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Abstract Aims Liver fibrosis predisposes patients to liver failure and hepatocellular carcinoma. Various markers, which can be calculated easily from serum parameters, have been reported to predict liver fibrosis accurately. This study investigated the prognostic factors, including blood‐based markers for liver fibrosis of patients with hepatocellular carcinoma following initial curative hepatectomy. Methods This retrospective study included 407 patients with hepatocellular carcinoma who underwent initial curative hepatectomy between April 2010 and December 2017. We investigated prognosis‐associated variables in these patients. Results Among the blood‐based markers for liver fibrosis examined in this study, the steatosis‐associated fibrosis estimator score demonstrated the best predictive capabilities. This score was revealed as a poor prognostic factor for both overall survival and recurrence‐free survival in patients with hepatocellular carcinoma following initial curative hepatectomy. A high steatosis‐associated fibrosis estimator score was independently associated with poor overall survival and recurrence‐free survival. After propensity score‐matching to minimize bias between high‐ and low‐steatosis‐associated fibrosis estimator score groups, the high steatosis‐associated fibrosis estimator score remained associated with poor overall survival and recurrence‐free survival. Conclusions The steatosis‐associated fibrosis estimator score is an independent predictor of long‐term prognosis in patients with hepatocellular carcinoma following initial curative hepatectomy.

The mean height is taller in males than in females, except for early teens. In this regard, previous studies have revealed that (1) distribution of the mean adult heights in subjects with disorders accompanied by discordance between sex chromosome complement and bioactive sex steroids and in control subjects (the British height standards) indicates that, of the ~12.5 cm of sex difference in the mean adult height, ~9 cm is accounted for by the difference in the sex chromosome complement and the remaining ~3.5 cm is explained by the dimorphism in sex steroids (primarily due to the growth-promoting effect of gonadal androgens); (2) according to the infancy-childhood-puberty growth model, the sex difference in the childhood growth function produces height differences of ~1 cm in childhood and 8–10 cm at 18–20 years of age, whereas the sex difference in the pubertal growth function yields height difference of ~4.5 cm at 18–20 years of age; and (3) SHOX expression and methylation analyses using knee cartilage tissues and cultured chondrocytes have shown lower SHOX expression levels in female samples than in male samples and methylation patterns consistent with partial spreading of X-inactivation affecting SHOX in female samples. These findings suggest that small but persistent sex difference in SHOX expression dosage leads to the variation in the sex steroid independent childhood growth function, thereby yielding the sex difference in height which remains small in childhood but becomes obvious in adulthood.

Abstract Background Primary central nervous system lymphoma (PCNSL) is a rare lymphoid malignancy. Systemic profiling of the PCNSL tumor microenvironment (TME) was previously conducted through gene expression analysis. We investigated the prognostic impact of TME on survival to establish novel prognostic biomarkers in PCNSL patients. Methods We analyzed expression levels of 770 neuroinflammation‐related (NFR) genes via NanoString nCounter technology in tumor samples from 30 PCNSL patients. Genes related to the “recurrence group (RG)” or “non‐recurrence group (NRG)” were identified and validated using whole transcriptomic analysis of an independent PCNSL cohort (n = 30). Results Forty‐five of 770 NFR genes were highly expressed in the RG (3‐year overall survival (OS, 22.2%), compared with the NRG group (3‐year OS 66.7%). Signatures related to glial cells were enriched in the RG‐associated gene set. Multivariate analysis revealed that high expressions of TUBB4A (p = 0.028, HR: 3.88), S100B (p = 0.046, HR: 3.093), and SLC6A1 (p = 0.034, HR: 3.765) were significantly related to death. Expression levels of these three genes were also significantly associated with poor OS in the validation cohort. Immunohistochemical staining against TUBB4A, S100B, and proteins specific to glial cells (GFAP, OLIG2, and CD68) revealed significantly higher positivity in RG glial cells. Conclusion These data suggest that TME‐related genes play a crucial role in the pathogenesis of PCNSL, complementing the well‐known involvement of the NF‐kB signaling pathway. TME targeting, especially glial cell‐specific proteins, may thus open new and complementary avenues of therapy for all stages of PCNSL.

Abstract Background A wearable cardioverter defibrillator (WCD) is indicated for a limited period in patients at high risk of sudden cardiac death (SCD). Nonischemic heart failure (HF) is common among Japanese patients with HF. The aim of this study was to evaluate the incidence of fatal arrhythmias during WCD use and the clinical outcomes after WCD withdrawal in Japanese patients with HF. Methods We retrospectively studied 105 hospitalized HF patients who were discharged with a WCD. The main outcome was SCD/ventricular arrhythmias during WCD use and the other outcomes were implantation of an implantable cardioverter‐defibrillator (ICD), SCD/ventricular arrhythmias after WCD withdrawal, and changes in left ventricular ejection fraction (LVEF). Results Eighty‐seven (83%) patients received a WCD for primary prevention of SCD, of whom 60 (69%) were new‐onset HF patients with an LVEF ≤35%. The median daily wear time was 22.1 h. Two patients experienced sustained ventricular tachycardia and one patient experienced atrioventricular block with asystole while on WCD. After WCD withdrawal, 81 (77%) patients decided not to receive ICD implantation. The percentage of patients with an LVEF ≥35% increased from 20% at baseline to 70% at 1 year after discharge. During the median follow‐up of 50 months, 78 (96%) of the 81 patients who did not have an ICD were free of SCD/ventricular arrhythmias. Conclusions The use of a WCD is useful for determining the appropriate indication for ICD implantation in Japanese patients with new‐onset HF, a low LVEF, and a risk of SCD.

Abstract Aim Social anxiety disorder (SAD) is a common disorder characterized by excessive fear of scrutiny and embarrassment, leading to severe distress and avoidance behaviors or dysfunctions. SAD and other relevant diseases have been reported to be associated with a higher risk of aging‐related diseases, such as Alzheimer's disease, Parkinson's disease, and diabetes mellitus. Recently, epigenetic clock analysis, which measures biological aging based on comprehensive DNA methylation (DNAm) status, has been widely conducted. We conducted epigenetic clock analyses in patients with SAD and controls, examining various epigenetic age acceleration and DNAm‐based predictive values of aging‐related proteins (GrimAge components and GrimAge2 components), including leptin level. Methods We used the publicly available DNAm dataset, GSE164056, which consists of 66 patients with SAD and 77 controls of Caucasian descent aged between 18 and 50 years. We conducted regression analyses investigating the association between SAD and various indices of epigenetic aging, using age and sex as covariates. Results None of the epigenetic clocks showed significant differences in age acceleration. Of the DNAm‐based predictive values of aging‐related proteins, leptin level in GrimAge components (q = 0.0123) and GrimAge2 components (q = 0.0123) were significantly lower in patients with SAD than in controls. Conclusions The results of this study suggested that leptin may be involved in SAD pathogenesis as an aging‐related protein. Therefore, further studies with different designs are required.

Abstract Aim Overweight is associated with low‐grade systemic inflammation. However, its effect on neuroinflammation remains unclear. We examined the possible association between overweight and neuroinflammation using cerebrospinal fluid (CSF) in a nonclinical adult population in Japan. Methods CSF and plasma levels of interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), plasma levels of C‐reactive protein (CRP), and leptin were measured in nonclinical adult participants (35 males and 34 females) who had no current or past history of neuropsychiatric diseases. We performed partial correlation analyses with sex and age as covariates between the body mass index (BMI) and the inflammatory markers and compared them between overweight and nonoverweight participants. Results The BMI significantly correlated with CSF levels of IL‐6 (rs = 0.32, p = 0.009), plasma levels of CRP (rs = 0.30, p = 0.016), IL‐1β (rs = 0.29, p = 0.019), IL‐6 (rs = 0.25, p = 0.042), TNF‐α (rs = 0.43, p

Abstract Introduction Studies have shown the antitumor efficacy of immune checkpoint inhibitors (ICI) in patients with non‐small cell lung cancer (NSCLC) and brain metastases (BM). However, it is unclear whether the efficacy of ICI is similar between patients with and without BM. It is yet unclear whether the efficacy of ICI in patients with BM increases with higher levels of programmed cell death‐ligand 1 (PD‐L1) expression, as observed in patients without BM. Methods We compared the outcomes of ICI treatment between patients with and without BM using a cohort containing 1741 prospectively enrolled patients with lung cancer. We investigated whether there were differences in the outcomes of ICI based on PD‐L1 expression levels between these patients. Results We enrolled 240 patients with NSCLC with or without BM who were treated with ICI or both chemotherapy and ICI. There were no significant differences in overall survival (OS) between all patients with or without BM (p = 0.489). However, OS was significantly shorter in patients with BM than in those without in the PD‐L1 ≥ 50% group (16.5 M vs. 30.6 M, p = 0.003) but not in the PD‐L1 ≥ 1% or negative group. BM was an independent poor prognostic factor for OS (hazard ratio: [95% confidence interval], 2.045; [1.058–3.953], p = 0.033) in the PD‐L1 ≥ 50% group. Conclusion Our study indicated that the outcomes of patients with or without BM treated with ICI were not significantly different. The efficacy of ICI in patients with PD‐L1 expression ≥50% would be lower in patients with BM than in those without.

P2X receptors (P2X1–7) are non-selective cation channels involved in many physiological activities such as synaptic transmission, immunological modulation, and cardiovascular function. These receptors share a conserved mechanism to sense extracellular ATP. TNP-ATP is an ATP derivative acting as a nonselective competitive P2X antagonist. Understanding how it occupies the orthosteric site in the absence of agonism may help reveal the key allostery during P2X gating. However, TNP-ATP/P2X complexes (TNP-ATP/human P2X3 (hP2X3) and TNP-ATP/chicken P2X7 (ckP2X7)) with distinct conformations and different mechanisms of action have been proposed. Whether these represent species and subtype variations or experimental differences remains unclear. Here, we show that a common mechanism of TNP-ATP recognition exists for the P2X family members by combining enhanced conformation sampling, engineered disulfide bond analysis, and covalent occupancy. In this model, the polar triphosphate moiety of TNP-ATP interacts with the orthosteric site, while its TNP-moiety is deeply embedded in the head and dorsal fin (DF) interface, creating a restrictive allostery in these two domains that results in a partly enlarged yet ion-impermeable pore. Similar results were obtained from multiple P2X subtypes of different species, including ckP2X7, hP2X3, rat P2X2 (rP2X2), and human P2X1 (hP2X1). Thus, TNP-ATP uses a common mechanism for P2X recognition and modulation by restricting the movements of the head and DF domains which are essential for P2X activation. This knowledge is applicable to the development of new P2X inhibitors.

The longevity of an extraoral prosthesis depends on its physical and mechanical properties and user maintenance. Faced with multiple outcome measures, researchers find it difficult to determine the most appropriate extraoral prosthetic material. This comprehensive review evaluates the most used extraoral prosthesis materials and qualitatively assesses their longevity and function. The study aims to identify and interpret the results of current updates on the factors that affect longevity and functionality. This comprehensive review summarizes and evaluates differences in the properties of commonly used extraoral maxillofacial prosthetic materials. The review was planned to focus on all factors related to the longevity and function of the extraoral maxillofacial prosthetics. An electronic search covered English articles in PubMed, Scopus, Google Scholar, Web of Science, and grey literature. Manual searching was also performed. Six authors participated in the screening. Search engines extracted 1107 records, and 88 studies were included for qualitative and bias assessments. Silicones are the most frequently used extraoral maxillofacial prosthetic materials. Heat-cured silicones are more color-stable than those cured at room temperature. Additional ingredients and processing techniques affect prosthesis longevity.

Neuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by spheroid (swollen axon) formation in the nervous system. In the present study, we focused on a newly established autosomal recessive mutant strain of F344-kk/kk rats with hind limb gait abnormalities and ataxia from a young age. Histopathologically, a number of axonal spheroids were observed throughout the central nervous system, including the spinal cord (mainly in the dorsal cord), brain stem, and cerebellum in F344-kk/kk rats. Transmission electron microscopic observation of the spinal cord revealed accumulation of electron-dense bodies, degenerated abnormal mitochondria, as well as membranous or tubular structures in the axonal spheroids. Based on these neuropathological findings, F344-kk/kk rats were diagnosed with NAD. By a positional cloning approach, we identified a missense mutation (V95E) in the Hspa8 (heat shock protein family A (Hsp70) member 8) gene located on chromosome 8 of the F344-kk/kk rat genome. Furthermore, we developed the Hspa8 knock-in (KI) rats with the V95E mutation using the CRISPR-Cas system. Homozygous Hspa8-KI rats exhibited ataxia and axonal spheroids similar to those of F344-kk/kk rats. The V95E mutant HSC70 protein exhibited the significant but modest decrease in the maximum hydrolysis rate of ATPase when stimulated by co-chaperons DnaJB4 and BAG1 in vitro, which suggests the functional deficit in the V95E HSC70. Together, our findings provide the first evidence that the genetic alteration of the Hspa8 gene caused NAD in mammals.

The present study examines the effects of novelty seeking (NS) personality trait on the undervaluation of product creativity, specifically the tendency to undervalue the usefulness of novel ideas or products, a bias termed “usefulness undervaluation bias”. Creativity is defined by novelty and usefulness, and it has been reported that there is a bias to undervalue the usefulness of novel creations due to uncertainty in judging it. In this study, two studies were conducted to determine whether individuals with high NS are reduced in this bias. Study 1 confirmed that individuals with higher NS rated creativity more positively, consistent with previous findings on openness to experience. Study 2 showed that raters with higher NS were less likely to underrate the usefulness of novel products, suggesting that NS moderates the relationship between perceived novelty and usefulness. These findings indicate that personality trait, especially NS, play an important role in creativity evaluation.

Animals use past experience to guide future choices. The integration of experiences typically follows a hyperbolic, rather than exponential, decay pattern with a heavy tail for distant history. Hyperbolic integration affords sensitivity to both recent environmental dynamics and long-term trends. However, it is unknown how the brain implements hyperbolic integration. We found that mouse behavior in a foraging task showed hyperbolic decay of past experience, but the activity of cortical neurons showed exponential decay. We resolved this apparent mismatch by observing that cortical neurons encode history information with heterogeneous exponential time constants that vary across neurons. A model combining these diverse timescales recreated the heavy-tailed, hyperbolic history integration observed in behavior. In particular, the time constants of retrosplenial cortex (RSC) neurons best matched the behavior, and optogenetic inactivation of RSC uniquely reduced behavioral history dependence. These results indicate that behavior-relevant history information is maintained across multiple timescales in parallel and that RSC is a critical reservoir of information guiding decision-making.