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Abstract We present the first direct evidence of an in situ excitation of drift‐compressional waves driven by drift resonance with ring current protons in the magnetosphere. Compressional Pc4–5 waves with frequencies of 4–12 mHz were observed by the Arase satellite near the magnetic equator at L ∼ 6 in the evening sector on 19 November 2018. Estimated azimuthal wave numbers (m) ranged from −100 to −130. The observed frequency was consistent with that calculated using the drift‐compressional mode theory, whereas the plasma anisotropy was too small to excite the drift‐mirror mode. We discovered that the energy source of the wave was a drift resonance instability, which was generated by the negative radial gradient in a proton phase space density at 20–25 keV. This proton distribution is attributed to a temporal variation of the electric field, which formed the observed multiple‐nose structures of ring current protons.

Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence, and apoptotic process. A single-cell RNA-Seq analysis revealed that osteal macrophages were heterogeneously clustered into 6 subsets that expressed proliferative, inflammatory, antiinflammatory, and efferocytosis gene signatures. Importantly, postmenopausal mice exhibited an increase in subset 3 that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopausal condition altered the osteal macrophage subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment. Furthermore, adoptive macrophage transfer onto calvarial bone was performed, and mice that received oxidatively stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in the development of inflammaging in the bone microenvironment. Consistently, depletion of senescent cells and the oxidatively stressed macrophage subset alleviated the excessive bone loss in postmenopausal mice. Our data provided insight into the pathogenesis of osteoporosis and shed light on a therapeutic approach for the treatment or prevention of postmenopausal osteoporosis.

Background: Allergy code systems are essential for safety and medical information interoperability. However, current terminology systems lack allergens unique to Japan., Objective: This study established a code system encompassing Japanese food and non-food/non-medication allergens (JFAGY), and developed a meta-code system for integration with existing drug code systems. The practicality and limitations of the JFAGY were assessed by profiling HL7 FHIR allergy intolerance., Methods: Allergen terms were selected based on the Standard Commodity Classification of Japan. Additional terms were extracted from clinical guidelines and public documents. For non-food, non-medication allergens, terms from the clinical guidelines were manually compiled to conform to a classification hierarchy. To validate the coverage of the developed food allergen code system, we extracted 823 unique food allergens, totaling 12,027 entries, from two years of electronic health records (EHRs) and performed manual mapping to the code system., Results: In total, 1,123 food and 607 non-food/non-medication allergen terms were included. The three-digit meta-code system comprises an identifier for coding systems, code length, and allergen categories. The codes allowed the determination of hierarchical relationships between any two terms. The Japanese allergy intolerance value set was developed and bound to the allergy intolerance code. Of the food allergens extracted from EHRs, 62.9% corresponded to unique codes, 6.1% to multiple codes, and 31.0% were unmapped, accounting for 91.5%, 1.9%, and 6.6% of entries, respectively., Conclusions: The JFAGY encompasses Japanese-specific food and non-food/non-medication allergens, enabling hierarchy determination between two terms, and playing a critical role in medical safety. When utilizing the JFAGY with the FHIR allergy intolerance resource, an FHIR extension must be included to denote a denied allergy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yoshimasa Kawazoe reports financial support was provided by EM Systems, Inc. Yoshimasa Kawazoe reports financial support was provided by EPNextS, Inc. Yoshimasa Kawazoe reports financial support was provided by MRP CO., LTD. Yoshimasa Kawazoe reports financial support was provided by SHIP HEALTHCARE HOLDINGS, INC. Yoshimasa Kawazoe reports financial support was provided by SoftBank Corp. Yoshimasa Kawazoe reports financial support was provided by NEC Corporation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The effect of antibodies elicited by bivalent mRNA vaccines (original and omicron BA.1) on preventing coronavirus disease 2019 (COVID-19) onset in the presence of the XBB variant remains unknown. A prospective cohort study conducted at Chiba University Hospital examined healthcare workers who received their sixth vaccination with the Pfizer-BioNTech COVID-19 bivalent mRNA vaccine (original and omicron BA.1). Researchers quantitatively measured serum anti-spike (S) antibody levels. Participants not infected during the 60-day observation period after vaccination had significantly higher S antibody titers than those who were newly infected (27756 U/mL, 95% CI [24988-30831 U/mL] vs. 15321 U/mL, 95% CI [10824-21688 U/mL], p<0.05). The risk of infection decreased by 84% when the S antibody titer exceeded 15500 U/ml. Neutralizing antibody titers against the XBB.1.16 and XBB.1.42 variants were higher in age- and sex-matched noninfected individuals than in newly infected individuals during the post-vaccination observation period. S antibody titers were highly correlated with neutralizing antibody titers. In conclusion, after the sixth COVID-19 vaccination with the bivalent mRNA vaccine (original and omicron BA.1), high S antibody titers correlated with disease prevention, even in the presence of XBB variants.

Macular hole (MH) is a retinal break involving the fovea that causes impaired vision. Although advances in vitreoretinal surgical techniques achieve >90% MH closure rate, refractory cases still exist. For such cases, autologous retinal transplantation is an optional therapy showing good anatomic success, but visual improvement is limited and peripheral visual field defects are inevitable after graft harvesting. Here, using a non-human primate model, we evaluated whether human embryonic stem cell-derived retinal organoid (RO) sheet transplantation can be an effective option for treating MH. After transplantation, MH was successfully closed by continuous filling of the MH space with the RO sheet, resulting in improved visual function, although no host-graft synaptic connections were confirmed. Mild xeno-transplantation rejection was controlled by additional focal steroid injections and rod/cone photoreceptors developed in the graft. Overall, our findings suggest pluripotent stem cell-derived RO sheet transplantation as a practical option for refractory MH treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Globally, prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing, and there is an urgent need to develop innovative therapies that promote liver regeneration following hepatectomy for this disease. Surgical excision is a key therapeutic approach with curative potential for liver tumors. However, hepatic steatosis can lead to delayed liver regeneration and higher post-operative complication risk. Mesenchymal stem cells-conditioned medium (MSC-CM) is considered a rich source of paracrine factors that can repair tissues and restore function of damaged organs. Meanwhile, hydrogels have been widely recognized to load MSC secretome and achieve sustained release. This study aimed to evaluate the therapeutic effect of hydrogel-encapsulated MSC-CM on liver regeneration following partial hepatectomy (PHx) in a rodent model of diet-induced hepatic steatosis., Methods: Male Lewis rats were fed with a methionine and choline-deficient diet. After 3 weeks of feeding, PHx was performed and rats were randomly allocated into two groups that received hydrogel-encapsulated MSC-CM or vehicle via the intra-mesenteric space of the superior mesenteric vein (SMV)., Results: The regeneration of the remnant liver at 30 and 168 h after PHx was significantly accelerated, and the expressions of proliferating cell nuclear antigen were significantly enhanced in the MSC-CM group. MSC-CM treatment significantly increased hepatic ATP and β-hydroxybutyrate content at 168 h after PHx, indicating that MSC-CM fosters regeneration not only in volume but also in functionality. The number of each TUNEL- and cleaved caspase-3 positive nuclei in hepatocytes at 9 h after PHx were significantly decreased in the MSC-CM group, suggesting that MSC-CM suppressed apoptosis. MSC-CM increased serum immunoregulatory cytokine interleukin-10 and interleukin-13 at 30 h after PHx. Additionally, mitotic figures and cyclin D1 expression decreased and hepatocyte size increased in the MSC-CM group, implying that this mode of regeneration was mainly through cell hypertrophy rather than cell division., Conclusions: MSC-CM represents a novel therapeutic approach for patients with MASLD requiring PHx., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Tocilizumab is effective in treating severe coronavirus disease 2019 (COVID-19). However, the specific time point it acts as a valid indicator of treatment efficacy remains unclear. This study aimed to determine the optimal day for assessing the prognostic value of the oxygen saturation/fraction of inspired oxygen (SpO 2 /FiO 2 ) and ratio of respiratory rate-oxygenation (ROX) index in patients receiving tocilizumab for COVID-19., Methods: All patients admitted to our hospital from March 2020 to July 2021 who received tocilizumab for COVID-19 were retrospectively identified from hospital charts. Biodata, medical history, and laboratory tests results were obtained from medical records. The prognostic values of the SpO 2 /FiO 2 and ROX index for predicting mortality were assessed. Cox proportional hazard and receiver operating characteristic curve models were utilized., Results: Of the 84 included patients, 34 died within 7 days after discharge. The patients who recovered had a mean age of 65 years and were younger than those who died. The multivariate analysis indicated that multiple comorbidities, cancer history, CURB-65 score, neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio, and lactate dehydrogenase levels were higher in those who died compared with those who survived. No significant differences were found in dyspnea or total bilirubin levels between the two groups. The SpO 2 /FiO 2 at 3 days post-tocilizumab initiation was strongly associated with survival., Conclusions: The SpO 2 /FiO 2 on day 3 post-tocilizumab initiation was a predictor of COVID-19 prognosis, which could be employed in determining clinical decisions. Prompt alternative interventions should be considered when this ratio does not improve., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

The reflexive excitation of the sympathetic nervous system in response to psychological stress leads to elevated blood pressure, a condition that persists even after the stress has been alleviated. This sustained increase in blood pressure, which may contribute to the pathophysiology of hypertension, could be linked to neural plasticity in sympathetic nervous activity. Given the critical role of astrocytes in various forms of neural plasticity, we investigated their involvement in maintaining elevated blood pressure during the post-stress phase. Specifically, we examined the effects of arundic acid, an astrocytic inhibitor, on blood pressure and heart rate responses to air-jet stress. First, we confirmed that the inhibitory effect of arundic acid is specific to astrocytes. Using c-Fos immunohistology, we then observed that psychological stress activates neurons in cardiovascular brain regions, and that this stress-induced neuronal activation was suppressed by arundic acid pre-treatment in rats. By evaluating astrocytic process thickness, we also confirmed that astrocytes in the cardiovascular brain regions were activated by stress, and this activation was blocked by arundic acid pre-treatment. Next, we conducted blood pressure measurements on unanesthetized, unrestrained rats. Air-jet stress elevated blood pressure, which remained high for a significant period during the post-stress phase. However, pre-treatment with arundic acid, which inhibited astrocytic activation, suppressed stress-induced blood pressure elevation both during and after stress. In contrast, arundic acid had no significant impact on heart rate. These findings suggest that both neurons and astrocytes play integral roles in stress-induced blood pressure elevation and its persistence after stress, offering new insights into the pathophysiological mechanisms underlying hypertension., (© 2024. The Author(s).)

The coronavirus disease (COVID-19) pandemic has negatively affected research activities across various fields. This study aimed to determine nursing researchers' concerns about research activities during the COVID-19 pandemic in Japan and subsequent changes brought on by it. For this study, we conducted descriptive statistics and text mining analyses using data from two surveys conducted by the Japan Academy of Nursing Science (JANS) in the early days of the pandemic (first survey: mid-2020) and after 2 years (second survey: early 2022). Concerns about research activities were observed in 89% and 80% of the nursing researchers in the first and second surveys, respectively. Furthermore, concerns about "Difficulty in collecting research data" and "Content and quality of your research" were stronger in the second survey. Text mining analyses revealed that in the first survey, they were concerned about environmental changes and restrictions when proceeding with research during the COVID-19 pandemic, which was unfamiliar at the time. In the second survey, after overcoming environmental changes in the early stages of the pandemic, nursing researchers' concerns shifted to anxiety about the future, such as concerns about degree acquisition, employment and career advancement, and research results. The current study highlights various concerns among nursing researchers regarding research activities that have evolved over time during the pandemic. Academic societies must flexibly construct support measures for nursing researchers when a new infectious disease occurs. Such measures should be sensitive to the prevailing social circumstances and the evolving needs of researchers., (© 2024 Wiley Periodicals LLC.)

Background: The efficacy of rituximab in steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown., Methods: This retrospective study included 45 patients with childhood-onset SRNS treated with rituximab across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. The primary outcome was the rate of CR, PR, and NR. Risk factors for non-CR were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were also evaluated., Results: The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. The median follow-up period after rituximab administration was 7.4 years. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5., Conclusion: Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with SRNS., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

The complement system plays an important role in biological defense as an effector to eliminate microorganisms that invade an organism and it is composed of more than 50 proteins, most of which are produced in the liver. Of these proteins, the mRNA expression of C3 and Cfb is known to be positively regulated by the nuclear receptor HNF4α. To investigate whether HNF4α regulates the complement system, we analyzed the hepatic expression of genes involved in the complement activation pathway and membrane attack complex (MAC) formation within the complement system using liver-specific Hnf4a-null mice (Hnf4a ΔHep mice) and tamoxifen-induced liver-specific Hnf4a-null mice (Hnf4a f/f;AlbERT2cre mice). We found that hepatic expression of many complement genes including C8a, C8b, C8g, and C9 that are involved in formation of the MAC was markedly decreased in Hnf4a ΔHep mice and Hnf4a f/f;AlbERT2cre mice. Furthermore, expression of C8A, C8B, and C8G was also decreased in human hepatoma cell lines in which the expression of HNF4α was suppressed, and expression of C8G and C9 was induced in a human immortalized hepatocyte cell line with forced expression of HNF4α. Transactivation of C8g and C9 was dependent on HNF4α expression of HNF4α binding sites, indicating that C8g and C9 are novel target genes of HNF4α. The results suggest that hepatic HNF4α plays an important role in regulation of the complement system, mainly MAC formation., (© 2024. The Society for In Vitro Biology.)

Background: Left ventricular (LV) unloading by Impella, an intravascular microaxial pump, has been shown to exert dramatic cardioprotective effects in acute clinical settings of cardiovascular diseases. Total Impella support (no native LV ejection) is far more efficient in reducing LV energetic demand than partial Impella support, but the manual control of pump speed to maintain stable LV unloading is difficult and impractical. We aimed to develop an Automatic IMpella Optimal Unloading System (AIMOUS), which controls Impella pump speed to maintain LV unloading degree using closed-feedback control. We validated the AIMOUS performance in an animal model., Methods: In dogs, we identified the transfer function from pump speed to LV systolic pressure (LVSP) under total support conditions (n = 5). Using the transfer function, we designed the feedback controller of AIMOUS to keep LVSP at 40 mmHg and examined its performance by volume perturbations (n = 9). Lastly, AIMOUS was applied in the acute phase of ischemia-reperfusion in dogs. Four weeks after ischemia-reperfusion, we assessed LV function and infarct size (n = 10)., Results: AIMOUS maintained constant LVSP, thereby ensuring a stable LV unloading condition regardless of volume withdrawal or infusion (±8 ml/kg from baseline). AIMOUS in the acute phase of ischemia-reperfusion markedly improved LV function and reduced infarct size (No Impella support: 13.9 ± 1.3 vs. AIMOUS: 5.7 ± 1.9%, P < 0.05)., Conclusions: AIMOUS is capable of maintaining optimal LV unloading during periods of unstable hemodynamics. Automated control of Impella pump speed in the acute phase of ischemia-reperfusion significantly reduced infarct size and prevented subsequent worsening of LV function., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Liver fibrosis, heralding the potential progression to cirrhosis and hepatocellular carcinoma (HCC), compromises patient survival and augments post-hepatectomy recurrence. This study examined the detrimental effects of liver fibrosis on the antitumor functions of liver natural killer (NK) cells and the interleukin-33 (IL-33) signaling pathway., Methods: Our investigation, anchored in both human physiologies using living and deceased donor livers and the carbon tetrachloride (CCl 4 )-induced mouse fibrosis model, aimed to show a troubling interface between liver fibrosis and weakened hepatic immunity., Results: The Fibrosis-4 (FIB-4) index emerged as a salient, non-invasive prognostic marker, and its elevation correlated with reduced survival and heightened recurrence after HCC surgery even after propensity matching (n = 385). We established a strong correlation between liver fibrosis and liver NK cell dysfunction by developing a method for extracting liver NK cells from the liver graft perfusate. Furthermore, liver fibrosis ostensibly disrupted chemokines and promoted IL-33 expression, impeding liver NK cell antitumor activities, as evidenced in mouse models. Intriguingly, our results implicated IL-33 in diminishing the antitumor responses of NK cells. This interrelation, consistent across both mouse and human studies, coincides with clinical data suggesting that liver fibrosis predisposes patients to an increased risk of HCC recurrence., Conclusion: Our study revealed a critical relationship between liver fibrosis and compromised tumor immunity, emphasizing the potential interference of IL-33 with NK cell function. These insights advocate for advanced immunostimulatory therapies targeting cytokines, such as IL-33, aiming to bolster the hepatic immune response against HCC in the context of liver fibrosis., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Background: Impella (Abiomed, Danvers, MA, USA) is a percutaneous ventricular assist device commonly used in cardiogenic shock, providing robust hemodynamic support, improving the systemic circulation, and relieving pulmonary congestion. Maintaining adequate left ventricular (LV) filling is essential for optimal hemodynamic support by Impella. This study aimed to investigate the impact of pulmonary vascular resistance (PVR) and right ventricular (RV) function on Impella-supported hemodynamics in severe biventricular failure using cardiovascular simulation., Methods: We used Simulink® (Mathworks, Inc., Natick, MA, USA) for the simulation, incorporating pump performance of Impella CP determined using a mock circulatory loop. Both systemic and pulmonary circulation were modeled using a 5-element resistance-capacitance network. The four cardiac chambers were represented by time-varying elastance with unidirectional valves. In the scenario of severe LV dysfunction (LV end-systolic elastance set at a low level of 0.4 mmHg/mL), we compared the changes in right (RAP) and left atrial pressures (LAP), total systemic flow, and pressure-volume loop relationship at varying degrees of RV function, PVR, and Impella flow rate., Results: The simulation results showed that under low PVR conditions, an increase in Impella flow rate slightly reduced RAP and LAP and increased total systemic flow, regardless of RV function. Under moderate RV dysfunction and high PVR conditions, an increase in Impella flow rate elevated RAP and excessively reduced LAP to induce LV suction, which limited the increase in total systemic flow., Conclusions: PVR is the primary determinant of stable and effective Impella hemodynamic support in patients with severe biventricular failure., Competing Interests: Declaration of competing interest Matsushita H, Nishikawa T, Unoki T, Yokota S, Sato K, Morita H, Yoshida Y, Fukumitsu M, Nishiura A, Uemura K, Kawada T, Kikuchi A, and Yamaura K, declare no conflicts of interest. Saku K received research funding from Abiomed Japan K.K., NTT Research, Inc., Asahi Kasei ZOLL Medical Corporation, Neuroceuticals Inc., and Zeon Medical Inc. and honoraria from Abiomed Japan K.K., Mallinckrodt Pharma K.K., and Ono Pharmaceutical Co., Ltd., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to explore the potential benefits of retinal pigment epithelium replacement therapy in patients with Bietti crystalline dystrophy (BCD) by assessing the disease pathology with the distinctive relationship between fundus autofluorescence (FAF) abnormality and visual field defect., Methods: Sixteen eyes from 16 patients with BCD and 16 eyes from 16 patients with RHO-associated retinitis pigmentosa were included. Fundus autofluorescence, optical coherence tomography, and Goldmann perimetry results were retrospectively reviewed and assessed using image analyses., Results: In patients with BCD, the FAF abnormality area was not correlated with the overall visual field defect area and median overall visual field defect area (57.5%) was smaller than FAF abnormality area (98.5%). By contrast, the ellipsoid zone width was significantly correlated with the central visual field area (r = 0.806, P < 0.001). In patients with RHO-associated retinitis pigmentosa, the FAF abnormality area and ellipsoid zone width were significantly correlated with the overall visual field defect area (r = 0.833, P < 0.001) and central visual field area (r = 0.887, P < 0.001), respectively., Conclusion: The FAF abnormality shown in patients with BCD involves retinal pigment epithelium degeneration without complete loss of photoreceptors or visual function. These results suggest that patients with BCD are good candidates for retinal pigment epithelium replacement therapy for preservation of residual visual function., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Background: Social anxiety disorder (SAD) is a common mental disorder in adolescents and young adults. Early intervention and support could help prevent the development of full-blown SAD. Considering that adolescents with social anxiety symptoms do not prefer face-to-face sessions due to their fear of communicating with therapists, internet-based cognitive behavioral therapy (ICBT) was implemented., Objective: This study aimed to examine the effectiveness of complete self-help ICBT for subthreshold SAD in high school and college students with no history of mental disorders., Methods: A multicenter randomized controlled trial designed to demonstrate the objective was conducted from December 2022 to October 2023. Participants were students enrolled at 6 universities and 1 high school. The intervention was a complete self-help ICBT and consisted of 10 text-based sessions that taught cognitive behavioral therapy techniques for social anxiety in youths and young adults. The comparison was a no-treatment condition (control group), which was randomly assigned in a 1:1 ratio by a computer program. A total of 2 psychological scales were used to assess the severity of social anxiety, and 1 psychological scale each was used to measure symptoms of depression, general anxiety, and quality of life., Results: In total, 77 students were enrolled as study participants. Through the randomization procedure, 38 participants were included in the intervention group, and 39 patients were included in the control group. Results from the analysis of covariance with depression as covariates showed that the participants in the intervention group had significantly reduced symptoms of social anxiety, depression, and general anxiety compared to the control group. The response rate was 61% (19/31) in the intervention group and 24% (9/38) in the control group: odds ratio (OR) 4.97 (95% CI 1.61-16.53; P=.003) in the Fisher exact test. The recovery rate was 68% (21/31) in the intervention group and 34% (13/38) in the control group: OR 3.95 (95% CI 1.32-12.56; P=.008). The OR for the remission ratio was 2.01 (95% CI 0.64-6.60; P=.20) and for the risk of worsening was 0.23 (95% CI 0.002-1.33; P=.10), but no significant difference was observed., Conclusions: The results of this randomized controlled trial show that fully unguided ICBT improves subthreshold SAD in adolescents and young adults. Interpretation of the effectiveness in preventing SAD that meets the diagnostic criteria is limited by sample size and the follow-up period. Future studies should include more extended observations and larger sample sizes in high-risk populations., Trial Registration: UMIN-CTR UMIN000050064; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000057035., (©Kazuki Matsumoto, Sayo Hamatani, Kiko Shiga, Kiyoko Iiboshi, Makiko Kasai, Yasuhiro Kimura, Satoshi Yokota, Katsunori Watanabe, Yoko Kubo, Masayuki Nakamura. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 22.07.2024.)

Objective: We identified the associated factors and compared the survival times of feline hyperthyroidism (FHT) between thyroidectomy and methimazole alone., Methods: The medical records of 41 cats diagnosed with new-onset hyperthyroidism were retrospectively reviewed. The cats were categorized into the thyroidectomy (n = 15) and methimazole (26) treatment groups. Survival analyses using the Kaplan-Meier method, log-rank test, and Cox proportional hazards models were conducted to compare the time to the selected outcomes., Results: Univariate analysis revealed that survival time was significantly longer with thyroidectomy than with methimazole (P < .001). Multivariate analyses revealed thyroidectomy as an independent prognostic factor for good outcomes (hazard ratio, 0.209; 95% CI, 0.073 to 0.601; P = .004). The recurrence rate was significantly lower in cats that underwent thyroidectomy than in those that received methimazole alone (P = .011)., Clinical Relevance: Compared with methimazole alone, thyroidectomy was associated with a longer survival time in FHT and can be considered an irreversible treatment modality in settings where radioisotopes are not available.

Objective: Comparing the utility of the anti-human serum amyloid A (SAA)-specific monoclonal and polyclonal antibodies assays (LZ-SAA) with the pure monoclonal anti-human antibody assays (VET-SAA) during clinical practice in primary care hospital populations by measuring SAA measurement in healthy and diseased domestic cats., Animals: 52 healthy and 185 diseased client-owned cats., Methods: SAA concentration was measured using different LZ-SAA and VET-SAA measurements for healthy and various diseased cats. Sensitivity, specificity, and accuracy were calculated for each disease., Results: VET-SAA has higher sensitivity than LZ-SAA for the most common diseases presenting to primary care veterinary hospitals, including chronic kidney disease, tumors, and gingivostomatitis. Our results reveal the capability of detecting low SAA concentrations in healthy and diseased cats using VET-SAA in contrast to LZ-SAA, which found elevations of SAA concentrations only in diseased cats., Clinical Relevance: Our findings indicate that switching to the new VET-SAA instead of the conventional LZ-SAA will likely enhance the diagnostic performance in primary care veterinary hospitals.

Objective: Total artificial heart (TAH) using dual rotary blood pumps (RBPs) is a potential treatment for end-stage heart failure. A well-noted challenge with RBPs is their low sensitivity to preload, which can lead to venous congestion and ventricular suction. To address this issue, we have developed an innovative closed-loop control system of dual RBPs in TAH. This system emulates the Frank-Starling law of the heart in controlling RBPs while monitoring stressed blood volume (V) based on the circulatory equilibrium framework. We validated the system in in-vivo experiments., Methods: In 9 anesthetized dogs, we prepared a TAH circuit using 2 centrifugal-type RBPs. We first investigated whether the flow and inlet atrial pressure in each RBP adhered to a logarithmic Frank-Starling curve. We then examined whether the RBP flows and atrial pressures were maintained stably during aortic occlusion (AO) and pulmonary cannula stenosis (PS), whether averaged flow of dual RBPs and bilateral atrial pressures were controlled to their predefined target values for a specific V, and whether this system could maintain the atrial pressures within predefined control ranges under significant changes in V., Results: This system effectively emulated the logarithmic Frank-Starling curve. It robustly stabilized the flow and atrial pressures during AO and PS without venous congestion or ventricular suction, accurately achieved target values in averaged flow and atrial pressures, and efficaciously maintained these pressures within the control ranges., Conclusion: This system controls dual RBPs in TAH accurately and stably., Significance: This system may accelerate clinical application of TAH with dual RBPs.

Purpose: This study aimed to investigate the relationship between various clinical factors and physical function in the early postoperative period in patients with soft tissue sarcomas (STSs) by subjective and objective evaluations., Materials and Methods: The 90 patients enrolled in this study were classified into five groups according to tumor location: retroperitoneal, gluteal, groin, thigh, and lower leg. The Musculoskeletal Tumor Society (MSTS) score was evaluated at discharge; the timed up-and-go test (TUGT) was performed preoperatively and at discharge. Group comparisons by tumor location were performed. To identify significant factors associated with physical dysfunction, multivariate analysis was performed using an MSTS score of <80% and a change in pre and postoperative TUGT score., Results: There were no significant differences between the tumor location and physical function. The change in pre- and postoperative TUGT scores was significantly associated with an MSTS score of <80%. Quadriceps and tibialis anterior muscle resections were significantly associated with the change in pre- and post-operative TUGT scores., Conclusions: The quadriceps and tibialis anterior muscles may affect physical dysfunction after surgery for STSs. Early postoperative rehabilitation should include the identification of resected muscles and functional improvement of residual muscles, possibly with orthotic support for knee extension and ankle dorsiflexion.

Nitric oxide (NO) inhalation improves pulmonary hemodynamics in participants with pulmonary arterial hypertension (PAH). Although it can reduce pulmonary vascular resistance (PVR) in PAH, its impact on the dynamic mechanics of pulmonary arteries and its potential difference between control and participants with PAH remain unclear. PA impedance provides a comprehensive description of PA mechanics. With an arterial model, PA impedance can be parameterized into peripheral pulmonary resistance ( R p ), arterial compliance ( C p ), characteristic impedance of the proximal arteries ( Z c ), and transmission time from the main PA to the reflection site. This study investigated the effects of inhaled NO on PA impedance and its associated parameters in control and monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) male rats (6/group). Measurements were obtained at baseline and during NO inhalation at 40 and 80 ppm. In both groups, NO inhalation decreased PVR and increased the left atrial pressure. Notably, its impact on PA impedance was frequency dependent, as revealed by reduced PA impedance modulus in the low-frequency range below 10 Hz, with little effect on the high-frequency range. Furthermore, NO inhalation attenuated R p , increased C p , and prolonged transmission time without affecting Z c . It reduced R p more pronouncedly in MCT-PAH rats, whereas it increased C p and delayed transmission time more effectively in control rats. In conclusion, the therapeutic effects of inhaled NO on PA impedance were frequency dependent and may differ between the control and MCT-PAH groups, suggesting that the effect on the mechanics differs depending on the pathological state. NEW & NOTEWORTHY Nitric oxide inhalation decreased pulmonary arterial impedance in the low-frequency range (<10 Hz) with little impact on the high-frequency range. It reduced peripheral pulmonary resistance more pronouncedly in pulmonary hypertension rats, whereas it increased arterial compliance and transmission time in control rats. Its effect on the mechanics of the pulmonary arteries may differ depending on the pathological status.

Background: Based on the Japanese Pediatric Orthopaedic Association's guidelines, secondary screening and imaging including ultrasonography and radiography, are recommended in infants with limited hip abduction (<70°) or in those with multiple risk factors including the following: asymmetrical skin creases, a family history of developmental dysplasia of the hip, female sex, and pelvic position at delivery. However, there is still little information regarding the usefulness of this guideline. The objective of this study was to investigate the association between the risk factors and developmental dysplasia of the hip diagnosed using ultrasound and radiography., Methods: A total of 356 infants (67 boys and 289 girls) underwent secondary ultrasonographic and radiological screening for developmental dysplasia of the hip in our hospital. Risk factors were documented from their medical records. The recommended item score, which we defined as an integrated value of the recommended item, was calculated for each patient. The limitation of hip abduction alone was a criterion for secondary screening; therefore, we defined the scores as follows: the limitation of hip abduction scored 2 points and other recommended scores were assigned 1 point. If the recommended item score was 2 points or more, we classified the infants as high-risk., Results: A total of 280 of 356 infants were included in the high-risk group, which showed a higher ratio of cases with abnormal imaging findings than the low-risk group. According to the multivariate logistic regression analyses among the recommended items, being female, skin asymmetry, and limb limitation were identified as independent risk factors for imaging abnormality and the need for Pavlik harness treatment., Conclusions: The recommended items for secondary screening based on the Japanese Pediatric Orthopaedic Association's guidelines could be useful for screening infants in need of treatment., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy and a major cause of blindness. RP is caused by several variants of multiple genes, and genetic diagnosis by identifying these variants is important for optimizing treatment and estimating patient prognosis. Next-generation sequencing (NGS), which is currently widely used for diagnosis, is considered useful but is known to have limitations in detecting copy number variations (CNVs). In this study, we re-evaluated CNVs in EYS, the main causative gene of RP, identified via NGS using multiplex ligation-dependent probe amplification (MLPA). CNVs were identified in NGS samples of eight patients. To identify potential CNVs, MLPA was also performed on samples from 42 patients who were undiagnosed by NGS but carried one of the five major pathogenic variants reported in Japanese EYS-RP cases. All suspected CNVs based on NGS data in the eight patients were confirmed via MLPA. CNVs were found in 2 of the 42 NGS-undiagnosed RP cases. Furthermore, results showed that 121 of the 661 patients with RP had EYS as the causative gene, and 8.3% (10/121 patients with EYS-RP) had CNVs. Although NGS using the CNV calling criteria utilized in this study failed to identify CNVs in two cases, no false-positive results were detected. Collectively, these findings suggest that NGS is useful for CNV detection during clinical diagnosis of RP., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hiraoka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: A new algorithm for causality assessment of drugs and fatal cerebral haemorrhage (ACAD-FCH) was published in 2021. However, its use in clinical practice has not been verified., Objectives: This study aimed to explore the practical value of the ACAD-FCH when applying information available in clinical practice., Methods: The medical records of patients who died at the University of Tokyo Hospital in 2020 were reviewed, and cases with intracranial haemorrhage were selected. Two evaluators independently assessed these cases using three methods (the ACAD-FCH, Naranjo algorithm, and WHO-UMC scale). The number of 'Yes', 'No', and 'No information/Do not know' responses to each question by both evaluators were summed and compared. Inter-rater reliability was evaluated for each method using agreement rates and kappa coefficients with 95% confidence intervals (CI)., Results: Among 316 deaths, 24 cases with intracranial haemorrhage were evaluated. The proportion of ‛No information/Do not know' responses for each question was 35.6% (95% CI 31.4-40.6%) for the ACAD-FCH and 66.9% (95% CI 62.5-71.1%) for the Naranjo algorithm. The respective agreement rates and kappa coefficients were 0.917 (0.798-1.00) and 0.867 (0.675-1.00) for the ACAD-FCH, 0.708 (0.512-0.904) and 0.139 (-0.236 to 0.513) for the Naranjo algorithm, and 0.50 (0.284-0.716) and 0.326 (0.110-0.541) for the WHO-UMC scale, respectively., Conclusion: Our findings suggest the utility of the ACAD-FCH when assessing death cases with intracranial haemorrhage. However, larger studies including intra-rater assessments are warranted for further validation of this algorithm., (© 2024. The Author(s).)

Introduction: Intra-operative hypotension is a common complication of surgery under general anesthesia in dogs and humans. Computer-controlled closed-loop infusion systems of norepinephrine (NE) have been developed and clinically applied for automated optimization of arterial pressure (AP) and prevention of intra-operative hypotension in humans. This study aimed to develop a simple computer-controlled closed-loop infusion system of NE for the automated control of the mean arterial pressure (MAP) in dogs with isoflurane-induced hypotension and to validate the control of MAP by the developed system., Methods: NE was administered via the cephalic vein, whereas MAP was measured invasively by placing a catheter in the dorsal pedal artery. The proportional-integral-derivative (PID) controller in the negative feedback loop of the developed system titrated the infusion rate of NE to maintain the MAP at the target value of 60 mmHg. The titration was updated every 2 s. The performance of the developed system was evaluated in six laboratory Beagle dogs under general anesthesia with isoflurane., Results: In the six dogs, when the concentration [median (interquartile range)] of inhaled isoflurane was increased from 1.5 (1.5-1.5)% to 4 (4-4)% without activating the system, the MAP was lowered from 95 (91-99) to 41 (37-42) mmHg. In contrast, when the concentration was increased from 1.5 (1.0-1.5)% to 4 (4-4.8)% for a 30-min period and the system was simultaneously activated, the MAP was temporarily lowered from 92 (89-95) to 47 (43-49) mmHg but recovered to 58 (57-58) mmHg owing to the system-controlled infusion of NE. If the acceptable target range for MAP was defined as target MAP ±5 mmHg (55 ≤ MAP ≤65 mmHg), the percentage of time wherein the MAP was maintained within the acceptable range was 96 (89-100)% in the six dogs during the second half of the 30-min period (from 15 to 30 min after system activation). The median performance error, median absolute performance error, wobble, and divergence were - 2.9 (-4.7 to 1.9)%, 2.9 (2.0-4.7)%, 1.3 (0.8-1.8)%, and - 0.24 (-0.34 to -0.11)%·min -1 , respectively. No adverse events were observed during the study period, and all dogs were extubated uneventfully., Conclusion: This system was able to titrate the NE infusion rates in an accurate and stable manner to maintain the MAP within the predetermined target range in dogs with isoflurane-induced hypotension. This system can be a potential tool in daily clinical practice for the care of companion dogs., Competing Interests: JA and YK are employees of NTT Res. Inc. The remaining 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 Sasaki, Kawada, Matsushita, Yokota, Kakuuchi, Yokoi, Yoshida, Morita, Sato, Nishikawa, Kutter, Kataoka, Alexander, Saku, Ishikawa and Uemura.)

Clinical studies using suspensions or sheets of human pluripotent cell-derived retinal pigment epithelial cells (hiPSC-RPE) have been conducted globally for diseases such as age-related macular degeneration. Despite being minimally invasive, cell suspension transplantation faces challenges in targeted cell delivery and frequent cell leakage. Conversely, although the RPE sheet ensures targeted delivery with correct cell polarity, it requires invasive surgery, and graft preparation is time-consuming. We previously reported hiPSC-RPE strips as a form of quick cell aggregate that allows for reliable cell delivery to the target area with minimal invasiveness. In this study, we used a microsecond pulse laser to create a local RPE ablation model in cynomolgus monkey eyes. The hiPSC-RPE strips were transplanted into the RPE-ablated and intact sites. The hiPSC-RPE strip stably survived in all transplanted monkey eyes. The expansion area of the RPE from the engrafted strip was larger at the RPE injury site than at the intact site with no tumorigenic growth. Histological observation showed a monolayer expansion of the transplanted RPE cells with the expression of MERTK apically and collagen type 4 basally. The hiPSC-RPE strip is considered a beneficial transplantation option for RPE cell therapy., (© 2024. The Author(s).)

Cleft palate is the most common facial birth defect worldwide. It is caused by environmental factors or genetic mutations. Environmental factors such as pharmaceutical exposure in women are known to induce cleft palate. The aim of the present study was to investigate the protective effect of Sasa veitchii extract against medicine-induced inhibition of proliferation of human embryonic palatal mesenchymal cells. We demonstrated that all-trans -retinoic acid inhibited human embryonic palatal mesenchymal cell proliferation in a dose-dependent manner, whereas dexamethasone treatment had no effect on cell proliferation. Cotreatment with Sasa veitchii extract repressed all-trans -retinoic acid-induced toxicity in human embryonic palatal mesenchymal cells. We found that cotreatment with Sasa veitchii extract protected all-trans -retinoic acid-induced cyclin D1 downregulation in human embryonic palatal mesenchymal cells. Furthermore, Sasa veitchii extract suppressed all-trans -retinoic acid - induced miR-4680-3p expression. Additionally, the expression levels of the genes that function downstream of the target genes ( ERBB2 and JADE1 ) of miR-4680-3p in signaling pathways were enhanced by cotreatment with Sasa veitchii extract and all-trans -retinoic acid compared to all-trans -retinoic acid treatment. These results suggest that Sasa veitchii extract suppresses all-trans -retinoic acid-induced inhibition of cell proliferation via modulation of miR-4680-3p expression., Competing Interests: The authors declare no conflicts of interest.

The acetylcholinesterase inhibitor donepezil restores autonomic balance, reduces inflammation, and improves long-term survival in rats with chronic heart failure (CHF) following myocardial infarction (MI). As arterial hypertension is associated with a significant risk of cardiovascular death, we investigated the effectiveness of donepezil in treating CHF in spontaneously hypertensive rats (SHR). CHF was induced in SHR by inducing permanent MI. After 2 weeks, the surviving SHR were randomly assigned to sham-operated (SO), untreated (UT), or oral donepezil-treated (DT, 5 mg/kg/day) groups, and various vitals and parameters were monitored. After 7 weeks of treatment, heart rate and arterial hypertension reduced significantly in DT rats than in UT rats. Donepezil treatment improved 50-day survival (41% to 80%, P = 0.004); suppressed progression of cardiac hypertrophy, cardiac dysfunction (cardiac index: 133 ± 5 vs. 112 ± 5 ml/min/kg, P < 0.05; left ventricular end-diastolic pressure: 12 ± 3 vs. 22 ± 2 mmHg, P < 0.05; left ventricular +dp/dt max : 5348 ± 338 vs. 4267 ± 114 mmHg/s, P < 0.05), systemic inflammation, and coronary artery remodeling (wall thickness: 26.3 ± 1.4 vs. 34.7 ± 0.7 μm, P < 0.01; media-to-lumen ratio: 3.70 ± 0.73 vs. 8.59 ± 0.84, P < 0.001); increased capillary density; and decreased plasma catecholamine, B-type natriuretic peptide, arginine vasopressin, and angiotensin II levels. Donepezil treatment attenuated cardiac and coronary artery remodeling, mitigated cardiac dysfunction, and significantly improved the prognosis of SHR with CHF., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Successful treatment of pediatric cancers often results in long-term health complications, including potential effects on fertility. Therefore, assessing the male reproductive toxicity of anti-cancer drug treatments and the potential for recovery is of paramount importance. However, in vivo evaluations are time-intensive and require large numbers of animals. To overcome these constraints, we utilized an innovative organ culture system that supports long-term spermatogenesis by placing the testis tissue between a base agarose gel and a polydimethylsiloxane ceiling, effectively mirroring the in vivo testicular environment. The present study aimed to determine the efficacy of this organ culture system for accurately assessing testicular toxicity induced by cisplatin, using acrosin-green fluorescent protein (GFP) transgenic neonatal mouse testes. The testis fragments were treated with different concentrations of cisplatin-containing medium for 24 h and incubated in fresh medium for up to 70 days. The changes in tissue volume and GFP fluorescence over time were evaluated to monitor the progression of spermatogenesis, in addition to the corresponding histopathology. Cisplatin treatment caused tissue volume shrinkage and reduced GFP fluorescence in a concentration-dependent manner. Recovery from testicular toxicity was also dependent on the concentration of cisplatin received. The results demonstrated that this novel in vitro system can be a faithful replacement for animal experiments to assess the testicular toxicity of anti-cancer drugs and their reversibility, providing a useful method for drug development., (© 2024 John Wiley & Sons Ltd.)

The high prevalence of obesity has become a pressing global public health problem and there exists a strong association between increased BMI and mortality at a BMI of 25 kg/m 2 or higher. The prevalence of obesity is higher among middle-aged adults than among younger groups and the combination of aging and obesity exacerbate systemic inflammation. Increased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha (TNFα) are hallmarks of obesity, and promote the secretion of hepatic C-reactive protein (CRP) which further induces systematic inflammation. The neuropeptide oxytocin has been shown to have anti-obesity and anti-inflammation effects, and also suppress sweet-tasting carbohydrate consumption in mammals. Previously, we have shown that the Japanese herbal medicine Kamikihito (KKT), which is used to treat neuropsychological stress disorders in Japan, functions as an oxytocin receptors agonist. In the present study, we further investigated the effect of KKT on body weight (BW), food intake, inflammation, and sweet preferences in middle-aged obese mice. KKT oral administration for 12 days decreased the expression of pro-inflammatory cytokines in the liver, and the plasma CRP and TNFα levels in obese mice. The effect of KKT administration was found to be different between male and female mice. In the absence of sucrose, KKT administration decreased food intake only in male mice. However, while having access to a 30% sucrose solution, both BW and food intake was decreased by KKT administration in male and female mice; but sucrose intake was decreased in female mice alone. In addition, KKT administration decreased sucrose intake in oxytocin deficient lean mice, but not in the WT lean mice. The present study demonstrates that KKT ameliorates chronic inflammation, which is strongly associated with aging and obesity, and decreases food intake in male mice as well as sucrose intake in female mice; in an oxytocin receptor dependent manner., Competing Interests: HO and KM were employed by Tsumura & Co. The remaining 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 Maejima, Yokota, Yamachi, Misaka, Ono, Oizumi, Mizuno, Hidema, Nishimori, Aoyama, de Wet and Shimomura.)

The increased incidence of osteoarthritis (OA), particularly knee and hip OA, and osteoporosis (OP), owing to population aging, have escalated the medical expense burden. Osteoarthritis is more prevalent in older women, and the involvement of subchondral bone fragility spotlights its association with OP. Notably, subchondral insufficiency fracture (SIF) may represent a more pronounced condition of OA pathophysiology. This review summarizes the relationship between OA and OP, incorporating recent insights into SIF. Progressive SIF leads to joint collapse and secondary OA and is associated with OP. Furthermore, the thinning and fragility of subchondral bone in early-stage OA suggest that SIF may be a subtype of OA (osteoporosis-related OA, OPOA) characterized by significant subchondral bone damage. The high bone mineral density observed in OA may be overestimated due to osteophytes and sclerosis and can potentially contribute to OPOA. The incidence of OPOA is expected to increase along with population aging. Therefore, prioritizing OP screening, early interventions for patients with early-stage OA, and fracture prevention measures such as rehabilitation, fracture liaison services, nutritional management, and medication guidance are essential.

Objectives: Cellular differentiation is based on the effects of various growth factors. Transforming growth factor (TGF)-β1 plays a pivotal role in inducing osteogenic differentiation of mesenchymal stem cells (MSCs). In this study, we investigated the influence of connective tissue growth factor (CTGF), known to function synergistically with TGF-β1, on osteogenic differentiation in MSCs., Methods: UE7T-13 cells were treated with TGF-β1 and/or CTGF. Subsequently, protein levels of intracellular signaling pathway molecules were determined through western blot analysis. The mRNA expression levels of osteogenic differentiation markers were investigated using reverse transcription-quantitative polymerase chain reaction. Bone matrix mineralization was evaluated through alizarin red staining., Results: Co-treatment with TGF-β1 and CTGF resulted in the suppression of TGF-β1-induced phosphorylation of extracellular signal-regulated kinase 1/2, an intracellular signaling pathway molecule in MSCs, while significantly enhancing the phosphorylation of p38 mitogen-activated protein kinase (MAPK). In MSCs, co-treatment with CTGF and TGF-β1 led to increased expression levels of alkaline phosphatase and type I collagen, markers of osteogenic differentiation induced by TGF-β1. Osteopontin expression was observed only after TGF-β1 and CTGF co-treatment. Notably, bone sialoprotein and osteocalcin were significantly upregulated by treatment with CTGF alone. Furthermore, CTGF enhanced the TGF-β1-induced mineralization in MSCs, with complete suppression observed after treatment with a p38 MAPK inhibitor., Conclusions: CTGF enhances TGF-β1-induced osteogenic differentiation and subsequent mineralization in MSCs by predominantly activating the p38 MAPK-dependent pathway., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to this article’s authorship and publication., (Copyright © 2024 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)

Although body fluid volume control by the kidneys may be classified as a long-term arterial pressure (AP) control system, it does not necessarily follow that the urine flow (UF) response to changes in AP is slow. We quantified the dynamic characteristics of the UF response to short-term AP changes by changing mean AP between 60 mmHg and 100 mmHg every 10 s according to a binary white noise sequence in anesthetized rats ( n = 8 animals). In a baro-on trial (the carotid sinus baroreflex was enabled), the UF response represented the combined synergistic effects of pressure diuresis (PD) and neurally mediated antidiuresis (NMA). In a baro-fix trial (the carotid sinus pressure was fixed at 100 mmHg), the UF response mainly reflected the effect of PD. The UF step response was quantified using the sum of two exponential decay functions. The fast and slow components had time constants of 6.5 ± 3.6 s and 102 ± 85 s (means ± SD), respectively, in the baro-on trial. Although the gain of the fast component did not differ between the two trials (0.49 ± 0.21 vs. 0.66 ± 0.22 µL·min -1 ·kg -1 ·mmHg -1 ), the gain of the slow component was greater in the baro-on than in the baro-fix trial (0.51 ± 0.14 vs. 0.09 ± 0.39 µL·min -1 ·kg -1 ·mmHg -1 , P = 0.023). The magnitude of NMA relative to PD was calculated to be 32.2 ± 29.8%. In conclusion, NMA contributed to the slow component, and its magnitude was approximately one-third of that of the effect of PD. NEW & NOTEWORTHY We quantified short-term dynamic characteristics of the urine flow (UF) response to arterial pressure (AP) changes using white noise analysis. The UF step response approximated the sum of two exponential decay functions with time constants of ∼6.5 s and 102 s. The neurally mediated antidiuretic (NMA) effect contributed to the slow component of the UF step response, with the magnitude of approximately one-third of that of the pressure diuresis (PD) effect.

Myeloid-derived suppressor cells (MDSCs) are immature cells with immunosuppressive properties found in the tumor microenvironment. MDSCs are divided into two major subsets: polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs). Both MDSC subsets contribute to the creation of an immunosuppressive environment for tumor progression. In humans, patients with high levels of MDSCs show worse outcomes for several types of cancers. However, the association between MDSCs and clinical features has rarely been investigated in canine studies. In the present study, we measured the proportion of PMN-MDSCs and M-MDSCs in the peripheral blood and tumor tissue of dogs with hepatocellular carcinoma (HCC), prostate cancer (PC), transitional cell carcinoma (TCC), lymphoma, and pulmonary adenocarcinoma. Additionally, we examined immunosuppressive ability of PMN-MDSCs and M-MDSCs in peripheral blood mononuclear cells of TCC case on CD4 + , CD8 + and interferon-γ + cells and investigated the relationships of MDSCs with clinical features and outcomes. PMN-MDSCs increased in HCC, PC, TCC, and lymphoma. In contrast, M-MDSCs increased in the TCC. Both PMN-MDSCs and M-MDSCs exhibited immunosuppressive effects on CD8 + , CD4 + and interferon-γ + cells. In dogs with TCC, lymph node metastasis was associated with high level of PMN-MDSCs but not with M-MDSCs. High levels of both PMN-MDSCs and M-MDSCs were related to advanced tumor stage. Kaplan-Meier analysis revealed that high levels of both PMN-MDSCs and M-MDSCs were significantly associated with shorter overall survival. In addition, the Cox proportional hazard regression model showed that M-MDSCs and the tumor stage were independent prognostic factors for TCC. These results suggest that PMN-MDSCs and M-MDSCs may be involved in tumor progression and could be prognostic factors and promising therapeutic targets in dogs with TCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Intestinal adaptation does not necessarily recover absorptive capacity in short bowel syndrome (SBS), sometimes resulting in intestinal failure-associated liver disease (IFALD). Additionally, its therapeutic options remain limited. Polyamines (spermidine and spermine) are known as one of the autophagy inducers and play important roles in promoting the weaning process; however, their impact on intestinal adaptation is unknown. The aim of this study was to investigate the impact of polyamines ingestion on adaptation and hepatic lipid metabolism in SBS. We performed resection of two-thirds of the small intestine in male Lewis rats as an SBS model. They were allocated into three groups and fed different polyamine content diets (0%, 0.01%, 0.1%) for 30 days. Polyamines were confirmed to distribute to remnant intestine, whole blood, and liver. Villous height and number of Ki-67-positive cells in the crypt area increased with the high polyamine diet. Polyamines increased secretory IgA and mucin content in feces, and enhanced tissue Claudin-3 expression. In contrast, polyamines augmented albumin synthesis, mitochondrial DNA copy number, and ATP storage in the liver. Moreover, polyamines promoted autophagy flux and activated AMP-activated protein kinase with suppression of lipogenic gene expression. Polyamines ingestion may provide a new therapeutic option for SBS with IFALD., (© 2024. The Author(s).)

Background: ECPELLA, a combination of veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) and Impella, a percutaneous left ventricular (LV) assist device, has emerged as a novel therapeutic option in patients with severe cardiogenic shock (CS). Since multiple cardiovascular and pump factors influence the haemodynamic effects of ECPELLA, optimising ECPELLA management remains challenging. In this study, we conducted a comprehensive simulation study of ECPELLA haemodynamics. We also simulated global oxygen delivery (DO 2 ) under ECPELLA in severe CS and acute respiratory failure as a first step to incorporate global DO 2 into our developed cardiovascular simulation., Methods and Results: Both the systemic and pulmonary circulations were modelled using a 5-element resistance‒capacitance network. The four ventricles were represented by time-varying elastances with unidirectional valves. In the scenarios of severe LV dysfunction, biventricular dysfunction with normal pulmonary vascular resistance (PVR, 0.8 Wood units), and biventricular dysfunction with high PVR (6.0 Wood units), we compared the changes in haemodynamics, pressure-volume relationship (PV loop), and global DO 2 under different VA-ECMO flows and Impella support levels., Results: In the simulation, ECPELLA improved total systemic flow with a minimising biventricular pressure-volume loop, indicating biventricular unloading in normal PVR conditions. Meanwhile, increased Impella support level in high PVR conditions rendered the LV-PV loop smaller and induced LV suction in ECPELLA support conditions. The general trend of global DO 2 was followed by the changes in total systemic flow. The addition of veno-venous ECMO (VV-ECMO) augmented the global DO 2 increment under ECPELLA total support conditions., Conclusions: The optimal ECPELLA support increased total systemic flow and achieved both biventricular unloading. The VV-ECMO effectively improves global DO 2 in total ECPELLA support conditions., (© 2024. The Author(s).)

Cleft palate (CP) is one of the most common congenital diseases, and is accompanied by a complicated etiology. Medical exposure in women is among one of the reasons leading to CP. Recently, it has been reported that microRNA (miRNA) plays a crucial role in palate formation and the disruption of miRNA that influence the development of CP. Although association with pharmaceuticals and miRNAs were suggested, it has remained largely unknow. The aim of the current investigation is to elucidate upon the miRNA associated with the inhibition of phenobarbital (PB)-induced cell proliferation in human embryonic palatal mesenchymal (HEPM) cells. We showed that PB inhibited HEPM cell viability in a dose-dependent manner. We demonstrated that PB treatment suppressed cyclin-D1 expression in HEPM cells. Furthermore, PB upregulated let-7c-5p expression and downregulated the expression of two downstream genes (BACH1 and PAX3). Finally, we demonstrated that the let-7c-5p inhibitor alleviated PB-induced inhibition of cell proliferation and altered BACH1 and PAX3 expression levels. These results suggest that PB suppresses cell viability by modulating let-7c-5p expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study aimed to investigate how the extent and central/peripheral location of the residual visual field (VF) in patients with late-stage inherited retinal diseases (IRDs) are related to retinal sensitivity detected using full-field stimulus testing (FST). We reviewed the results of Goldmann perimetry and FST from the medical records of patients with IRDs whose VF represents central (within 10°) and/or peripheral islands, or undetectable. In total, 19 patients (19 eyes) were analyzed in this study. The median value of residual VF area was 1.38%. The median values of rod and cone sensitivities were  - 14.9 dB and 7.4 dB, respectively. Patients with only the peripheral island (- 33.9 dB) had better median rod sensitivity than other groups (only central,  - 18.9 dB; both,  - 3.6 dB). VF area significantly correlated with rod sensitivity (r = - 0.943, p = 0.005) in patients with only peripheral island, but not with cone sensitivity. Peripheral VF islands were significant contributors to FST results, especially rod sensitivity. With reduced or loss of central vision, the extent of residual peripheral VF significantly affected rod sensitivity, suggesting that FST can be useful in quantitatively estimating the overall remaining vision in patients with late-stage IRD., (© 2024. The Author(s).)

Objective: This study examined the association between a single preoperative physiotherapy session during neoadjuvant chemotherapy and physical function and that between preoperative physical activity and prognosis., Methods: In this retrospective, single-center, observational study, we evaluated data from 234 patients scheduled for neoadjuvant chemotherapy and thoracoscopic-laparoscopic esophagectomy who underwent a single preoperative physiotherapy session. The five-repetition sit-to-stand test was performed before and after neoadjuvant chemotherapy. After neoadjuvant chemotherapy, patients were classified into high- and low-physical activity groups based on preoperative physical activity. To examine the association between preoperative physiotherapy and changes in physical function, a multivariate regression analysis was performed. The Cox proportional hazards model was used to investigate the association between preoperative physical activity and overall survival., Results: The median percentage change in the five-repetition sit-to-stand test score was - 3.36%. In the multivariate regression analysis, the regression coefficient of the constant term was - 23.93 (95% confidence interval - 45.31 to - 2.56; P = 0.028). Low physical activity was significantly associated with overall survival after adjustment for confounding factors (P = 0.040)., Conclusions: This study demonstrated that a single preoperative physiotherapy session during neoadjuvant chemotherapy improves physical function, and preoperative physical activity is significantly associated with prognosis., (© 2023. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

The hazardous plasma environment surrounding Earth poses risks to satellites due to internal charging and surface charging effects. Accurate predictions of these risks are crucial for minimizing damage and preparing for system failures of satellites. To forecast the plasma environment, it is essential to know the current state of the system, as the accuracy of the forecast depends on the accuracy of the initial condition of the forecast. In this study, we use data assimilation techniques to combine observational data and model predictions, and present the first global validation of a data-assimilative electron ring current nowcast during a geomagnetic storm. By assimilating measurements from one satellite and validating the results against another satellite in a different magnetic local time sector, we assess the global response and effectiveness of the data assimilation technique for space weather applications. Using this method, we found that the simulation accuracy can be drastically improved at times when observations are available while eliminating almost all of the bias previously present in the model. These findings contribute to the construction of improved operational models in estimating surface charging risks and providing realistic 'source' populations for radiation belt simulations., (© 2024. The Author(s).)

In this study, we investigated the relationship between head length, leg length, offset, and dislocation resistance using range of motion (ROM) simulations based on computed tomography data to examine if a longer femoral head reduces the risk of dislocation. The femoral components were set to eliminate leg length differences with a + 0 mm head, and variations for + 4-, + 7-, and + 8-mm heads were analyzed. Offset and ROM were assessed when longer heads were used, with the leg length adjusted to be similar to that of the contralateral side. While internal rotation at flexion and external rotation at extension increased with + 4-mm longer heads, the + 7- and + 8-mm heads did not increase dislocation resistance. When adjusting for leg length, the longer heads showed no significant differences in offset and ROM. Enhancing dislocation resistance by solely increasing the offset with a longer head, while simultaneously adjusting the depth of stem insertion, may be a beneficial intraoperative technique. Although a + 4-mm longer head possibly increases ROM without impingement, heads extended by + 7 or + 8 mm may not exhibit the same advantage. Therefore, surgeons should consider this technique based on the implant design., (© 2024. The Author(s).)

Adult neurogenesis confers the hippocampus with unparalleled neural plasticity, essential for intricate cognitive functions. The specific influence of sparse newborn neurons (NBNs) in modulating neural activities and subsequently steering behavior, however, remains obscure. Using an engineered NBN-tetanus toxin mouse model (NBN-TeTX), we noninvasively silenced NBNs, elucidating their crucial role in impulse inhibition and cognitive flexibility as evidenced through Morris water maze reversal learning and Go/Nogo task in operant learning. Task-based functional MRI (tb-fMRI) paired with operant learning revealed dorsal hippocampal hyperactivation during the Nogo task in male NBN-TeTX mice, suggesting that hippocampal hyperexcitability might underlie the observed behavioral deficits. Additionally, resting-state fMRI (rs-fMRI) exhibited enhanced functional connectivity between the dorsal and ventral dentate gyrus following NBN silencing. Further investigations into the activities of PV + interneurons and mossy cells highlighted the indispensability of NBNs in maintaining the hippocampal excitation/inhibition balance. Our findings emphasize that the neural plasticity driven by NBNs extensively modulates the hippocampus, sculpting inhibitory control and cognitive flexibility.

Objective: Cystoid macular edema (CME) in retinitis pigmentosa (RP) is an important complication causing visual dysfunction. We investigated the effect of CME on photoreceptors in RP patients with previous or current CME, using an adaptive optics (AO) fundus camera., Methods: We retrospectively observed the CME and ellipsoid zone (EZ) length (average of horizontal and vertical sections) by optical coherence tomography. The density and regularity of the arrangement of photoreceptor cells (Voronoi analysis) were examined at four points around 1.5° from superior to inferior and temporal to nasal. We also performed a multivariate analysis using CME duration, central macular thickness and transversal length of CME., Results: We evaluated 18 patients with previous or current CME (18 eyes; age, 48.7 ± 15.6 years) and 24 patients without previous or current CME (24 eyes; age, 46.0 ± 14.5 years). There were no significant differences in age, logMAR visual acuity, or EZ length. In groups with and without CME, cell density was 11967 ± 3148 and 16239 ± 2935 cells/mm2, and sequence regularity was 85.5 ± 3.4% and 88.5 ± 2.8%, respectively; both parameters were significantly different. The correlation between photoreceptor density and age was more negative in group with CME. The CME group tended toward greater reductions in duration of CME., Conclusion: Complications of CME in RP patients may lead to a decrease in photoreceptor density and regularity. Additionally, a longer duration of CME may result in a greater reduction in photoreceptor density., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kitahata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Less than 10% of the candidate drug compounds are associated with male reproductive toxicity. Genetic and/or epigenetic information on sperm may be crucial for fetal development. Therefore, developmental toxicity, such as paternally transmitted birth defects, is possible if genetic abnormalities in the male germ line persist and accumulate in the sperm during spermatogenesis. First, this study provides an overview of chemical and male reproductive toxicity, which may lead to developmental toxicity from the perspective of male reproduction. Second, we demonstrate methods for evaluating male reproductive toxicity to anticipate male-mediated developmental toxicity. We developed a novel staining technique for evaluating sperm quality, as well as a noninvasive imaging analysis of male reproductive toxicity. The former is a mammalian male germ cell-specific staining method using reactive blue 2 dye (RB2), as previously confirmed in human sperm, and a method for detecting the early-stage DNA fragmentation in a single nucleus from mouse spermatozoa using single-cell pulsed-field gel electrophoresis. The latter is a new, ready-to-use, and compact magnetic resonance imaging (MRI) platform utilizing a high-field permanent magnet to evaluate male reproductive toxicity. The histopathological analysis supported the suitability of the MRI platform. The present study, for the first time, revealed a rapid, noninvasive evaluation of male reproductive toxicity in vivo using compact MRI. These novel toxicity assessments can help predict male-mediated developmental toxicity, contributing to accelerated drug discovery and drug repositioning.

Busulfan is an anticancer drug known to cause serious damage to seminiferous tubules in the testes and deplete germ cells in human and animal models. The testicular artery is anastomosed with deferential and cremasteric arteries and is divided into capsular arteries, which give rise to the centripetal arteries and then recurrent arteries. The arterial blood in the testicular tissue is supplied by such a consequent system of arterial vessels, in order from the peripheral to the central area. As anticancer drugs are generally distributed throughout the whole body via the bloodstream and the running and distribution of arteries differ among the testicular areas, we hypothesized that the efficacy of busulfan differs in different testicular areas, particularly between the central and peripheral areas. In this study, busulfan was intraperitoneally injected at 40 mg/kg body weight into C57BL/6J male mice. After 28 days, in busulfan-treated mice, the diameters of seminiferous tubules were significantly higher in the central than in the peripheral area of the testes. The seminiferous tubular areas also significantly decreased in the peripheral areas compared with the central areas. The number of germ cells per seminiferous tubule was significantly higher in the central than in the peripheral area. Sertoli cell nuclei were detached into the lumen in the peripheral area. The number of Leydig cells was significantly lower in the peripheral areas. These data suggest that the effects of busulfan differ between the central and peripheral areas of the testis at 4 weeks after busulfan administration.

Objectives: We previously reported a higher left atrial volume index (LAVI) was independently associated with left atrial (LA) appendage (LAA) thrombus formation in 737 patients with non-valvular atrial fibrillation (NVAF) receiving appropriate oral anticoagulation therapy. Since our previous study was a retrospective single-center study, we designed and conducted a prospective multi-center study to verify our findings for LAVI as a predictor of LAA thrombus in patients with NVAF receiving appropriate oral anticoagulation therapy., Methods: This prospective multi-center study comprised 746 consecutive patients with NVAF recruited between December 2021 and March 2023 from eight institutions in Japan, who were receiving appropriate oral anticoagulation therapy, had undergone transthoracic echocardiography and transesophageal echocardiography (TEE)., Results: LAA thrombi were observed in 21 patients (2.8%). The prevalence of LAA thrombus formation in patients with paroxysmal AF (PAF) was significantly lower than that in patients with non-PAF (0.7% vs. 4.1%, p = .006). LAA thrombus formation was detected in none (0/171) of the patients with normal size LA (LAVI ≤ 34 mL/m 2 ). The prevalence of LAA thrombus formation in patients with mildly dilated LA (LAVI: 34-49.9 mL/m 2 ) was 2.1% (6/283), but that in PAF patients was low at 1.0% (1/104). Furthermore, this prevalence in patients with severely dilated LA (LAVI ≥ 50 mL/m 2 ) was high at 5.1% (15/292)., Conclusions: The findings of this prospective multi-center study are consistent with those of our previous study. Thus, the need for TEE prior to catheter ablation or electrical cardioversion can be determined by the level of LAVI., (© 2024 Wiley Periodicals LLC.)