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Abstract Craniometaphyseal dysplasia (CMD), a rare craniotubular disorder, occurs in an autosomal dominant (AD) or autosomal recessive (AR) form. CMD is characterized by hyperostosis of craniofacial bones and metaphyseal flaring of long bones. Many patients with CMD suffer from neurological symptoms. The pathogenesis of CMD is not fully understood. Treatment is limited to craniofacial surgery. Here, we report a knock in (KI) mouse model for AR CMD carrying a Cx43R239Q mutation. Cx43 KI/KI mice replicate typical features of AR CMD, including thickening of craniofacial bones, club-shaped femurs, and widened diaphyseal cortical bones. Female Cx43 KI/KI mice display remarkably more bone overgrowth than male Cx43 KI/KI mice as they age. In contrast to Cx43 +/+ littermates, Cx43 KI/KI mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones. Although formation of resting OCs in Cx43 +/+ and Cx43 KI/KI mice is comparable, the actively resorbing Cx43 KI/KI OCs have reduced resorption on bone chips. Cx43 KI/KI mice display reduced osteocyte dendrites. RNA from Cx43 KI/KI femoral cortical bones show reduced expression levels of Sost, Tnf-α, IL-1β, Esr1, Esr2, and a lower Rankl/Opg ratio. Moreover, the Cx43R239Q mutation results in altered spatial expression of Cx43 protein and mild reduction of gap junction and hemichannel activity. The distinct phenotype seen in Cx43 KI/KI mice but not in Cx43 ablation models suggests that Cx43 loss-of-function is unlikely the main cause of AR CMD. Additional studies are required to investigate new roles of CMD-mutant Cx43.

Abstract This study investigated the association between green tea or coffee consumption with cerebral white matter lesions and hippocampal and total brain volumes among 8766 community-dwelling participants recruited from the Japan Prospective Studies Collaboration for Aging and Dementia between 2016 and 2018. A Food Frequency Questionnaire was used to assess green tea and coffee consumption, whereas brain magnetic resonance imaging was performed to assess cerebral white matter lesions, hippocampal volume, and total brain volume. Multivariable-adjusted analysis revealed significant correlations between fewer cerebral white matter lesions and higher green tea consumption, whereas no significant differences were found between green tea consumption and hippocampal or total brain volume. Regarding coffee consumption, no significant differences were observed in cerebral white matter lesions or hippocampal or total brain volumes. Hence, higher green tea consumption was associated with fewer cerebral white matter lesions, suggesting that it may be useful in preventing dementia.

Excimer fluorescent ultraviolet (UV) lamps (UV–228) function as mercury–free sources that use excimer emissions as excitation light sources. First, we evaluated the effects of UV–228–based irradiation (λmax = 228 nm) on the viability of fungi, using Penicillium digitatum, and compared these effects with those of other light sources, such as OEL–222 (λmax = 222 nm) and GL–6 (λmax = 254 nm), to evaluate the effectiveness of the excimer fluorescent lamp. Next, we investigated the effects of UV–228–based irradiation on strawberry storage. Although UV–228 affected weight loss, Brix, ascorbic acid, polyphenol, and DPPH, the effects of UV irradiation for 5 min on strawberry fruit quality were minimal; i.e., only weight loss and ascorbic acid content were higher than those in the non–irradiated treatment. We found that 5 min of UV–C irradiation using UV–228 prevented mold emergence for up to 11 days of storage in strawberries These results indicate that UV–228 contributes to long–term strawberry storage.

Background The effect of sarcopenia on depressive mood during geriatric rehabilitation remains unclear. This study investigated the potential influence of sarcopenia on depressive mood among geriatric patients in a rehabilitation setting. Methods This observational cohort study enrolled 204 patients aged ≥65 years (mean age, 78.8±7.6 years; women, 45.1%) admitted to a rehabilitation unit between April 2020 and July 2021. Sarcopenia was diagnosed based on the Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment criteria, which include low handgrip strength and muscle mass. Depressive mood was defined as a 15-item Geriatric Depression Scale score of ≥6 points. We applied logistic regression models to examine the influence of sarcopenia on depressive mood at discharge. Results We observed sarcopenia in 58.3% of patients. The logistic regression model showed that sarcopenia negatively influenced depressive mood at discharge (odds ratio=5.460; 95% confidence interval, 2.344–13.415). Of the 68 patients without depressive mood at admission, those with sarcopenia (n=31) had a significantly higher incidence of depressive mood at discharge compared with patients without sarcopenia (n=37) (41.9% vs. 16.2%, p=0.037). Conclusion Sarcopenia at admission negatively affected depressive mood at discharge from geriatric rehabilitation. Thus, early and routine assessment of sarcopenia is vital for patients undergoing geriatric rehabilitation.

Migratory birds carry ticks harboring various pathogens, including the zoonotic Yezo virus. In Hokkaido, Japan, we collected ticks from migratory birds during 2020–2021. Eight of 385 pools, comprising 2,534 ticks, tested positive for Yezo virus RNA, suggesting Yezo virus might be spread through the flyways of migratory birds.

This study applies ecosystem research and knowledge creation theory to examine the process of forming sustainable regional ecosystems. In particular, we will focus on the connections and movements of local people and entities. This will open up a new research field, and by doing so, we aim to make both ecosystem research and knowledge creation theory research contribute to solving social issues and creating social value that the world of the 21st century will face.

Abstract Background Over the past half-century, numerous scales have been designed to quantify outcomes in people with severe mental health disorders. However, little is known about the views of people diagnosed with schizophrenia on individual outcome scales, particularly outside of European countries. Aim We conducted a qualitative study to examine the perspectives of people with schizophrenia on multiple scales in Japan. Methods Eleven participants took part in focus group interviews. Five had extensive experience as mental health peer supporters; the others had no such experience. To address potential power imbalances and facilitate dynamic discourse, participants were intentionally divided into two groups on the basis of peer support experience, and two simultaneous two-hour focus group interviews were conducted in separate rooms. The participants reviewed 12 clinical and patient-reported outcome measures and discussed their views on each measure. Interview data for each group were combined prior to analysis and qualitatively analyzed by four researchers using a thematic analysis approach. Results The average age of the participants was 42.7 years (SD = 8.3), and six were male. On average, the participants had been living with schizophrenia for 22.2 years (SD = 11.1). After analyzing the interview data, the following five themes were identified, each containing two to seven subthemes: 1) validity and format of the scale construct, 2) factors affecting the accuracy of responses, 3) plain language and familiar words in Japanese culture, 4) psychological impact on the respondents, and 5) containing important items in everyday life. Conclusion The participants provided both favorable and unfavorable feedback on each scale. When implementing research utilizing clinical outcome scales and patient-reported outcome measures, researchers should exercise caution considering the potential emotional impact on respondents. Furthermore, scale development should take into account the cultural background and psychological burden experienced by the respondents.

Abstract Background Age and sex differences in sarcopenic dysphagia are unknown. The purpose is to characterize age and sex differences in sarcopenic dysphagia. Methods A cross‐sectional and retrospective cohort study using information from the Japanese database on sarcopenic dysphagia was performed. We investigated age and sex differences between sarcopenic dysphagia and other forms of dysphagia. We investigated whether differences in prognosis for swallowing function, as assessed by the Food Intake Level Scale, and activities of daily living (ADL), as assessed by the Barthel Index were influenced by age and sex in patients with sarcopenic dysphagia. Results The study included 460 patients, including 229 men and 231 women, with a mean age of 81 ± 10 years. Fifty‐eight percent of the patients had sarcopenic dysphagia. Age was independently associated with sarcopenic dysphagia (odds ratio (OR): 1.056, 95% confidence interval (CI): 1.035, 1.078), although sarcopenic dysphagia could also be seen in those younger than 65 years. Sex was not independently associated with sarcopenic dysphagia. The age cut‐off for the diagnosis of sarcopenic dysphagia was 82 years in all patients (sensitivity, 0.660; specificity, 0.644), 80 years in men (sensitivity, 0.619; specificity, 0.631), and 83 years in women (sensitivity, 0.723; specificity, 0.577). Sarcopenic dysphagia showed no significant differences in the improvement of swallowing function and ADL based on age and sex. Conclusions Sarcopenic dysphagia was most common in older adults in their 80s or older. The possibility of sarcopenic dysphagia should be considered when dysphagia is present in people 80 years of age or older.

Abstract The level of dynamic mechanical instability between the bony parts of the ankle joint provides important information on biomechanical function. However, the dynamics of the distance between the talus and lateral malleolus during gait remain unclear. This study aimed to compare the distance between the talus and lateral malleolus and the ankle joint angles during the stance phase of gait between individuals with chronic ankle instability (CAI) and healthy adults. The comparison was conducted using a synchronized ultrasound (US) imaging with a three-dimensional motion analysis (MA) system. This cross-sectional study included 12 participants (5 males, 7 females; age, 20.5 ± 1.8 years; height, 166.6 ± 9.4 cm; body weight, 60.2 ± 5.3 kg; body mass index, 21.7 ± 2.0 kg/m2; 16 feet) with CAI and 10 healthy controls (4 males, 6 females; age, 21.2 ± 1.6 years; height, 164.6 ± 10.5 cm; body weight, 56.8 ± 11.3 kg; body mass index, 20.8 ± 2.6 kg/m2; 20 feet). The distance between the talus and lateral malleolus during gait was significantly increased in the CAI group compared with that in the control group throughout the stance phase. The ankle dorsiflexion angle was smaller in the CAI group during the middle and terminal stance phases. Additionally, the ankle inversion angle was greater in the CAI group than in the control group. Our findings show the application of the synchronized US and MA system in the assessment of mechanical instability in CAI group, which may be used to determine treatment efficacy.

Abstract Background Interatrial right-to-left shunt flow through a patent foramen ovale (PFO) can be caused by changes in heart position for anastomosis during off-pump coronary artery bypass (OPCAB). We herein present a case in which the direction of PFO shunt flow changed with heart position during OPCAB and the ventilation settings after sternal closure. Case presentation A 66-year-old man with interstitial pneumonia underwent OPCAB. Preoperative transesophageal echocardiography revealed right-to-left shunt flow through a PFO induced by the Valsalva maneuver. During OPCAB, heart displacement resulted in right-to-left shunting and acute hypoxemia, which quickly improved with increase of inspired oxygen fraction. After chest closure, bidirectional shunt flow developed under increased airway pressure. Conclusions Vigilant intraoperative monitoring with TEE and postoperative airway pressure management are important to address shunt flow and hypoxemia due to PFO.

Abstract This study aimed to translate a web-based hamstring outcome score (HaOS) questionnaire to the Japanese context. First, the validity and reliability of the translated questionnaires were examined among Japanese athletes. Second, the association between the previous history of hamstring strain and HaOS was examined. The translation was performed according to internationally recognized methodologies. A total of 233 athletes were asked to complete the HaOS questionnaire, and four questions were added to examine the content validity of the questionnaire. Intraclass correlation coefficient (ICC) was calculated to evaluate the test–retest reliability. Internal consistency was determined by calculating Cronbach’s alpha values. The translated questionnaires had high acceptance and compliance rates, with a response rate of 84.4%. The ICC for each scale ranged from 0.80 to 0.93, and Cronbach's α from 0.72 to 0.96, confirming good reliability and high internal consistency. HaOS of the previous injury group (93.4 [78.9, 100]) was significantly lower than that of the healthy group (86.2 [68.1, 100]) (p

Abstract We recorded dopamine release signals in centromedial and centrolateral sectors of the striatum as mice learned consecutive versions of visual cue-outcome conditioning tasks. Dopamine release responses differed for the centromedial and centrolateral sites. In neither sector could these be accounted for by classic reinforcement learning alone as classically applied to the activity of nigral dopamine-containing neurons. Medially, cue responses ranged from initial sharp peaks to modulated plateau responses; outcome (reward) responses during cue conditioning were minimal or, initially, negative. At centrolateral sites, by contrast, strong, transient dopamine release responses occurred at both cue and outcome. Prolonged, plateau release responses to cues emerged in both regions when discriminative behavioral responses became required. At most sites, we found no evidence for a transition from outcome signaling to cue signaling, a hallmark of temporal difference reinforcement learning as applied to midbrain dopaminergic neuronal activity. These findings delineate a reshaping of striatal dopamine release activity during learning and suggest that current views of reward prediction error encoding need review to accommodate distinct learning-related spatial and temporal patterns of striatal dopamine release in the dorsal striatum.

Abstract Introduction Mathematical modeling can provide quantitative understanding of the viral dynamics and viral reduction effects of drugs and enable simulations of the dynamics in various scenarios. In this study, a drug effect model of ensitrelvir was developed to describe the viral reduction effect. Using the model, we also estimated the impact of treatment with ensitrelvir on the reduction in the number of infected patients at the population level in Japan. Methods The drug effect model of ensitrelvir was developed based on a viral dynamic model for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a population pharmacokinetic model of ensitrelvir using 10,477 samples of viral load from 1447 patients with coronavirus disease 2019 (COVID-19) in a phase 2/3 study. It was assumed that the drug effect on SARS-CoV-2 promoted the viral clearance depending on the free plasma concentrations. We estimated the impact of ensitrelvir treatment on the reduction in the number of infected patients at the population level in Japan using the susceptible–infectious–recovered–susceptible (SIRS) model including transmission mitigation. Results The viral reduction effect of ensitrelvir was characterized as a promotion of viral clearance depending on the plasma ensitrelvir concentrations using the E max model. The maximum reduction effect was considered to depend on the time from symptom onset to treatment. The maximum transmission mitigation effect was observed when treatment was initiated within 12–24 h of symptom onset, and secondary infections could be reduced by administering ensitrelvir as soon as possible after symptom onset. Conclusion The viral reduction by ensitrelvir could be characterized based on the viral dynamics, and the dynamics could be estimated using the drug effect model. Furthermore, the drug effect on population level transmission based on the dynamics could be estimated. Thus, the simulation could be conducted for various conditions.

Abstract Skeletal muscle mesenchymal progenitors (MPs) play a critical role in supporting muscle regeneration. However, under pathological conditions, they contribute to intramuscular adipose tissue accumulation, involved in muscle diseases, including muscular dystrophy and sarcopenia, age-related muscular atrophy. How MP fate is determined in these different contexts remains unelucidated. Here, we report that Ror2, a non-canonical Wnt signaling receptor, is selectively expressed in MPs and regulates their pathological features in a differential ligand-dependent manner. We identified Wnt11 and Wnt5b as ligands of Ror2. In vitro, Wnt11 inhibited MP senescence, which is required for normal muscle regeneration, and Wnt5b promoted MP proliferation. We further found that both Wnts are abundant in degenerating muscle and synergistically stimulate Ror2, leading to unwanted MP proliferation and eventually intramuscular adipose tissue accumulation. These findings provide evidence that Ror2-mediated signaling elicited by differential Wnts plays a critical role in determining the pathological fate of MPs.

Objectives: The objective of this study was to investigate the safety and utility of hybrid uterine septal resection. Materials and Methods: This retrospective cohort trial included 16 patients who underwent hybrid uterine septal resection at Hyogo Medical University Hospital between January 2017 and September 2021. Hysteroscopic uterine septum resection was performed in 16 patients, whereas 5 patients with vaginal septal complications underwent an additional vaginal septectomy under supervision by thin laparoscopy and fluoroscopy. The main outcome measures were pregnancy success rate and procedure safety. Results: The results showed that the median operative time was 77 (46–114) min, and no cases of intraoperative or postoperative adverse events were identified. The postoperative pregnancy rate was 100.0% (7/7) and the live birth rate was 71% (5/7) in women with recurrent pregnancy loss. Among women with infertility, the postoperative pregnancy rate was 55.5% (5/9), and the live birth rate was 20% (1/5). Conclusion: These findings indicate that our hybrid septal resection technique reduces patient burden and ensures safe and reliable surgery, with good results in terms of postoperative complications, pregnancy, and miscarriage rates.

Fibroblast growth factor (FGF) 21, a hormone produced by the liver, improves glucose and lipid metabolism. We recently demonstrated that the FGF21 gene (Fgf21) underwent DNA demethylation in the mouse liver via peroxisome proliferator-activated receptor (PPAR) α during the fetal to lactation periods. Furthermore, we found that the DNA methylation state of Fgf21 was involved in obesity in adult animals. In the present study, we analyzed the DNA methylation state of the FGF21 gene (FGF21) in obese patients using genomic DNA extracted from human monocytes and macrophages and investigated the pathophysiological significance of the FGF21 expression response to pemafibrate (PM), a PPARα ligand. We examined 67 patients with obesity stratified into in- and outpatient cohorts. A positive correlation was observed between serum FGF21 levels and triglyceride (TG) levels before PM administration. However, changes in serum FGF21 levels following PM administration did not correlate with the FGF21 DNA methylation rate, except at one CpG site. The body mass index (BMI) and serum TG levels positively correlated with the FGF21 DNA methylation rate, particularly at different CpG positions. A negative correlation was observed between absolute changes in serum FGF21 levels and the ratio of change in serum TG levels after PM administration. Collectively, these results indicate the potential of FGF21 DNA methylation as a surrogate indicator of BMI and serum TG levels, while absolute changes in serum FGF21 levels after PM administration may offer prognostic insights into the efficacy of reducing serum TG levels through PM administration.

Dental pulp stem cells (DPSCs) demonstrate high proliferative and multilineage differentiation potential. As previously reported, the helioxanthin derivative 4-(4-methoxyphenyl)pyrido[40,30:4,5]thieno[2,3-b]pyridine-2-carboxamide (TH) has been demonstrated to induce the osteogenic differentiation of DPSCs. However, the mechanism of osteogenesis induced by TH in DPSCs remains unknown. The objective of this study was to identify functional extracellular vesicle (EV) microRNAs (miRNAs), and the principal genes involved in the TH-induced osteogenesis of DPSCs. DPSCs were derived from dental pulp extracted from the third molars of three healthy subjects, and were cultured with or without TH. miRNAs were extracted from DPSC-derived EVs. The gene expression patterns of mRNA and miRNA were compared using RNA-Seq and miRNA-Seq. To investigate miRNA/mRNA interacting networks, functional analyses were performed by Ingenuity Pathway Analysis. Alkaline phosphatase (ALP) staining demonstrated that treatment with TH resulted in enhanced ALP activity in DPSCs after 7 days. The expression levels of ALP and type 1 collagen alpha 1 were significantly higher in TH-induced DPSCs on day 7. RNA-Seq and miRNA-Seq analyses identified 869 differentially expressed genes (DEGs) and 18 miRNA-DEGs. Gene Ontology analysis of the mRNA-Seq results showed that TH induced several biological activities associated with signal transduction, cell adhesion, and cell differentiation. Integrated miRNA-mRNA analyses showed that these miRNAs contain the targeting information of 277 mRNAs of the DEGs. Among them, 17 target genes known to be involved in the differentiation of osteoblasts, and 24 target genes known to be involved in the differentiation of bone cells were identified. Quantitative real-time PCR showed that WNT5a expression in DPSCs was upregulated by 48 h of TH treatment. Upstream regulator analysis indicated that WNT3a, FOS, and RAC1 may be responsible for gene expression changes in DPSCs after TH treatment. EV miRNA regulatory networks might play crucial roles in TH-induced osteogenic differentiation of DPSCs. Our results presented herein offer valuable insights that will facilitate further research into the mechanism of osteogenesis of DPSCs, which is expected to lead to the clinical application of TH-induced DPSCs for bone regeneration. Furthermore, EVs derived from TH-induced DPSCs might be useful as therapeutic tools for bone defects.

Resveratrol, a polyphenol found in grapes and peanuts, is known for diverse biological activities, yet its effects on dermal hyperpigmentation (so-called dark spots) remain unexplored. We investigated resveratrol's ability to enhance melanosomal degradation in human dermal fibroblasts. At concentrations of 25–50 μM, resveratrol increased autophagy as measured by microtubule-associated protein 1A/1B-light chain 3 (LC3)-II/LC3-I ratio and enhanced lysosomal activity as assessed by a lysosomal activity reporter system. RNA sequencing revealed upregulation of lysosomal and autophagy-related genes, including cathepsins. Furthermore, reporter assays showed resveratrol's activation of antioxidant response via nuclear factor erythroid 2-related factor 2 (NRF2)-mediated, leading to upregulation of transcription factor EB/transcription factor E3 (TFEB/TFE3), master regulators of lysosomal function. In fibroblasts pre-loaded with melanosomes, resveratrol reduced melanosome content compared to control by day 3. The findings reveal the activation of interconnected autophagy, lysosomal, and antioxidant pathways by resveratrol, suggesting potential applications in functional foods targeting dermal hyperpigmentation.

ABSTRACT The effects of sodium‐glucose cotransporter 2 (SGLT2) inhibitors on mesenchymal‐epithelial transition factor (MET) inhibitor‐induced edema remain unclear. In a patient with tepotinib‐induced edema and an N‐terminal pro‐brain natriuretic peptide (NTproBNP) level ≥ 300 pg/mL, the addition of empagliflozin to loop diuretics reduced the edema. This suggests that empagliflozin may be a treatment option for MET inhibitor‐induced edema.

ABSTRACT Sacubitril/valsartan, an angiotensin receptor‐neprilysin inhibitor, has demonstrated a superior blood pressure‐lowering effect compared with renin‐angiotensin system inhibitors in several clinical trials. However, there has been no available evidence on the comparison between sacubitril/valsartan and calcium channel blockers (CCBs), a well‐established class of antihypertensive drugs. In this open‐label, multicenter study, we aimed to demonstrate the efficacy and safety of sacubitril/valsartan versus amlodipine, one of the most widely used CCBs, after 8 weeks of treatment. A total of 359 Japanese patients with essential hypertension (office systolic blood pressure [SBP] ≥ 150 to

Summary: The amino acid sequence of the T cell receptor (TCR) varies between T cells of an individual’s immune system. Particular TCR residues nearly guarantee mucosal-associated invariant T (MAIT) and natural killer T (NKT) cell transcriptional fates. To define how the TCR sequence affects T cell fates, we analyze the paired αβTCR sequence and transcriptome of 961,531 single cells. We find that hydrophobic complementarity-determining region (CDR)3 residues promote regulatory T cell fates in both the CD8 and CD4 lineages. Most strikingly, we find a set of TCR sequence features that promote the T cell transition from naive to memory. We quantify the extent of these features through our TCR scoring function “TCR-mem.” Using TCR transduction experiments, we demonstrate that increased TCR-mem promotes T cell activation, even among T cells that recognize the same antigen. Our results reveal a common set of TCR sequence features that enable T cell activation and immunological memory.

OX40, a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed on the surface of activated T cells. Upon interaction with its cognate ligand, OX40L, OX40 transmits costimulatory signals to antigen-primed T cells, promoting their activation, differentiation, and survival—processes essential for the establishment of adaptive immunity. Although the OX40-OX40L interaction has been extensively studied in the context of disease treatment, developing a substitute for the naturally expressed membrane-bound OX40L, particularly a multimerized OX40L trimers, that effectively regulates OX40-driven T cell responses remains a significant challenge. In this study, we successfully engineered soluble OX40L-fusion proteins capable of robustly activating OX40 on T cells. This was achieved by incorporating functional multimerization domains into the TNF homology domain of OX40L. These OX40L proteins bound to OX40, subsequently activated NF-κB signaling, and induced cytokine production by T cells in vitro. In vivo, mice treated with one of the OX40L-fusion proteins—comprising a single-chain OX40L trimer linked to the C-terminus of the human IgG1 Fc domain, forming a dimer of trimers—exhibited significantly enhanced clonal expansion of antigen-specific CD4+ T cells during the primary phase of the immune response. A comparable antibody-fusion single-chain TNF protein incorporating 4-1BBL, CD70 (CD27L), or GITRL in place of OX40L elicited similar in vivo T cell responses. Thus, we propose that optimizing the multimerization of OX40L proteins through innovative design strategies may facilitate the development of more effective agonists for targeted immunotherapies.

Abstract Whether or not vascular endothelial growth factor pathway inhibitors (VPIs) increase the risk of artery dissection is still unknown. This study aimed to quantitatively evaluate the possibility of artery dissection as a class effect of VPIs using nationwide real‐world data. This cohort study was conducted based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), which spans nearly the entire Japanese population of over 100 million individuals. We included the patients prescribed with 12 types of VPIs between 2012 and 2020. The incidence rate (IR) ratio of artery dissection for each VPI were estimated in comparison with bevacizumab, the only VPI in Japan with artery dissection listed in the package insert. Artery dissection as an outcome was targeted for acute artery dissection requiring hospitalization (including dissecting aneurysm). As a reference, a natural IR standardized by sex and age of bevacizumab‐prescribed patients was also estimated using the direct method for the general population of NDB. Of 503,342 patients, the IR of artery dissection for bevacizumab was 44.4 (/100,000 person‐years), and the adjusted IR ratios for each VPI compared with bevacizumab were consistently similar to or >1.0. The IRs for each VPI were also higher than the crude natural IR (1.66/100,000 person‐years; 95% CI: 1.59–1.73) and the standardized natural IR (2.18/100,000 person‐years; 95% CI: 1.86–2.50). Real‐world evidence suggests the risk of artery dissection as a class effect of VPIs. More attention on this risk will be necessary when using VPIs in clinical practice.

Abstract Fatty acid binding protein 4 (FABP4) is highly expressed in adipocytes. Lipolysis, caused by an elevated adrenergic input, has been suggested to contribute to elevated serum FABP4 levels in patients with cardiovascular diseases. However, the relationship between the serum FABP4 and efferent sympathetic nerve activity remains poorly understood. Twenty‐one healthy subjects (average age, 29.1 years; 15 men) performed an isometric handgrip (HG) exercise at 30% of the maximal voluntary contraction until they were fatigued. The beat‐by‐beat heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were recorded. Blood samples were collected at rest and at the time of peak fatigue. The MSNA, HR, and systolic BP were significantly increased by the HG exercise (all, p

The accumulation of a disease-specific isoform of prion protein (PrPSc) and histopathological lesions, such as neuronal loss, are unevenly distributed in the brains of humans and animals affected with prion diseases. This distribution varies depending on the diseases and/or the combinations of prion strain and experimental animal. The brain region-dependent distribution of PrPSc and neuropathological lesions suggests a neuronal cell-type-dependent prion propagation and vulnerability to prion infection. However, the underlying mechanism is largely unknown. In this study, we provided evidence that the prion 22L strain propagates more efficiently in excitatory neurons than inhibitory neurons and that excitatory neurons in the thalamus are vulnerable to prion infection. PrPSc accumulation was less intense in the striatum, where GABAergic inhibitory neurons predominate, compared to the cerebral cortex and thalamus, where glutamatergic excitatory neurons are predominant, in mice intracerebrally or intraperitoneally inoculated with the 22L strain. PrPSc stains were observed along the needle track after stereotaxic injection into the striatum, whereas they were also observed away from the needle track in the thalamus. Consistent with inefficient prion propagation in the striatum, the 22L prion propagated more efficiently in glutamatergic neurons than GABAergic neurons in primary neuronal cultures. RNAscope in situ hybridization revealed a decrease in Vglut1- and Vglut2-expressing neurons in the ventral posterolateral nuclei of the thalamus in 22L strain-infected mice, whereas no decrease in Vgat-expressing neurons was observed in the adjacent reticular nucleus, mainly composed of Vgat-expressing interneurons. The excitatory neuron-prone prion propagation and excitatory neuronal loss in 22L strain-infected mice shed light on the neuropathological mechanism of prion diseases.

IntroductionInvolved in immunity and reproduction, natural killer (NK) cells offer opportunities to develop new immunotherapies to treat infections and cancer or to alleviate pregnancy complications. Most current strategies use cytokines or antibodies to enhance NK-cell function, but none use ion channel modulators, which are widely used in clinical practice to treat hypertension, diabetes, epilepsy, and other conditions. Little is known about ion channels in NK cells. ResultsWe show that Kcnj8, which codes for the Kir6.1 subunit of a certain type of ATP-sensitive potassium (KATP) channel, is highly expressed in murine splenic and uterine NK cells compared to other K+ channels previously identified in NK cells. Kcnj8 expression is highest in the most mature subset of splenic NK cells (CD27-/CD11b+) and in NKG2A+ or Ly49C/I+ educated uterine NK cells. Using patch clamping, we show that a subset of NK cells expresses a current sensitive to the Kir6.1 blocker PNU-37883A. Kcnj8 does not participate in NK cell degranulation in response to tumor cells in vitro or rejection of tumor cells in vivo, or IFN-γ release. Transcriptomics show that genes previously implicated in NK cell development are amongst those differentially expressed in CD27-/CD11b+ NK cells deficient for Kcnj8. Indeed, we found that mice with NK-cell specific Kcnj8 gene ablation have fewer CD27-/CD11b+ and KLRG-1+ NK cells in the bone barrow and spleen. DiscussionThese results show that the KATP subunit Kir6.1 has a key role in NK-cell development.

We discovered that the phospholipids present in the internal organs of scallops (Patinopecten yessoensis), which are primarily composed of glycerophospholipids and ceramide 2-aminoethylphosphonate (CAEP), reduced the serum and liver cholesterol contents in mice. This study evaluated the effects of scallop CAEP on lipid metabolism by comparing it to sphingomyelin. The study involved feeding four-week-old male KK-Ay mice either a high-fat diet or a high-fat diet supplemented with 0.5 wt% each of CAEP and sphingomyelin for 35 days. We found that CAEP intake lowered the serum triacylglycerol content, partly via a reduction in the mRNA expression levels of fatty acid synthesis-related genes in the liver. Furthermore, the CAEP diet reduced the serum and liver cholesterol contents. This effect was partially mediated by the increase in fecal total sterol excretion. Thus, this study indicates CAEP will be employed as a health-promoting component to lower the body’s triacylglycerol and cholesterol contents.

Background: The relationship between patterns of outpatient oral loop diuretic (LD) dose reduction and prognosis in patients with heart failure (HF) remains unclear. Methods: We evaluated 679 patients with HF-prescribed LDs at baseline between September 2015 and August 2019. Dose reduction was defined as a change to a lower LD dose than the previous outpatient dose. Dose intensification was defined as a change to a higher LD dose than the previous outpatient dose. Patients were classified into no-reduction (no LD dose reduction during follow-up) and reduction groups (categorized into successive-reduction [≥2 successive LD dose reductions without intervening LD dose intensification] and single-reduction [LD dose reduction without successive dose reduction] groups). The primary outcomes were all-cause death, HF hospitalization (HFH), and the composite of cardiovascular death (CVD) or HFH. Results: Within a median follow-up of 53.7 (range, 2.6–99.1) months, 156 deaths were recorded: 121 (29 %), 31 (15 %), and three (4 %) patients in the no-reduction (n = 411), single-reduction (n = 195), and successive-reduction (n = 73) groups, respectively. After adjusting for cofounders, the reduction group had a lower risk of primary outcomes than the no reduction group (all-cause death: hazard ratio (HR) = 0.65, 95 % confidence interval (CI) = 0.44–0.96; CVD or HFH: HR=0.69, 95 %CI=0.52–0.93; HFH: HR=0.69, 95 % CI=0.52–0.93). The successive-reduction group had a lower risk of the composite of CVD or HFH (HR=0.26, 95 % CI: 0.10–0.67) and HFH (HR=0.34, 95 % CI=0.13–0.86) than the single-reduction group. Conclusions: Outpatient LD dose reduction patterns can be indicators of good prognosis in HF patients.

Abstract Perampanel belongs to a novel class of antiseizure medications (ASMs). Studies examining the effect of hemodialysis on perampanel serum levels in clinical settings are lacking. We aimed to evaluate the changes in serum perampanel levels during hemodialysis. We studied patients with seizures who received oral perampanel between April 2020 and March 2023 and whose serum concentration of perampanel was measured before and after hemodialysis. We analyzed the serum concentrations of levetiracetam and lacosamide for comparison. Fourteen patients, with a mean age of 76.1 ± 7.88 years, were included. The dose of perampanel was 2.14 ± 1.27 mg. The hemodialysis clearance rate of perampanel, levetiracetam, and lacosamide was 0 ± 13%, 69 ± 11%, and 59.6 ± 8.2%, respectively. The post‐dialysis CD ratio decreased significantly with levetiracetam but not with perampanel. Adverse but acceptable effects of perampanel were observed in two patients. The serum concentrations of several ASMs have been shown to be reduced during hemodialysis. Our study revealed that the serum perampanel concentration does not decrease during hemodialysis. Owing to the low rate of adverse effects and the stability of perampanel serum concentration during hemodialysis, perampanel could be a favorable choice as an ASM for patients with seizures undergoing hemodialysis. Plain Language summary Our study looked at how hemodialysis affects the serum levels of perampanel, a new type of medication for seizures. In 14 patients who started treatment between April 2020 and March 2023, perampanel serum levels did not decrease during hemodialysis, unlike other seizure medications. This shows that perampanel can be a good option for patients with seizures who need hemodialysis, with fewer side effects compared to other medications.

Abstract Background Hyposalivation is treated using oral cholinergic drugs; however, systemic side effects occasionally lead to discontinuation of treatment. We aimed to investigate the effects of transdermal pilocarpine on the salivary gland skin on saliva secretion and safety in rats. Methods Pilocarpine was administered to rats orally (0.5 mg/kg) or topically on the salivary gland skin (5 mg/body). Saliva volume, the number of sweat dots, and fecal weight were measured along with pilocarpine concentration in plasma and submandibular gland tissues. Results Saliva volume significantly increased 0.5 h after oral administration and 0.5, 3, and 12 h after topical administration. Fecal weight and sweat dots increased significantly 1 h after oral administration; however, no changes were observed after topical application. The pilocarpine concentration in the submandibular gland tissues of the topical group was higher than that in the oral group at 0.5, 3, and 12 h of administration. Conclusions Pilocarpine application to salivary gland skin persistently increased salivary volume in rats without inducing sweating or diarrhea. Transdermal pilocarpine applied to the skin over the salivary glands may be an effective and safe treatment option for hyposalivation.

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35–74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women’s health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

Abstract Objective To reveal the clinical features and assess risk factors linked to brain fog and its societal implications, including labor productivity, providing valuable insights for the future care of individuals who have experienced coronavirus disease 2019 (COVID‐19). Methods We analyzed a comprehensive cohort dataset comprising 1,009 patients with COVID‐19 admitted to Japanese hospitals. To assess brain fog, we analyzed patients who responded to a questionnaire indicating symptoms such as memory impairment and poor concentration. Results The prevalence of brain fog symptoms decreased 3 months posthospitalization but remained stable up to 12 months. Neurological symptoms such as taste and smell disorders and numbness at hospitalization correlated with a higher frequency of identifying brain fog as a long COVID manifestation. Our findings indicated that advanced age, female sex, a high body mass index, oxygen required during hospitalization, chronic obstructive pulmonary disease, asthma, and elevated C‐reactive protein and elevated D‐dimer levels were risk factors in patients exhibiting brain fog. Additionally, we demonstrated the negative impact of brain fog on labor productivity by presenteeism scores. Interpretations This study clarified the clinical characteristics of patients experiencing brain fog as a long COVID manifestation, specifically emphasizing neurological symptoms during hospitalization and their correlation with brain fog. Additionally, the study identified associated risk factors for its onset and revealed that the emergence of brain fog was linked to a decline in labor productivity.

Abstract Background Central neuropathic pain after foramen magnum decompression (FMD) for Chiari malformation type 1 (CM-1) with syringomyelia can be residual and refractory. Here we present a case of refractory central neuropathic pain after FMD in a CM-1 patient with syringomyelia who achieved improvements in pain following spinal cord stimulation (SCS) using fast-acting sub-perception therapy (FAST™). Case presentation A 76-year-old woman presented with a history of several years of bilateral upper extremity and chest-back pain. CM-1 and syringomyelia were diagnosed. The pain proved drug resistant, so FMD was performed for pain relief. After FMD, magnetic resonance imaging showed shrinkage of the syrinx. Pain was relieved, but bilateral finger, upper arm and thoracic back pain flared-up 10 months later. Due to pharmacotherapy resistance, SCS was planned for the purpose of improving pain. A percutaneous trial of SCS showed no improvement of pain with conventional SCS alone or in combination with Contour™, but the combination of FAST™ and Contour™ did improve pain. Three years after FMD, percutaneous leads and an implantable pulse generator were implanted. The program was set to FAST™ and Contour™. After implantation, pain as assessed using the McGill Pain Questionnaire and visual analog scale was relieved even after reducing dosages of analgesic. No adverse events were encountered. Conclusion Percutaneously implanted SCS using FAST™ may be effective for refractory pain after FMD for CM-1 with syringomyelia.

Abstract Cathepsin C (CatC) is an enzyme which regulates the maturation of neutrophil serine proteases (NSPs) essential for neutrophil activation. Activated neutrophils are key players in the innate immune system, and are also implicated in the etiology of various inflammatory diseases. This study aims to demonstrate a therapeutic potential for CatC inhibitors against disorders in which activated neutrophil-derived neutrophil extracellular traps (NETs) play a significant role. We demonstrate that a CatC inhibitor, MOD06051, dose-dependently suppresses the cellular activity of NSPs, including neutrophil elastase (NE), in vitro. Neutrophils derived from MOD06051-administered rats exhibit significantly lower NE activity and NET-forming ability than controls. Furthermore, MOD06051 dose-dependently ameliorates vasculitis and significantly decreases NETs when administered to a rat model of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody-associated vasculitis (AAV). These findings suggest that CatC inhibition is a promising strategy to reduce neutrophil activation and improve activated neutrophil-mediated diseases such as MPO-AAV.

The adenohypophysis is composed of the anterior and intermediate lobes (AL and IL, respectively), and secretes hormones that play an important role in reproduction. CD9- and SOX2-double (CD9/SOX2) positive cells located in the marginal cell layer (MCL) facing the Rathke’s cleft in the AL and IL form the primary stem cell niche in the adult adenohypophysis of rats. In this study, we successfully obtained 3-dimensional (3D) cell aggregates that closely resembled the primary niche of MCL in vivo. After incubation in a Matrigel containing several growth factors, approximately 20% of the cells in the CD9/SOX2-positive cell aggregates were differentiated into hormone-producing cells. The cell aggregates generated in this study may provide insight into the regulation of the pituitary stem/progenitor cell niche and the turnover of hormone-producing cells.

Introduction Hibernomas are benign tumors of brown adipose tissue. Hibernoma in the renal sinus is extremely rare. Herein, we present the third known case of renal hibernoma. Case presentation A 71‐year‐old man reported to our department with a left kidney tumor with an average growth rate of 5 mm/year and a progressive contrast effect on computed tomography. It was diagnosed as a hibernoma following a laparoscopic radical nephrectomy. Conclusion We encountered a rare case of a hibernoma in the renal sinus. Development of new and accurate diagnostic methods for hibernoma, without resorting to nephrectomy, is essential.

Abstract Background Labor pain is uniquely experienced and described by the woman giving birth, and it is often considered one of the most excruciating experiences for many women. This study aimed to evaluate factors associated with the willingness to receive labor analgesia among women attending the antenatal clinic at Dr. Bogalech Gebre Memorial General Hospital Central Ethiopia in 2022. Methods An institution-based, cross-sectional study was conducted from January to March 2022. Data were collected using semi-structured questionnaires by a convenience sampling technique. Data was entered in EpiData 4.2 and exported to SPSS version 20 for analysis. Both Bivariable and multivariable logistic regressions were conducted to determine factors associated with pregnant women’s willingness to choose labor analgesia. Crude odds ratio (COR) and adjusted odds ratio (AOR) were computed to assess the association between variables. Results A total of 398 pregnant women have participated in the study with a response rate of 94%. Nearly 30%, (29.4%) of the pregnant women had a willingness to practice labor pain management. Being a housewife (AOR: 8.35, 95% CI: 2.07, 33.63). Women who live in urban (AOR: 2.60, 95% CI: 1.29, 5.29). Having had awareness about labor analgesia (AOR: 1.70, 95% CI: 1.00, 2.60) and the short duration of labor time (AOR: 1.84, 95% CI: 1.15, 2.96) were statistically significant with a willingness to practice labor analgesia. Conclusion We conclude that the willingness of pregnant mothers’ toward obstetric analgesia practice was low in the study area. Being a housewife, urban residence, awareness about labor analgesia, and short duration of labor were statistically significant with the willingness of the mothers to practice labor analgesia. To increase willingness to use labor analgesia, authorities should prioritize delivering health education on pain management choices to address concerns and promote effective methods and practices.

Background: Uremic toxin indoxyl sulfate (IS) induces vascular inflammation, a crucial event in renal failure, and vascular complications in patients with chronic kidney disease (CKD). In endothelial cells, IS increases the production of inflammatory cytokines partially via the activation of the aryl hydrocarbon receptor (AhR), and several food flavonoids have been reported to act as antagonists of AhR. Objective: This study aimed to investigate whether antagonistic flavonoids can attenuate IS-induced inflammatory responses in vascular endothelial cells in vitro and renal failure in vivo. Design: Human umbilical vein endothelial cells (HUVECs) pretreated with the flavones apigenin, chrysin, or luteolin were stimulated with IS. Expression levels of genes involved in AhR signaling, inflammatory cytokine production, and reactive oxygen species (ROS) production were analyzed. Uninephrectomized mice were orally administered chrysin and received daily intraperitoneal injections of IS for 4 weeks. Results: In HUVECs, IS upregulated the mRNA expression of AhR-targeted genes (CYP1A1 and AhRR), and genes involved in inflammation (NOX4, MCP-1, IL-6, and COX2) and monocyte invasion/adhesion (ICAM1). All three flavones attenuated the IS-induced increase in the expression of these mRNAs. They also suppressed the IS-induced nuclear translocation of AhR and intracellular ROS production. Furthermore, IS-induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was inhibited by treatment with these flavones. The results of in-vivo experiments showed that administration with chrysin attenuated the elevation of blood urea nitrogen levels and AhR-target gene expression and the pathological impairment of renal tissues in mice, regardless of higher serum levels of IS. Conclusions: Natural food flavones antagonizing AhR exerted protective effects against IS-induced inflammation through the inhibition of the AhR–STAT3 pathway in HUVECs. Moreover, chrysin ameliorated IS-induced renal dysfunction in a mouse model of CKD. These flavonoids could be a therapeutic strategy for vascular inflammation in CKD.

Background The association of the combination of body mass index (BMI) and weight change at admission with prognoses in patients with heart failure (HF) is unclear. Therefore, we investigated whether BMI and weight changes at admission affect mortality in patients with HF. Methods This retrospective cohort study lasted 99 months, starting in April 2014, and included 4,862 patients with HF from a Japanese real-world database. Cubic and thin-plate smoothing spline analyses were performed to investigate the association of BMI and weight changes with mortality. The percentage weight change was calculated every 6 months. The study outcome was the presence or absence of death. Results The patients’ mean age was 81.5±9.6 years, and 1,239 (25.5%) patients died. Cubic spline analysis revealed a negative correlation of BMI with mortality hazard ratio (HR) (BMI of 18.5 kg/m2 and 25 kg/m2; HR=1.3 [1.2–1.4] and 0.8 [0.7–0.9], respectively). Cubic spline analysis of weight change showed that weight loss tended to increase the mortality HR (each 6% decrease in weight change rate was associated with a 1.1 times higher mortality risk (95% CI [1.0–1.2]) Thin-plate smoothing spline analysis showed that the odds ratio (OR) negatively correlated with BMI (1-year mortality: BMI of 18.5 kg/m2, 22 kg/m2, and 25 kg/m2; OR at 0% weight change=1.5, 1.0, and 0.7, respectively; 2-year mortality: BMI=18.5 kg/m2, 22 kg/m2, and 25 kg/m2; OR at 0% weight change=1.4, 0.9, and 0.7, respectively). Conclusion A low BMI in patients with HF was associated with a higher risk of mortality. Weight loss in patients, regardless of BMI, was associated with a higher OR for mortality.

Abstract BackgroundTo prevent the further development of cardiovascular diseases, it is a growing global priority to detect untreated hypertension in patients and ensure adequate blood pressure control via drug therapy. However, few effective tools that facilitate the initiation of antihypertensive medications among such patients have been identified. ObjectiveWe aimed to determine whether a mobile health (mHealth) app facilitates the initiation of antihypertensive medications among patients with untreated hypertension. MethodsWe analyzed a large longitudinal integrated database mainly comprised of data from middle-aged, employed people and their families. The database contained data from health checkups, health insurance claims, and the mHealth app kencom. kencom is used to manage daily life logs (eg, weight, number of steps) and to provide health information tailored to customers. Patients with untreated hypertension were identified using the baseline health checkup data, and follow-up health checkups were conducted to identify the rate of initiation of antihypertensive medications between mHealth app users and nonusers. Antihypertensive medication status was confirmed via a questionnaire administered during the medical checkup as well as a review of the health insurance claims database. We conducted a modified Poisson regression analysis, weighted by inverse probability of treatment weighting, to examine the effect of mHealth app usage on the initiation of antihypertensive medications. Additionally, data from four lifestyle questionnaires from the baseline and follow-up health checkups were collected to evaluate lifestyle modifications that could be attributed to the mHealth app. ResultsData were collected from 50,803 eligible patients (mean age 49, SD 9 years; men n=39,412, 77.6%; women n=11,391, 22.4%) with a median follow-up period of 3.0 (IQR 2.3‐3.1) years. The rate of initiation of antihypertensive medications was significantly higher in the mHealth app user group than in the nonuser group: 23.4% (3482/14,879) versus 18.5% (6646/35,924; P ConclusionsFor patients with untreated hypertension, the use of the mHealth app kencom, which was not dedicated to hypertension treatment, was associated with a higher initiation of antihypertensive medications.

The International Classification of Functioning, Disability, and Health (ICF) is a widely used framework in rehabilitation that provides standardized measures to describe health and health-related states of people. The strength of the ICF lies in its provision of a common language for describing rehabilitation progress. However, personal factors are not classified within the ICF due to their significant variability across cultures, which may render it not adequately capturing the subjective and social dimensions of disability. Our objective in this research was to propose theoretical frameworks that could help identify relevant personal factors for inclusion in the ICF. We discuss the Personality Systems Interaction (PSI) Theory to identify personal variability in goal pursuit, highlighting the importance of emotions like negative and positive affect in handling adverse situations and managing habitual behaviors. Additionally, the theory helps to determine personality factors relevant to patients, facilitating the resolution of potential issues that may emerge during the goal achievement process. We also emphasize the role of goal setting in rehabilitation and suggest the Goal-Oriented Action Linking (GOAL) model as a useful tool for understanding how motivational values change over time, distance, and progress. Following from this, we discuss the importance of self-efficacy and its relationship to effort and goal achievement, while noting potential issues in its assessment. Finally, we propose viable assessment methods for measuring the potential components to be incorporated as personal factors.

Circadian disruption is an important factor driving the current-day high prevalence of obesity and type-2 diabetes. While the impact of incorrect timing of caloric intake on circadian disruption is widely acknowlegded, the contribution of incorrect timing of physical activity remains relatively understudied. Here, we modeled the incorrect timing of physical activity in nightshift workers in male Wistar rats, by restricting running wheel access to the innate inactive (light) phase (LR). Controls included no wheel access (NR); access only during the innate active (dark) period (DR); or unrestricted (ad libitum) access (ALR). LR did not shift the phase of the muscle or liver clock, but dampened the muscle clock amplitude. As our previous study demonstrated that light-phase restricted feeding did shift the liver clock, but made the muscle clock arrhythmic, we next combined the time restriction of wheel and food access to either the light phase (LRLF) or dark phase (DRDF). LRLF produced a ∼12 h shift in the majority of clock gene rhythms in both skeletal muscle and liver. On the other hand, DRDF was most effective in reducing body weight and the accumulation of fat mass. Therefore, in order to shift the muscle clock in male Wistar rats, synergy between the timing of feeding and physical activity is necessary. These findings may contribute to further improve the design of lifestyle strategies that try to limit metabolic misalignment caused by circadian disruption.

BackgroundsHypoxemia develops more quickly in children than in adults due to their high oxygen consumption relative to their body weight and small functional residual capacity. Therefore, cricothyroid puncture must be performed promptly in cannot-intubate and cannot-ventilate situations. However, the success rate of cricothyroid puncture in children is

Childhood-onset craniopharyngiomas, though rare, are intracranial malformations that can cause obesity by disrupting the hypothalamus, a condition that often persists even after tumor resection. This severe obesity increases the risk of diabetes and fatty liver disease in childhood. Concurrently, panhypopituitarism, including growth hormone (GH) deficiency, may develop. Notably, some individuals with GH deficiency may exhibit a normal growth rate, making GH therapy unnecessary for growth purposes. However, in these cases, GH therapy may still be beneficial in preventing the progression of nonalcoholic fatty liver disease or nonalcoholic steatohepatitis. Although weight management is traditionally considered the gold standard for preventing liver cirrhosis, its effectiveness can be limited by hypothalamic dysfunction and the difficulty of achieving successful weight control. Our case study highlights a patient with normal growth despite GH deficiency, who did not receive GH replacement therapy and continued to struggle with hypothalamic obesity. Despite effective body weight control, the patient developed hepatopulmonary syndrome, indicating that relying solely on weight management may not be sufficient to prevent liver complications. This case underscores the importance of addressing GH deficiency even when growth is normal. Our findings suggest that GH replacement therapy could be beneficial for preventing liver cirrhosis in such cases.

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

Summary: Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented clinical outcomes in patients with relapsed/refractory B cell leukemias; however, response rates in patients with large B cell lymphoma (LBCL) are less impressive. Expression of PD-1 on activated T cells and PD-L1 on malignant, stromal, and immune cells within the tumor microenvironment (TME) contribute to CAR-T exhaustion, hypofunction, and treatment failures. Here, a comparative approach is taken to develop a chimeric switch receptor (CSR) with potential to augment CAR-T persistence, function, and clinical efficacy in immune competent, pet dogs with spontaneous B cell lymphoma (BCL). We show that similar to human CAR-T cells, expression of a PD-1/CD28 CSR in canine CAR-T cells results in enhanced function against PD-L1+ targets and preserves central memory phenotype. We also demonstrate that these effects depend upon active CSR signaling. This work paves the way for in vivo studies in canine BCL patients to inform human trial design.

Objective: To investigate the feasibility of poststroke interventions using a motivational instructional design model with occupational therapy (OT) and swallowing therapy (ST) and the model's potential physical and mental health effects. Design: An open-label, single-arm, feasibility study on the Attention, Relevance, Confidence, and Satisfaction model. Setting: Two convalescent rehabilitation wards. Participants: Twenty-five patients with stroke (N=25) (19 men; mean age, 62.4±11.9y; 61.9±36.8d from the first stroke) were recruited. Interventions: Twelve participants received a motivational approach based on the Attention, Relevance, Confidence, and Satisfaction model during OT (OT group), and 13 received it during ST (ST group). The intervention lasted 40-60 minutes daily, 5 days weekly, for 4 weeks. Main Outcome Measures: The primary outcomes included the dropout rate, an adverse event, and the participants’ acceptability of the intervention. Paretic arm function was assessed in the OT group; swallowing ability was assessed in the ST group; and activities of daily living, depressive symptoms, and apathy were assessed in both groups. Results: No participants dropped out of the intervention or experienced an adverse event. Twenty-one participants (84%) were satisfied with the intervention, and 19 (76%) hoped to continue receiving it. The OT group showed statistically significant improvements in paretic arm function and activities of daily living (Cohen's r=0.68-0.77), whereas the ST group improved in swallowing ability, activities of daily living, and depressive symptoms (Cohen's r=0.62-0.85). Conclusions: The interventions using the motivational instructional model with OT and ST were feasible and could improve poststroke paretic arm function, swallowing ability, and activities of daily living after stroke.

Abstract Background Vitrification procedures decrease intracytoplasmic lipid content and impair developmental competence. Adding fatty acids (FAs) to the warming solution has been shown to recover the lipid content of the cytoplasm and improve developmental competence and pregnancy outcomes. However, the influence of the FA supplementation on live birth rates after embryo transfers and perinatal outcomes remains unknown. In the present study, we examined the influence of FA-supplemented warming solutions on live birth rates, pregnancy complications, and neonatal outcomes after single vitrified-warmed cleavage-stage embryo transfers (SVCTs). Methods The clinical records of 701 treatment cycles in 701 women who underwent SVCTs were retrospectively analyzed. Vitrified embryos were warmed using solutions (from April 2022 to June 2022, control group) or FA-supplemented solutions (from July 2022 to September 2022, FA group). The live birth rate, pregnancy complications, and perinatal outcomes were compared between the control and FA groups. Results The live birth rate per transfer was significantly higher in the FA group than in the control group. Multivariate logistic regression analysis further demonstrated a higher probability of live births in the FA group than in the control group. Miscarriage rates, the incidence and types of pregnancy complications, the cesarean section rate, gestational age, incidence of preterm delivery, birth length and weight, incidence of low birth weight, infant sex, and incidence of birth defects were all comparable between the control and FA groups. Multivariate logistic regression analysis further demonstrated no adverse effects of FA-supplemented warming solutions. Conclusions FA-supplemented warming solutions improved live birth rates after SVCTs without exerting any adverse effects on maternal and obstetric outcomes. Therefore, FA-supplemented solutions can be considered safe and effective for improving clinical outcomes and reducing patient burden.

Abstract Unlike adult mammalian wounds, early embryonic mouse skin wounds completely regenerate and heal without scars. Analysis of the underlying molecular mechanism will provide insights into scarless wound healing. Twist2 is an important regulator of hair follicle formation and biological patterning; however, it is unclear whether it plays a role in skin or skin appendage regeneration. Here, we aimed to elucidate Twist2 expression and its role in fetal wound healing. ICR mouse fetuses were surgically wounded on embryonic day 13 (E13), E15, and E17, and Twist2 expression in tissue samples from these fetuses was evaluated via in situ hybridization, immunohistochemistry, and reverse transcription-quantitative polymerase chain reaction. Twist2 expression was upregulated in the dermis of E13 wound margins but downregulated in E15 and E17 wounds. Twist2 knockdown on E13 left visible marks at the wound site, inhibited regeneration, and resulted in defective follicle formation. Twist2-knockdown dermal fibroblasts lacked the ability to undifferentiate. Furthermore, Twist2 hetero knockout mice (Twist + /-) formed visible scars, even on E13, when all skin structures should regenerate. Thus, Twist2 expression correlated with skin texture formation and hair follicle defects in late mouse embryos. These findings may help develop a therapeutic strategy to reduce scarring and promote hair follicle regeneration.