events, MACE group)., Field Strength/sequence: 3.0 T/steady-state free precession sequence, modified Look-Locker imaging., Assessment: MRI image qualities were assessed by three independent radiologists. VRLN values were measured in the myocardium on the mid-ventricular short-axis slice of T1 mapping. Left ventricular (LV) mass, LV end-diastolic and end-systolic volume, as well as LV global strain cardiac parameters were measured., Statistical Tests: The primary endpoint was the incident of MACE from enrollment time to January 2023. MACE is a composite endpoint consisting of all-cause mortality, acute myocardial infarction, stroke, heart failure hospitalization, and life-threatening arrhythmia. Cox proportional-hazards regression was performed to test whether VRLN independently correlated with MACE. The intraclass correlation coefficients of VRLN were calculated to evaluate intraobserver and interobserver reproducibility. The C-index was computed to examine the prognostic value of VRLN. P-value <0.05 were considered statistically significant., Results: Participants were followed for a median of 26 months. VRLN, age, LV end-systolic volume index, and global longitudinal strain remained significantly associated with MACE in the multivariable model. Adding VRLN to a baseline model containing clinical and conventional cardiac MRI parameters significantly improved the accuracy of the predictive model (C-index of the baseline model: 0.781 vs. the model added VRLN: 0.814)., Data Conclusion: VRLN is a novel marker for risk stratification toward MACE in patients with ESRD, superior to native T1 mapping and LV ejection fraction., Evidence Level: 2 TECHNICAL EFFICACY STAGE: 2., (© 2023 International Society for Magnetic Resonance in Medicine.)

Objective: To test whether sonographically determined fecal width (SDFW) correlates with symptom improvement in a population of children with bladder and bowel dysfunction (BBD) managed with standard urotherapy (SU), even for those patients lacking initial bowel complaints., Methods: We retrospectively analyzed 200 pediatric BBD patients managed with SU for at least 3 months. Self-reported symptom improvement (complete, partial, no response) following International Children's Continence Society guidelines was tabulated. Patients with complex urologic diagnoses other than vesicoureteral reflux (VUR) were excluded. Pharmacotherapy choice, physical therapy (PT), urinary tract infection (UTI) occurrence, and VUR status were tabulated. SDFW was recorded. Non-parametric analysis of variants (ANOVA) and parametric/non-parametric t testing were used for analysis., Results: Patients had a mean age of 9.5 years (4-12). Forty-eight patients had no gastrointestinal complaints at presentation. Urotherapy yielded complete, partial, and no responses in 14% (n = 27), 33% (n = 67), and 53% (n = 106) of patients, respectively. The average SDFW for those patients with complete response (2.6 cm) was smaller than the SDFW of those with a partial response (3.1 cm) or no response (3.3 cm) (P = .0001). Non-compliance led to greater SDFW compared to compliant patients (3.7 cm and 3.1 cm, respectively, P = .0001). Fecal width was unaffected by VUR, UTI, PT, or pharmacotherapy., Conclusion: SDFW correlates well with symptom improvement in pediatric patients managed for BBD, confirming our hypothesis. SDFW is reasonable as single objective parameter to identify successful management in patients with BBD, extending to those without bowel complaints at presentation., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Dissolved organic matter (DOM) plays important roles not only in maintaining the productivity and functioning of aquatic ecosystems but also in the global carbon cycle, although the sources and biogeochemical functions of terrestrially derived DOM have not been fully elucidated, particularly in the tropics and subtropics. This study aimed to evaluate the factors influencing spatiotemporal variability in (i) the concentration and composition of DOM, including dissolved organic carbon (DOC), ultraviolet absorption coefficient at 254-nm wavelength (a 254 ), and components identified by fluorescence excitation-emission matrix coupled with parallel factor analysis (EEM-PARAFAC), and (ii) the concentration of dissolved iron (DFe) across freshwater systems (rivers, forested streams, and dam reservoirs) on a tropical island (Ishigaki Island, Japan) based on the results of water quality monitoring at 2-month intervals over a 2-year period. Random forests (RF) machine learning algorithm was employed, with the catchment characteristics (land use, soil type) and water temperature as the predictor variables for DOM and the composition of DOM (EEM-PARAFAC components) and hydrochemistry (water temperature, pH, and concentrations of divalent cations) as the predictor variables for DFe. The RF models for DOC, a 254 , and three humic-like components exhibited excellent predictive performance, indicating that these DOM properties are not only seasonally variable but also strongly influenced by the compositions of land uses and soil types in the upstream watershed. Poorly drained riparian lowland soil (Gleyic Fluvisols) was identified as the most important catchment parameter that positively influences these DOM variables. The RF model also explained a large portion of the variation in DFe, while terrestrial humic-like components were the most important parameters, emphasizing their significance as organic ligands for iron. These results improve our understanding of the impacts of terrestrial DOM and iron loadings on tropical and subtropical coastal ecosystems as well as on regional and global carbon budgets., 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 © 2023 Elsevier B.V. All rights reserved.)

The craniofacial bones provide structural support for the skull and accommodate the vulnerable brain tissue with a protective cavity. The bone tissue undergoes constant turnover, which relies on skeletal stem cells (SSCs) and/or mesenchymal stem cells (MSCs) and their niches. SSCs/MSCs and their perivascular niche within the bone marrow are well characterized in long bones. As for cranial bones, besides bone marrow, the suture mesenchyme has been identified as a unique niche for SSCs/MSCs of craniofacial bones. However, a comprehensive study of the two different cranial stem cell niches at single-cell resolution is still lacking. In addition, during the progression of aging, age-associated changes in cranial stem cell niches and resident cells remain uncovered. In this study, we investigated age-related changes in cranial stem cell niches via single-cell RNA sequencing (scRNA-seq). The transcriptomic profiles and cellular compositions have been delineated, indicating alterations of the cranial bone marrow microenvironment influenced by inflammaging. Moreover, we identified a senescent mesenchymal cell subcluster and several age-related immune cell subclusters by reclustering and pseudotime trajectory analysis, which might be closely linked to inflammaging. Finally, differentially expressed genes (DEGs) and cell-cell communications were analyzed during aging, revealing potential regulatory factors. Overall, this work highlights the age-related changes in cranial stem cell niches, which deepens the current understanding of cranial bone and suture biology and may provide therapeutic targets for antiaging and regenerative medicine., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The oral cavity serves as the initial segment of the digestive system and is responsible for both nutritional supplementation and the mechanical breakdown of food. It comprises distinct hard and soft tissues; the oral mucosa is subject to mechanical stress and interaction with microbiota. In oral cancer, tumors exhibit abnormal cellular networks and aberrant cell-cell interactions arising from complex interplays between environmental and genetic factors. This presents a challenge for clinicians and researchers, impeding the understanding of mechanisms driving oral cancer development and treatment strategies. Lesions with dysplastic features are categorized under oral potentially malignant disorders, including oral leukoplakia, erythroplakia, oral submucous fibrosis, and proliferative verrucous leukoplakia, carrying a high malignancy risk. In this review, we discuss oral cancer cell characteristics and the stiffness of the surrounding matrix. We also discuss the significance of stiffness equilibrium in oral potentially malignant disorders, particularly oral submucous fibrosis, possibly triggered by mechanical stress such as betel quid chewing., Competing Interests: The authors declare no conflict of interest. Given his role as Guest Editor, Takehito Ouchi had no involvement in the peer-review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Amedeo Amedei., (© 2023 The Author(s). Published by IMR Press.)

The number of robotic hiatal hernia repairs (RHHR) is increasing. However, the superiority of this minimally invasive approach remains controversial. The aim of this study was to evaluate the available literature reporting on outcomes of RHHR compared with laparoscopic hiatal hernia repair (LHHR) in adult patients. The design of this systematic review was developed using the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Web of Science, PubMed, the Cochrane Library, and ClinicalTrials.gov databases were searched. Identified publications were reviewed independently by two authors. High heterogeneity was further explored through sensitivity analysis. The primary endpoint was the development of postoperative complications. Secondary endpoints included operation time, intraoperative complications, 30 day readmission rates and length of stay. The analysis was performed using Stata 17.0 software. A total of 7 studies totaling 10078 patients met the inclusion criteria. Five studies included postoperative complications. The postoperative complications rate was 4.25% (302/7111) in the LHHR group, and 3.49% (38/1088) in the RHHR group. Postoperative complications significantly decreased after RHHR compared with LHHR (OR 0.52; 95% CI 0.36 to 0.75, P = 0.000). Three studies involving 2176 patients reported length of hospital stay. In the three studies, the mean Length of hospital stay was 3.2 days in the RHHR group, and 4.2 days in the LHHR group. Length of hospital stay was decreased by a mean of 0.68 days for RHHR compared with LHHR (WMD, - 0.68 days; 95% CI - 1.32 to - 0.03, P = 0.02). There was no significant difference between the RHHR group and the LHHR group regarding operative time, intraoperative complications, and 30 day readmission (P > 0.05). Our research shows that RHHR may be the better option, as the approach decreases postoperative complications and length of hospital stay., (© 2023. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Cranial bones constitute a protective shield for the vulnerable brain tissue, bound together as a rigid entity by unique immovable joints known as sutures. Cranial sutures serve as major growth centres for calvarial morphogenesis and have been identified as a niche for mesenchymal stem cells (MSCs) and/or skeletal stem cells (SSCs) in the craniofacial skeleton. Despite the established dogma of cranial bone and suture biology, technological advancements now allow us to investigate these tissues and structures at unprecedented resolution and embrace multiple novel biological insights. For instance, a decrease or imbalance of representation of SSCs within sutures might underlie craniosynostosis; dural sinuses enable neuroimmune crosstalk and are newly defined as immune hubs; skull bone marrow acts as a myeloid cell reservoir for the meninges and central nervous system (CNS) parenchyma in mediating immune surveillance, etc. In this review, we revisit a growing body of recent studies that explored cranial bone and suture biology using cutting-edge techniques and have expanded our current understanding of this research field, especially from the perspective of development, homeostasis, injury repair, resident MSCs/SSCs, immunosurveillance at the brain's border, and beyond., (© 2023 Cambridge Philosophical Society.)

The field of facial plastic and reconstructive surgery (FPRS) is an incredibly diverse, multispecialty field that seeks innovative and novel solutions for the management of physical defects on the head and neck. To aid in the advancement of medical and surgical treatments for these defects, there has been a recent emphasis on the importance of translational research. With recent technological advancements, there are now a myriad of research techniques that are widely accessible for physician and scientist use in translational research. Such techniques include integrated multiomics, advanced cell culture and microfluidic tissue models, established animal models, and emerging computer models generated using bioinformatics. This study discusses these various research techniques and how they have and can be used for research in the context of various important diseases within the field of FPRS., Competing Interests: None declared., (Thieme. All rights reserved.)

The age-related hearing loss allele (Cdh23 ahl ) of the cadherin 23 gene leads to a more severe hearing loss phenotype through additive effects with risk alleles for hearing loss. In this study, we genome edited the Cdh23 ahl allele to the wild-type Cdh23 + allele in outbred ICR mice and inbred NOD/Shi mice established from ICR mice and investigated their effects on hearing phenotypes. Several hearing tests confirmed that ICR mice developed early onset high-frequency hearing loss and exhibited individual differences in hearing loss onset times. Severe loss of cochlear hair cells was also detected in the high-frequency areas in ICR mice. These phenotypes were rescued by genome editing the Cdh23 ahl allele to Cdh23 + , suggesting that abnormal hearing phenotypes develop because of the interaction of the Cdh23 ahl and risk alleles in the genetic background of ICR mice. NOD/Shi mice developed more severe hearing loss and hair cell degeneration than ICR mice. Hearing loss was detected at 1 month old. Hair cell loss, including degeneration of cell bodies and stereocilia, was observed in all regions of the cochlea in NOD/Shi mice. Although these phenotypes were partially rescued by genome editing to the Cdh23 + allele, the phenotypes associated with high-frequency hearing were mostly unrecovered in NOD/Shi mice. These results strongly suggest that the genetic background of NOD/Shi mice contain a potential risk allele for the acceleration of early onset high-frequency hearing loss., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

G protein-coupled receptors in trigeminal ganglion (TG) neurons are often associated with sensory mechanisms, including nociception. We have previously reported the expression of P2Y 12 receptors, which are G i protein-coupled receptors, in TG cells. Activating P2Y 12 receptors decreased the intracellular free Ca 2+ concentration ([Ca 2+ ] i ). This indicated that intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels can mediate Ca 2+ signaling in TG cells. Here, we report more extensive-expression patterns of G s protein-coupled receptors in primary cultured TG neurons isolated from 7-day-old newborn Wistar rats and further examine the roles of these receptors in cAMP signaling using the BacMam sensor in these neurons. To identify TG neurons, we also measured [Ca 2+ ] i using fura-2 in TG cells and measured intracellular cAMP levels. TG neurons were positive for Gα s protein-coupled receptors, beta-2 adrenergic (β 2 ), calcitonin gene-related peptide (CGRP), adenosine A 2A (A 2A ), dopamine 1 (D1), prostaglandin I 2 (IP), and 5-hydroxytriptamine 4 (5-HT 4 ) receptor. Application of forskolin (FSK), an activator of adenylyl cyclase, transiently increased intracellular cAMP levels in TG neurons. The application of a phosphodiesterase inhibitor augmented the FSK-elicited intracellular cAMP level increase. These increases were significantly suppressed by the application of SQ22536, an adenylyl cyclase inhibitor, in TG neurons. Application of agonists for β 2 , CGRP, A 2A , D1-like, IP, and 5-HT 4 receptors increased intracellular cAMP levels. These increases were SQ22536-sensitive. These results suggested that TG neurons express β 2 , CGRP, A 2A , D1, IP, and 5-HT 4 receptors, and the activations of these Gα s protein-coupled receptors increase intracellular cAMP levels by activating adenylyl cyclase.

Background: Information is scarce regarding the clinical implications of aortic valve replacement (AVR) for patients suffering from moderate mixed aortic valve disease (MAVD), characterized by a combination of moderate aortic stenosis (AS) and regurgitation (AR). The objective of this retrospective study was to explore the clinical effects of AVR in individuals with moderate MAVD., Methods: We examined the clinical data from patients with moderate MAVD and preserved left ventricular ejection fraction, who had undergone echocardiography in the period spanning from 2010 to 2018. Moderate AS was defined as aortic valve area index of 0.60-0.85 cm 2 /m 2 and peak velocity of 3.0-4.0 m/s. Moderate AR was defined as a vena contracta width of 3.0-6.0 mm. The primary endpoint was a composite of all-cause death and heart failure hospitalization., Results: Among 88 patients (mean age, 74.4 ± 6.8 years; 48.9%, men), 44 (50.0%) required AVR during a median follow-up period of 3.3 years (interquartile range, 0.5-4.9). Mean values of specific aortic valve variables are as follows: aortic valve area index, 0.64 ± 0.04 cm 2 /m 2 ; peak velocity, 3.40 ± 0.30 m/s; and vena contracta width, 4.1 ± 0.7 mm. The primary endpoint occurred in 32 (36.4%) patients during a median follow-up duration of 5.3 years (interquartile range, 3.2-8.0). Multivariable analysis revealed that AVR was significantly associated with the endpoint (hazard ratio, 0.248; 95% confidence interval, 0.107-0.579; p  = 0.001) after adjusting for age, B-type natriuretic peptide, and the Charlson comorbidity index. Patients who underwent AVR during follow-up had significantly lower incidence rates of the endpoint than those managed with medical treatment (10.2% vs. 44.1% at 5 years; p  < 0.001)., Conclusions: Approximately half of the patients diagnosed with moderate MAVD eventually necessitated AVR throughout the period of observation, leading to positive clinical results. Vigilant tracking of these patients and watchful monitoring for signs requiring AVR during this time frame are essential., 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., (© 2023 Onishi, Izumo, Ouchi, Yuki, Naganuma, Nakao and Nakamura.)

Although the recommended preoperative cessation period for sodium-glucose cotransporter 2 inhibitors (SGLT2is) changed in 2020 (from 24 h to 3-4 days preoperatively) to reduce the risk of SGLT2i-associated perioperative ketoacidosis (SAPKA), the validity of the new recommendation has not been verified. Using case reports, we assessed the new recommendation effectiveness and extrapolated precipitating factors for SAPKA. We searched electronic databases up to June 1, 2022 to assess SAPKA (blood pH < 7.3 and blood or urine ketone positivity within 30 days postoperatively in patients taking SGLT2i). We included 76 publications with 99 cases. The preoperative SGLT2i cessation duration was reported for 59 patients (59.6%). In all cases with available cessation periods, the SGLT2is were interrupted < 3 days preoperatively. No SAPKA cases with > 2-day preoperative cessation periods were found. Many case reports lack important information for estimating precipitating factors, including preoperative SGLT2i cessation period, body mass index, baseline hemoglobin A1c level, details of perioperative fluid management, and type of anesthesia. Our study suggested that preoperative SGLT2i cessation for at least 3 days could prevent SAPKA. Large prospective epidemiologic studies are needed to identify risk factors for SAPKA., (© 2023. The Author(s).)

Odontoblasts are involved in sensory generation as sensory receptor cells and in dentin formation. We previously reported that an increase in intracellular cAMP levels by cannabinoid 1 receptor activation induces Ca 2+ influx via transient receptor potential vanilloid subfamily member 1 channels in odontoblasts, indicating that intracellular cAMP/Ca 2+ signal coupling is involved in dentinal pain generation and reactionary dentin formation. Here, intracellular cAMP dynamics in cultured human odontoblasts were investigated to understand the detailed expression patterns of the intracellular cAMP signaling pathway activated by the G s protein-coupled receptor and to clarify its role in cellular functions. The presence of plasma membrane Gα s as well as prostaglandin I 2 (IP), 5-hydroxytryptamine 5-HT 4 (5-HT 4 ), dopamine D 1 (D 1 ), adenosine A 2A (A 2A ), and vasoactive intestinal polypeptide (VIP) receptor immunoreactivity was observed in human odontoblasts. In the presence of extracellular Ca 2+ , the application of agonists for the IP (beraprost), 5-HT 4 (BIMU8), D 1 (SKF83959), A 2A (PSB0777), and VIP (VIP) receptors increased intracellular cAMP levels. This increase in cAMP levels was inhibited by the application of the adenylyl cyclase (AC) inhibitor SQ22536 and each receptor antagonist, dose-dependently. These results suggested that odontoblasts express G s protein-coupled IP, 5-HT 4 , D 1 , A 2A , and VIP receptors. In addition, activation of these receptors increased intracellular cAMP levels by activating AC in odontoblasts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered as potential conflicts of interest.

Recent work has demonstrated that force-triggered mechanochemical reactions within a polymeric material are capable of inducing measurable changes in macroscopic material properties, but examples of bulk property changes without irreversible changes in shape or structure are rare. Here, we report a double-network hydrogel that undergoes order-of-magnitude increases in acidity when strained, while recovering its initial shape after large deformation. The enabling mechanophore design is a 2-methoxy- gem -dichlorocyclopropane mechanoacid that is gated within a fused methyl methoxycyclobutene carboxylate mechanophore structure. This gated mechanoacid is incorporated via radical co-polymerization into linear and network polymers. Sonication experiments confirm the mechanical release of HCl, and single-molecule force spectroscopy reveals enhanced single-molecular toughness in the covalent strand. These mechanochemical functions are incorporated into a double-network hydrogel, leading to mechanically robust and thermally stable materials that undergo strain-triggered acid release. Both quasi-static stretching and high strain rate uniaxial compression result in substantial acidification of the hydrogel, from pH ∼ 7 to ∼5.

Pemphigus and pemphigoid are autoimmune blistering diseases that affect mucosa and skin. Several clinical scoring systems, including the pemphigus disease area index (PDAI) and the bullous pemphigoid disease area index (BPDAI), have been validated for managing disease activity and severity. Current guidelines recommend that treatment response be evaluated with clinical scores and that additional second-line therapies be considered if initial treatment is insufficient for disease control. However, there have been few studies analyzing correlations between PDAI/BPDAI transitions and initial treatment effects. To investigate whether PDAI/BPDAI transitions during the treatment initiation phase correlate with initial treatment responses and whether such information can be used as a guide for necessary additional treatment, we retrospectively analyzed 67 pemphigus patients and 47 pemphigoid patients who received initial treatment at Keio University between 2012 and 2018. The clinical symptoms were evaluated weekly with PDAI/BPDAI. The patients were divided into two groups: in group A, disease was controlled only with oral corticosteroids and immunosuppressants (initial treatment), whereas in group B additional therapies were required due to insufficient responses. In pemphigus, the PDAI ratio of day 7/day 0 was significantly reduced in group A compared to group B (0.548 vs 0.761, P < 0.01) after initial treatment had started. In pemphigoid, the ratios of day 7/day 0 of BPDAI (erosion/blister) and BPDAI (urticaria/erythema) significantly decreased in group A compared to group B (0.565 vs 0.901 and 0.350 vs 0.760, respectively, P < 0.05). Receiver operating characteristic analyses on PDAI, BPDAI (erosion/blister) and BPDAI (urticaria/erythema) revealed that the cut-off values in the ratios of day 7/day 0 were 0.762, 0.675, and 0.568, respectively. Our results suggest that PDAI/BPDAI transitions during the initial phase of the treatments may be useful to predict the outcome of the treatment provided and the necessity of additional therapies to achieve disease control., (© 2022 Japanese Dermatological Association.)

BACKGROUND Human papilloma virus is a ubiquitous and preventable disease with the potential to cause recurrent respiratory papillomatosis. These papillomas affect the mucosal surface of the airways and may lead to airway obstruction. The papillomas require excision when breathing is compromised, and may be fatal if untreated. Rarely, these papillomas progress to cancer. CASE REPORT We report the case of a 21-year-old woman with a history of HPV 11- and 16-positive recurrent laryngeal and respiratory papillomatosis (RRP) since the age of 7 months, requiring multiple local resections in her respiratory tract. Chest CT demonstrated multiple cavitary lesions throughout both lungs with a rapidly growing mass that occupied most of her right lung. Imaging supported a diagnosis of malignant transformation to squamous cell carcinoma of the lung. Bilateral involvement of the lungs indicated stage IVa squamous cell lung cancer, which is not curable. CONCLUSIONS Clinicians should suspect malignant transformation in patients with HPV type 11, especially if they have required multiple excisions. Earlier age at onset and number of excisions may be predictors for severity of the disease course. These patients need continued surveillance imaging to allow early interventions if malignant transformation occurs. We present the case of a 21-year-old being diagnosed with an incurable disease that may have been avoided with adequate preventive care.

Objective: This study aimed to investigate the correlation between increased extracellular matrix estimated by cardiac magnetic resonance (CMR) and left ventricular aneurysm after acute myocardial infarction., Methods: A total of 175 patients from 3 centers with an isolated left anterior descending culprit vessel underwent CMR examinations within 1 week and at a 6-month follow-up. Of these, 92 were identified to have left ventricular aneurysms (LVAs): 74 with functional aneurysm and 18 with anatomical aneurysm. The predictive significance of acute extracellular volume (ECV), left gadolinium enhancement (LGE), and other characteristics were analyzed using binary logistic regression analysis., Results: Patients with LVA were more likely to present with left ventricular adverse remodeling (LVAR) than those without (p = 0.009). With optimal cutoff values of 30.90% for LGE and 33% for ECV to discriminate LVA from non-LVA, the area under the curve (AUC) by receiver operator characteristic curve (ROC) analysis was 0.92 (95% CI: 0.87-0.96; p < 0.001) and 0.93 (95% CI: 0.88-0.96; p < 0.001), respectively. ECV was significantly better than LGE at discriminating between functional and anatomical LVA (p < 0.001). Both acute LGE and ECV were predictors of LVA, with an odds ratio of 1.35 (95% CI: 1.21-1.52, p < 0.001) and 1.23 (95% CI: 1.13-1.33, p < 0.001), respectively, by multivariable logistic regression analysis., Conclusions: Acute LGE and ECV of the myocardium provided predictive significance for LVA. The discriminative significance of ECV for functional versus anatomical LVA was better than the discriminative significance of LGE., Key Points: • Patients with LVA were more likely to present with LVAR. • Acute LGE and ECV of the myocardium provided the strongest predictive significance for LVA. • The discriminative significance of ECV for functional versus anatomical LVA was better than that of LGE., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Cold agglutinin disease (CAD) is a rare form of acquired autoimmune hemolytic anemia driven mainly by antibodies that activate the classical complement pathway. Several patients with CAD experience its development or exacerbation of hemolysis after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or after receiving the SARS-CoV-2 mRNA vaccine. Therefore, these patients cannot receive an additional SARS-CoV-2 mRNA vaccination and have a higher risk of severe SARS-CoV-2 infection. Sutimlimab is a monoclonal antibody that inhibits the classical complement pathway of the C1s protein and shows rapid and sustained inhibition of hemolysis in patients with CAD. However, whether sutimlimab could also inhibit hemolysis caused by SARS-CoV-2 mRNA vaccination is uncertain. Here, we present the case of a 70-year-old man with CAD who repeatedly experienced a hemolytic crisis after receiving SARS-CoV-2 mRNA vaccines. The patient eventually underwent SARS-CoV-2 mRNA vaccination safely, without hemolytic attack, under classical pathway inhibition therapy with sutimlimab. This report suggests that appropriate sutimlimab administration can suppress SARS-CoV-2 mRNA vaccination-induced CAD exacerbation, and that it could be a preventive strategy to minimize hemolytic attacks in susceptible populations.

Introduction: Transcranial magnetic resonance-guided focused ultrasound surgery (TcMRgFUS) has the advantage of allowing immediate evaluation of therapeutic effects after each sonication and intraoperative magnetic resonance imaging (MRI) to visualize the lesion. When the image shows that the lesion has missed the planned target and the therapeutic effects are insufficient, the target of the subsequent ablation can be finely adjusted based on the image. The precision of this adjustment is determined by the image quality. However, the current intraoperative image quality with a 3.0T MRI system is insufficient for precisely detecting the lesion. Thus, we developed and validated a method for improving intraoperative image quality., Methods: Because intraoperative image quality is affected by transmitter gain (TG), we acquired T2-weighted images (T2WIs) with two types of TG: the automatically adjusted TG (auto TG) and the manually adjusted TG (manual TG). To evaluate the character of images with 2 TGs, the actual flip angle (FA), the image uniformity, and the signal-to-noise ratio (SNR) were measured using a phantom. Then, to assess the quality of intraoperative images, T2WIs with both TGs were acquired during TcMRgFUS for 5 patients. The contrast-to-noise ratio (CNR) of the lesion was retrospectively estimated., Results: The images of the phantom with the auto TG showed substantial variations between the preset and actual FAs (p &lt; 0.01), whereas on the images with the manual TG, there were no variations between the two FAs (p &gt; 0.05). The total image uniformity was considerably lower with the manual TG than with the auto TG (p &lt; 0.01), indicating that the image's signal values with the manual TG were more uniform. The manual TG produced significantly higher SNRs than the auto TG (p &lt; 0.01). In the clinical study, the lesions were clearly detected in intraoperative images with the manual TG, but they were difficult to identify in images with the auto TG. The CNR of lesions in images with manual TG was considerably higher than in images with auto TG (p &lt; 0.01)., Conclusion: Regarding intraoperative T2WIs using a 3.0T MRI system during TcMRgFUS, the manual TG method improved image quality and delineated the ablative lesion more clearly than the current method with auto TG., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Excessive loadings of terrestrial nitrogen and phosphorus, as well as their imbalances with silicon, have been recognized as one of the major causes of water quality and ecosystem deterioration in receiving waters. In this study, a periodic water quality monitoring was conducted in the rivers and streams of a tropical island (Ishigaki Island, Japan) to identify the factors controlling the concentrations of dissolved inorganic nitrogen (DIN), total phosphorus (TP) and dissolved silicon (DSi) with a special focus on the catchment characteristics (e.g., land use, surface geology, topography). Random Forest (RF) machine learning algorithm was employed to develop predictive models for nutrient concentrations from the catchment properties. The developed models could predict nutrient concentrations with sufficient accuracy, demonstrating that the studied nutrients are strongly affected by catchment properties. Agricultural land uses (e.g., livestock barn, sugarcane field) were ranked as the most important parameters for DIN and TP, while broadleaf forest was the most influential factor for DSi. Using the RF models, the contributions of DIN originating from sugarcane fields (i.e., fertilizers) and barns (i.e., manure) to riverine DIN were estimated, which were up to 60% in total in the studied river basins. Furthermore, the yield of DIN from sugarcane fields, calculated as the concentration of DIN derived from sugarcane fields divided by the percent area of sugarcane fields, strongly positively correlated with the areal coverage of limestone, suggesting that fertilizer-derived DIN is more prone to leaching out from cropland soil to groundwater and rivers in catchments with a higher dominance of calcareous geology. These results, including the methodology employed, have implications for water quality assessment and management in inland and coastal waters not only at the study site but also other regions., 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 © 2022 Elsevier Ltd. All rights reserved.)

We report the mechanochemical reactivity of the highly strained pentacyclic hydrocarbon cubane. The mechanical reactivity of cubane is explored for three regioisomers with 1,2-, 1,3-, and 1,4-substituted pulling attachments. Whereas all compounds can be activated thermally, mechanical activation is observed via pulsed ultrasonication of cubane-containing polymers only when force is applied via 1,2-attachment. The single observed product of the force-coupled reaction is a thermally inaccessible syn -tricyclooctadiene, in contrast to cyclooctatetraene (observed thermally) or a pair of cyclobutadienes that would result from sequential cyclobutane scission. We further quantify the mechanochemical reactivity of cubane by single molecule force spectroscopy, and force-coupled rate constants for ring opening reach ∼33 s -1 at a force of ∼1.55 nN, lower than forces of 1.8-2.0 nN that are typical of conventional cyclobutanes.

According to the "hydrodynamic theory," dentinal pain or sensitivity is caused by dentinal fluid movement following the application of various stimuli to the dentin surface. Recent convergent evidence in Vitro has shown that plasma membrane deformation, mimicking dentinal fluid movement, activates mechanosensitive transient receptor potential (TRP)/Piezo channels in odontoblasts, with the Ca 2+ signal eliciting the release of ATP from pannexin-1 (PANX-1). The released ATP activates the P2X 3 receptor, which generates and propagates action potentials in the intradental Aδ afferent neurons. Thus, odontoblasts act as sensory receptor cells, and odontoblast-neuron signal communication established by the TRP/Piezo channel-PANX-1-P2X 3 receptor complex may describe the mechanism of the sensory transduction sequence for dentinal sensitivity. To determine whether odontoblast-neuron communication and odontoblasts acting as sensory receptors are essential for generating dentinal pain, we evaluated nociceptive scores by analyzing behaviors evoked by dentinal sensitivity in conscious Wistar rats and Cre-mediated transgenic mouse models. In the dentin-exposed group, treatment with a bonding agent on the dentin surface, as well as systemic administration of A-317491 (P2X 3 receptor antagonist), mefloquine and 10 PANX (non-selective and selective PANX-1 antagonists), GsMTx-4 (selective Piezo1 channel antagonist), and HC-030031 (selective TRPA1 channel antagonist), but not HC-070 (selective TRPC5 channel antagonist), significantly reduced nociceptive scores following cold water (0.1 ml) stimulation of the exposed dentin surface of the incisors compared to the scores of rats without local or systemic treatment. When we applied cold water stimulation to the exposed dentin surface of the lower first molar, nociceptive scores in the rats with systemic administration of A-317491, 10 PANX, and GsMTx-4 were significantly reduced compared to those in the rats without systemic treatment. Dentin-exposed mice, with somatic odontoblast-specific depletion, also showed significant reduction in the nociceptive scores compared to those of Cre-mediated transgenic mice, which did not show any type of cell deletion, including odontoblasts. In the odontoblast-eliminated mice, P2X 3 receptor-positive A-neurons were morphologically intact. These results indicate that neurotransmission between odontoblasts and neurons mediated by the Piezo1/TRPA1-pannexin-1-P2X 3 receptor axis is necessary for the development of dentinal pain. In addition, odontoblasts are necessary for sensory transduction to generate dentinal sensitivity as mechanosensory receptor cells., 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 © 2022 Ohyama, Ouchi, Kimura, Kurashima, Yasumatsu, Nishida, Hitomi, Ubaidus, Kuroda, Ito, Takano, Ono, Mizoguchi, Katakura and Shibukawa.)

An inflammatory response following dental pulp injury and/or infection often leads to neurogenic inflammation via the axon reflex. However, the detailed mechanism underlying the occurrence of the axon reflex in the dental pulp remains unclear. We sought to examine the intracellular cyclic adenosine monophosphate (cAMP) signaling pathway in odontoblasts via the activation of G s protein-coupled receptors and intercellular trigeminal ganglion (TG) neuron-odontoblast communication following direct mechanical stimulation of TG neurons. Odontoblasts express heterotrimeric G-protein α-subunit Gα s and calcitonin receptor-like receptors. The application of an adenylyl cyclase (AC) activator and a calcitonin gene-related peptide (CGRP) receptor agonist increased the intracellular cAMP levels ([cAMP] i ) in odontoblasts, which were significantly inhibited by the selective CGRP receptor antagonist and AC inhibitor. Mechanical stimulation of the small-sized CGRP-positive but neurofilament heavy chain-negative TG neurons increased [cAMP] i in odontoblasts localized near the stimulated neuron. This increase was inhibited by the CGRP receptor antagonist. In the mineralization assay, CGRP impaired the mineralization ability of the odontoblasts, which was reversed by treatment with a CGRP receptor antagonist and AC inhibitor. CGRP establishes an axon reflex in the dental pulp via intercellular communication between TG neurons and odontoblasts. Overall, CGRP and cAMP signaling negatively regulate dentinogenesis as defensive mechanisms.

Vascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary high-risk plaques defined according to intravascular imaging have not been systematically studied. A total of 69 patients with coronary artery disease who underwent both optical coherence tomography and intravascular ultrasound imaging, and who provided blood specimens were included. Comprehensive biomarkers for inflammation, lipid, and coagulation were analyzed. Composite models sought biomarker patterns associated with thin-cap fibroatheroma (TCFA) and "high-risk plaques" (TCFA and large plaque burden). Two different composite models were developed for TCFA, based on the finding that high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1, fibrinogen, IL-6, homocysteine and amyloid A levels were elevated, and high-density lipoprotein cholesterol (HDL) and bile acid levels were decreased in these patients. Both composite models were highly accurate for detecting patients with TCFA (area under curve [AUC]: 0.883 in model-A and 0.875 in model-B, both p < 0.001). In addition, creatinine, hsCRP, fibrinogen, tumor necrosis factor-α, IL-6, homocysteine, amyloid A, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques". Two composite models were highly accurate for detection of patients with "high-risk plaques" (AUC: 0.925 in model-A and 0.947 in model-B, both p < 0.001). Biomarkers useful for detection of patients with high-risk coronary plaques defined according to intravascular imaging have been identified. These biomarkers may be useful to risk stratify patients and to develop targeted therapy.Clinical Trial Registration https://www.umin.ac.jp/ctr/ , UMIN000041692. Biomarkers and high-risk plaques hsCRP, PAI-1, fibrinogen, IL-6, homocysteine, amyloid A, HDL, and bile acid were useful for detecting patients with TCFA. hsCRP, fibrinogen, IL-6, homocysteine, amyloid A, creatinine, TNFα, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques" (plaque which has both TCFA and large plaque burden). White arrowhead denotes TCFA. Red and green dashed lines denote lumen area and external elastic membrane area, respectively., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The impact of psoas muscle area on overall survival is unknown for older patients undergoing elective thoracic endovascular aortic repair., Methods: We retrospectively reviewed 105 patients aged 75 years or more who underwent elective thoracic endovascular aortic repair for descending thoracic aortic aneurysm between January 2010 and December 2019. Psoas muscle area was measured at the L3 level with preoperative computed tomography and adjusted by height squared to derive psoas muscle mass index. The patients were stratified into two groups, sarcopenia and nonsarcopenia. sarcopenia was defined as a psoas muscle mass index less than 5.40 cm 2 /m 2 for men and less than 3.56 cm 2 /m 2 for women. The overall survival was compared with the age- and sex-matched general population using the one-sample log rank test. The propensity score adjusted Cox proportional hazards model was applied to determine the hazard ratio for all-cause mortality., Results: Twenty-three patients died during the follow-up period (median, 3 years). Thirty-eight patients (36%) were classified as sarcopenia. The 5-year overall survival rate was 46% (95% confidence interval, 29% to 73%) for sarcopenia and 84% (95% confidence interval, 74% to 94%) for nonsarcopenia. The overall survival was significantly lower in the sarcopenia group than in its matched general population (P = .004), whereas no statistically significant difference in overall survival was found between the nonsarcopenia group and its matched general population (P = .417). Sarcopenia was an independent risk factor for all-cause mortality (adjusted hazard ratio 2.64; 95% confidence interval, 1.02 to 6.82; P = .045)., Conclusions: Psoas muscle mass index may be a good predictor of mortality among older patients undergoing elective thoracic endovascular aortic repair for descending thoracic aortic aneurysm., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Aims: Data on B-type natriuretic peptide (BNP) levels and adverse outcomes in patients with moderate mixed aortic valve disease (MAVD), defined as moderate aortic stenosis (AS) and regurgitation (AR), are scarce. Therefore, this study investigated the impact of BNP on the clinical outcomes in such patients., Methods and Results: Clinical data from 81 patients (mean age, 74.1 ± 6.8 years; 50.6%, men) treated for moderate MAVD and left ventricular ejection fraction (LVEF) ≥ 50% during 2010-2018 were retrospectively analysed. Specific echocardiographic data of the study patients were LVEF of 57.8 ± 5.0%, aortic valve index of 0.64 ± 0.04 cm 2 /m 2 , peak aortic valve velocity of 3.38 ± 0.29 m/s, and AR vena contracta width of 4.2 ± 0.7 mm. The median BNP level was 61.4 pg/mL (interquartile range, 29.7-109.9). The primary endpoint was a composite of all-cause death, heart failure hospitalization, and aortic valve replacement, and its cumulative incidence at 5 years was 57.7%. Multivariable analysis revealed that age (hazard ratio, 1.079; 95% confidence interval, 1.028-1.133; P = 0.002) and BNP levels (hazard ratio, 1.028; 95% confidence interval, 1.003-1.053; P = 0.027) were significantly related to the endpoint; specifically, BNP > 61.4 pg/mL had significantly higher incidence rates of the endpoint than those with a BNP ≤ 61.4 pg/mL (70.3% vs. 45.5% at 5 years; P = 0.018). Compared with patients with BNP ≤ 61.4 pg/mL, those with BNP > 61.4 pg/mL had significantly worse left ventricular global longitudinal strain (-17.1 ± 3.6% vs. -18.7 ± 2.6%; P = 0.029), along with higher left ventricular mass index (116.9 ± 27.8 g/m 2 vs. 103.5 ± 19.7 g/m 2 ; P = 0.014), relative wall thickness (0.45 ± 0.07 vs. 0.42 ± 0.05; P = 0.022), left atrial volume index (46.0 ± 28.4 mL/m 2 vs. 31.4 ± 10.3 mL/m 2 ; P = 0.003), pulmonary artery systolic pressure (32.6 ± 9.7 mmHg vs. 28.2 ± 4.7 mmHg; P = 0.011), and prevalence of moderate or greater tricuspid regurgitation (15.0% vs. 0.0%; P = 0.012)., Conclusions: Patients with moderate MAVD are at higher risk of unfavourable clinical outcomes, and age and BNP are independently related to the occurrence of adverse events. High BNP levels may reflect extravalvular cardiac damage in patients with moderate MAVD., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Connectivity is key to understanding neural circuit computations. However, estimating in vivo connectivity using recording of activity alone is challenging. Issues include common input and bias errors in inference, and limited temporal resolution due to large data requirements. Perturbations (e.g. stimulation) can improve inference accuracy and accelerate estimation. However, optimal stimulation protocols for rapid network estimation are not yet established. Here, we use neural network simulations to identify stimulation protocols that minimize connectivity inference errors when using generalized linear model inference. We find that stimulation parameters that balance excitatory and inhibitory activity minimize inference error. We also show that pairing optimized stimulation with adaptive protocols that choose neurons to stimulate via Bayesian inference may ultimately enable rapid network inference.

Objectives: In the selection of thoracic endovascular repair for aortic dissection (AD), it is important to distinguish between the subacute and chronic phases, but there is no reliable way to distinguish between them in patients with unknown onset of AD. The purpose of this study was to assess the diagnostic performance of 2-[18F] fluoro-2-deoxy-d-glucose (18F-FDG)-PET/computed tomography (PET/CT) for discriminating subacute AD from chronic AD., Methods: Thirteen patients with AD who were medically treated and followed up for 6 months were studied. 18F-FDG PET/CT images were obtained for each patient in the subacute phase (the first scan) and at 6 months (the second scan) after the onset. Target-to-background ratio (TBR) was measured as the maximum standardized uptake value (SUV) in the dissected aortic wall divided by blood pool SUV., Results: TBR was significantly higher in the first scan (mean ± SD, 1.97 ± 0.32) than in the second scan (1.69 ± 0.29, P = 0.007). The area under the receiver operating characteristic curve of TBR for discriminating subacute AD from chronic AD was 0.76. With a threshold of 1.74, the TBR showed the sensitivity, specificity, and positive and negative predictive value of 85%, 69%, 73%, and 82%, respectively, for the discrimination of subacute AD from chronic AD., Conclusion: Metabolic assessment of dissected aortic wall by 18F-FDG PET/CT is useful in differentiating between subacute and chronic AD and can provide important information in determining the appropriate indication for treatment for patients with AD of unknown onset., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Although the simple single stenting rather than complex double stenting is recommended on percutaneous coronary intervention (PCI) for bifurcation lesions, double stenting cannot always be avoided. We investigated the impact of directional coronary atherectomy (DCA), followed by drug-coated balloon (DCB) treatment to reduce the number of stents and avoid complex stenting in PCI for bifurcation lesions and short-term patency. DCA treatment without stents was attempted for 27 bifurcation lesions in 25 patients, of those, 26 bifurcation lesions in 24 patients were successfully treated and 3-month follow-up angiography and optical coherence tomography (OCT) were performed. Sixteen lesions (59.3%) were related to left main trunk distal bifurcations, and 7 (25.9%) were true bifurcation lesions. Among the true bifurcation lesions, 4 lesions (57.1%) needed 1 stent, and the other 3 lesions (42.9%) needed no stents. Among the non-true bifurcation lesions, 1 lesion (5.0%) needed bailout stent and other lesions (95.0%) needed no stents. According to DCA followed by DCB treatment, the angiographic mean diameter stenosis improved from 65.5 ± 15.0% to 7.8 ± 9.8%, and the mean plaque area in intravascular ultrasound improved from 80.4 ± 10.5% to 39.0 ± 11.5%, respectively. Angiographic and OCT late lumen loss values were 0.2 ± 0.6 mm and 1.4 ± 1.9 mm, respectively. No patient had in-hospital major adverse cardiac events (MACE) and 3-month MACE. In conclusion, compared with standard provisional side branch stenting strategy, DCA followed by DCB treatment might reduce the number of stents, avoid complex stenting for major bifurcation lesions and provide good short-term outcomes., (© 2021. Springer Japan KK, part of Springer Nature.)