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Objective: Integration of head-mounted virtual reality (VR) devices has been revolutionary in health professions education. In disaster preparedness training, VR simulation-based learning exposes health care professionals to the unique challenges of diverse scenarios, enhancing their adaptability. The aim of the study was to evaluate the effectiveness of a head-mounted VR tool for teaching basic radiation emergency medicine skills to medical students., Methods: The participants were 64 medical students (5th-year) who underwent a 3-hour training session in radiation emergency medicine that was conducted via head-mounted VR devices. Students scored their perceived emotion, performance, and self-efficacy at various time points in a self-reported online questionnaire., Results: Comparison of survey responses before and after the session showed significant differences in terms of neutral emotion ( P = 0.011), negative activating emotions ( P < 0.001), and negative deactivating emotions ( P = 0.004). The post-hoc test revealed statistically significant differences in negative activating emotions between before and during ( P < 0.05), and between before and after ( P < 0.05) the VR simulation. In addition, negative deactivation and neutral emotions changed significantly after the simulation., Conclusions: The use of head-mounted VR devices was effective in modulating medical students' emotions and contributed to improving their perceived performance in radiation emergency medicine.

Here an electrical stimulation system is described for maturing microfiber-shaped cardiac tissue (cardiac microfibers, CMFs). The system enables stable culturing of CMFs with electrical stimulation by placing the tissue between electrodes. The electrical stimulation device provides an electric field covering whole CMFs within the stimulation area and can control the beating of the cardiac microfibers. In addition, CMFs under electrical stimulation with different frequencies are examined to evaluate the maturation levels by their sarcomere lengths, electrophysiological characteristics, and gene expression. Sarcomere elongation (14% increase compared to control) is observed at day 10, and a significant upregulation of electrodynamic properties such as gap junction protein alpha 1 (GJA1) and potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) (maximum fourfold increase compared to control) is observed at day 30. These results suggest that electrically stimulated cultures can accelerate the maturation of microfiber-shaped cardiac tissues compared to those without electrical stimulation. This model will contribute to the pathological research of unexplained cardiac diseases and pharmacologic testing by stably constructing matured CMFs., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Background: Eating habits are a contributing factor to obesity. Higher-priced menu items have better nutritional quality/balance, as the relationship between the price of food per serving and nutritional quality/balance has been reported. However, previous studies on the nutritional content of restaurant menu items did not focus on the relationship between the nutritional balance of menu items and prices. Therefore, this study aimed to investigate this relationship., Methods: The nutritional balance score (NBS) was defined and calculated according to each nutritional criterion of men and women aged 18-29 years, covering more than 2,000 menu items in 26 Japanese restaurant chains. Furthermore, NBS distribution by gender and restaurant brand, and the relationship between the menu item's NBS and price were assessed., Results: The results showed that the average NBS of the analyzed menu items differed between the criteria for men and women, with the menu items assessed based on men's criterion being more nutritionally balanced on average. The compositions of the top 10 menu items differed between men and women, and most were set menus or rice bowl menus, which were offered by fast-food restaurants. The relationship between price and NBS in most fast-food and casual restaurants was expressed as a concave function. The maximum NBS based on the criteria for men and women were 64.9 and 64.1, with prices of 639.9 and 530.3 yen, respectively., Discussion: NBS score increased with price to a certain level before decreasing, suggesting that the price at which NBS was the highest differed between men and women. The results of this study could contribute to the development of a methodology for healthy eating out practices, with a focus on price., Competing Interests: The authors declare that they have no competing interests., (© 2024 Ogasawara et al.)

Background/objectives: Changes in muscle characteristics after post-anterior cruciate regiment (ACL) reconstruction are common. Knee robotic-assisted therapy using hybrid assistive limb (HAL) single-joint training for recovery from ACL injury has the potential to optimize muscle activity; however, its neurophysiological effects remain unclear. Thus, this study aimed to explore the electrophysiological parameters., Methods: This prospective, nonrandomized, controlled trial was conducted between December 2021 and January 2024. The patients were divided into two groups: the HAL group and the control group, each including five patients who underwent arthroscopic ACL reconstruction. Knee HAL single-joint training was conducted once weekly for three sessions. Three electrophysiological measures were examined related to knee neuromuscular responses pre-motor time, peak amplitude time, and neuromuscular rate of electromyography rise (RER) using surface electromyography (EMG). The pre-motor time and peak amplitude time were assessed in both groups at each session pre- and post-intervention. Both groups were evaluated for RER at postoperative weeks 17 and 21., Results: Regarding the interaction of pre-motor time within each group, the interaction of pre-motor time within each group, the effect size of vastus medialis (VM) was larger in the HAL group. The peak amplitude time of EMG, the overall estimated marginal means, and the HAL group exhibited a significant difference in the VM (p=0.019), while vastus lateralis (VL) showed no significant difference but a larger effect size (d=0.61). The RER revealed a significant difference in semitendinosus-RER30ms in the HAL group (p=0.044)., Conclusions: The knee HAL training for post-ACL reconstruction patients may influence neurophysiological outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committees of Tsukuba University Faculty of Medicine issued approval TCRB18-077. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Soma et al.)

Background: The clinical application of human induced pluripotent stem cell-derived cardiomyocytes (CMs) for cardiac repair commenced with the epicardial delivery of engineered cardiac tissue; however, the feasibility of the direct delivery of human induced pluripotent stem cell-derived CMs into the cardiac muscle layer, which has reportedly induced electrical integration, is unclear because of concerns about poor engraftment of CMs and posttransplant arrhythmias. Thus, in this study, we prepared purified human induced pluripotent stem cell-derived cardiac spheroids (hiPSC-CSs) and investigated whether their direct injection could regenerate infarcted nonhuman primate hearts., Methods: We performed 2 separate experiments to explore the appropriate number of human induced pluripotent stem cell-derived CMs. In the first experiment, 10 cynomolgus monkeys were subjected to myocardial infarction 2 weeks before transplantation and were designated as recipients of hiPSC-CSs containing 2×10 7 CMs or the vehicle. The animals were euthanized 12 weeks after transplantation for histological analysis, and cardiac function and arrhythmia were monitored during the observational period. In the second study, we repeated the equivalent transplantation study using more CMs (6×10 7 CMs)., Results: Recipients of hiPSC-CSs containing 2×10 7 CMs showed limited CM grafts and transient increases in fractional shortening compared with those of the vehicle (fractional shortening at 4 weeks after transplantation [mean ± SD]: 26.2±2.1%; 19.3±1.8%; P <0.05), with a low incidence of posttransplant arrhythmia. Transplantation of increased dose of CMs resulted in significantly greater engraftment and long-term contractile benefits (fractional shortening at 12 weeks after transplantation: 22.5±1.0%; 16.6±1.1%; P <0.01, left ventricular ejection fraction at 12 weeks after transplantation: 49.0±1.4%; 36.3±2.9%; P <0.01). The incidence of posttransplant arrhythmia slightly increased in recipients of hiPSC-CSs containing 6×10 7 CMs., Conclusions: We demonstrated that direct injection of hiPSC-CSs restores the contractile functions of injured primate hearts with an acceptable risk of posttransplant arrhythmia. Although the mechanism for the functional benefits is not fully elucidated, these findings provide a strong rationale for conducting clinical trials using the equivalent CM products., Competing Interests: S.T. is an advisor to Heartseed Inc. K.F. is the cofounder and CEO of Heartseed Inc. S.T., H. Kanazawa, and K.F. own equity in Heartseed Inc.

Background and Objectives : Bedridden patients are at a high risk of venous thromboembolism (VTE). Passive devices such as elastic compression stockings and intermittent pneumatic compression are common. Leg exercise apparatus (LEX) is an active device designed to prevent VTE by effectively contracting the soleus muscle and is therefore expected to be effective in preventing disuse of the lower limbs. However, few studies have been conducted on the kinematic properties of LEX. Therefore, this study aimed to compare the exercise characteristics of LEX with those of an ergometer, which is commonly used as a lower-limb exercise device, and examine its effect on the two domains of muscle activity and circulatory dynamics. Materials and Methods : This study used a crossover design in which each participant performed both exercises to evaluate the exercise characteristics of each device. Fifteen healthy adults performed exercises with LEX and an ergometer (Terasu Erugo, SDG Co., Ltd., Tokyo, Japan) for 5 min each and rested for 10 min after each exercise. Muscle activity was measured using surface electromyography (Clinical DTS, Noraxon, Scottsdale, AZ, USA), and circulatory dynamics were recorded using a non-invasive impedance cardiac output meter (Physioflow Enduro, Manatec Biomedical, Paris, France). The primary outcome was the mean percentage of maximum voluntary contraction (%MVC) of the soleus muscle during exercise. Results : The mean %MVC of the soleus muscle was significantly higher in the LEX group, whereas no significant differences were observed across the periods and sequences. Heart rate, stroke volume, and cardiac output increased during exercise and decreased thereafter; however, the differences between the devices were not significant. Conclusions : LEX may not only have a higher thromboprophylaxis effect, but also a higher effect on preventing muscle atrophy as a lower-extremity exercise device. Additionally, LEX could potentially be used safely in patients who need to be monitored for changes in circulatory dynamics.

Background and Objective: Opening wedge high tibial osteotomy (OWHTO) influences the knee extensor mechanism, the range of passive motion of knee extension and persistent quadriceps, and anterior knee pain and weakness. Rehabilitation should focus on quadriceps strength and improving joint mobility. The single-joint hybrid assistive limb device (HAL-SJ) is a wearable exoskeleton cyborg. In this study, we investigated the feasibility and safety of HAL-SJ training after the early postoperative period following OWHTO and whether the use of this device can improve functional outcomes, including knee muscle extensor strength and knee extension range of motion without knee pain., Methods: Patients who had been diagnosed with knee osteoarthritis and had undergone OWHTO were assessed for eligibility in this prospective trial conducted at our institution between June 2015 and November 2020. The participants were split into two groups, i.e., 10 patients in the hybrid assistive limb (HAL) group and eight patients in the control group. We initiated HAL-SJ therapy on postoperative day 8 and continued it until the patient's discharge. During the hospitalization period, patients engaged in HAL-SJ-assisted knee extension exercises. This exercise routine encompassed five sets, each comprising 10 repetitions, and was conducted twice a week. We conducted assessments aimed at detecting any potential adverse events that could be linked to HAL training. Assessment of the knee extension angle via the visual analog scale (VAS) and strength assessments using a hand-held dynamometer (HHD) were conducted. To compare clinical outcomes before and after OWHTO, knee extension angle, the VAS, HHD, Japanese Orthopaedics Association (JOA) score, and the Japanese Knee Osteoarthritis Measure (JKOM) were assessed at four distinct time points., Results: No adverse events were observed during the study. The assessment of clinical outcomes before and after OWHTO demonstrated a gradual improvement in outcomes., Conclusion: The single-joint hybrid assistive limb device in patients who underwent OWHTO appears to be potentially safe. It contributed to enhanced muscle activity efficiency by reducing knee pain and improving knee extension angles in the early postoperative phase., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Soma et al.)

This study examined whether SUKUBARA ® , a remotely managed training system that we developed, could improve skeletal muscle mass and muscle strength in community-dwelling older adults. SUKUBARA ® is a composite exercise program that combines lower-load resistance training and balance exercises. Participants were instructed to exercise while watching individually assigned videos on YouTube, such that the research administrators could verify the viewing records of each participant. Fifteen participants (69 ± 4 years) were randomly assigned to the intervention (eight participants; the RT group) or the control group (seven participants; the CO group). The primary endpoint was a change in fat-free mass (FFM; kg), whereas the secondary endpoints included a change in knee extension strength (KES; Nm/kg). Correlation analyses were conducted to examine the relationship between FFM and KES. During the 12-week intervention period, significant differences were observed between the RT and CO groups in the changes in FFM (0.5 ± 0.5 vs. -0.1 ± 0.5) and KES (0.20 ± 0.22 vs. 0.02 ± 0.13), and significant positive correlations were found between the changes. Thus, SUKUBARA ® -based interventions have the potential to improve muscle hypertrophy and enhance muscle strength among community-dwelling older adults. Thus, SUKUBARA ® -based interventions show promise in improving muscle hypertrophy and enhance muscle strength among community-dwelling older adults. However, appropriately powered future research is needed to replicate these findings.

Cardiac regenerative therapy using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is expected to become an alternative to heart transplantation for severe heart failure. It is now possible to produce large numbers of human pluripotent stem cells (hPSCs) and eliminate non-cardiomyocytes, including residual undifferentiated hPSCs, which can cause teratoma formation after transplantation. There are two main strategies for transplanting hPSC-CMs: injection of hPSC-CMs into the myocardium from the epicardial side, and implantation of hPSC-CM patches or engineered heart tissues onto the epicardium. Transplantation of hPSC-CMs into the myocardium of large animals in a myocardial infarction model improved cardiac function. The engrafted hPSC-CMs matured, and microvessels derived from the host entered the graft abundantly. Furthermore, as less invasive methods using catheters, injection into the coronary artery and injection into the myocardium from the endocardium side have recently been investigated. Since transplantation of hPSC-CMs alone has a low engraftment rate, various methods such as transplantation with the extracellular matrix or non-cardiomyocytes and aggregation of hPSC-CMs have been developed. Post-transplant arrhythmias, imaging of engrafted hPSC-CMs, and immune rejection are the remaining major issues, and research is being conducted to address them. The clinical application of cardiac regenerative therapy using hPSC-CMs has just begun and is expected to spread widely if its safety and efficacy are proven in the near future., Competing Interests: Declaration of Competing Interest K.F. is the co-founder and CEO of Heartseed, Inc. S.T. is an advisor from HeartSeed, Inc. S.T., H.K., and K.F. own equity in Heartseed, Inc. The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Three-dimensional (3D) cultures are known to more closely mimic in vivo conditions compared with 2D cultures. Cardiac spheroids (CSs) and organoids (COs) are useful for 3D tissue engineering and are advantageous for their simplicity and mass production for regenerative therapy and drug discovery. Herein, we describe a large-scale method for producing homogeneous human induced pluripotent stem cell (hiPSC)-derived CSs (hiPSC-CSs) and COs without scaffolds using a porous 3D microwell substratum with a suction system. Our method has many advantages, such as increased efficiency and improved functionality, homogeneity, and sphericity of hiPSC-CSs. Moreover, we have developed a substratum on a clinically relevant large scale for regenerative therapy and have succeeded in producing approximately 40,000 hiPSC-CSs with high sphericity at once. Furthermore, we efficiently produced a fused CO model consisting of hiPSC-derived atrial and ventricular cardiomyocytes localized on opposite sides of one organoid. This method will facilitate progress toward hiPSC-based clinical applications., Competing Interests: Declaration of interests S.T. is an advisor from Heartseed, Inc. K.F. is a co-founder and CEO of Heartseed, Inc. H.K., J.F., K.F., and S.T. owned equity in Heartseed, Inc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the field of applied microbiology, reproducibility and experimental variability are important factors that influence both basic research as well as process development for industrial applications. Experimental reproducibility and accuracy depend not only on culture conditions such as temperature and aeration but also on raw materials and procedures used for media preparation. The M9 minimal medium is one of the most common synthetic media for culturing Escherichia coli and other bacteria. This synthetic medium can be used to observe and evaluate the physiological activity of microbes under minimal nutritional requirements and determine the limiting factor for the desired phenotype. Although one of the advantages using the M9 medium is that its composition can be modulated, it is difficult to control presence of trace components and impurities from the reagents for preparing this medium. Herein, we showed that trace ingredients present in the reagents used for M9 media preparation affect the bacterial physiological activities (e.g., cell growth, substrate consumption, and byproduct formation). Additionally, we systematically identified the trace ingredient that influenced phenotypic differences. Our results showed that the selection of reagents and accuracy during reagent preparation is important for experimental reproducibility in the field of bio-engineering and systems biology focused on the systematic and continuous development of biomolecular systems (e.g., biorefinery, metabolic engineering, and synthetic biology)., (© 2023. Springer Nature Limited.)

Monitoring cardiac differentiation and maturation from human pluripotent stem cells (hPSCs) and detecting residual undifferentiated hPSCs are indispensable for the development of cardiac regenerative therapy. MicroRNA (miRNA) is secreted from cells into the extracellular space, and its role as a biomarker is attracting attention. Here, we performed an miRNA array analysis of supernatants during the process of cardiac differentiation and maturation from hPSCs. We demonstrated that the quantification of extracellular miR-489-3p and miR-1/133a-3p levels enabled the monitoring of mesoderm and cardiac differentiation, respectively, even in clinical-grade mass culture systems. Moreover, extracellular let-7c-5p levels showed the greatest increase with cardiac maturation during long-term culture. We also verified that residual undifferentiated hPSCs in hPSC-derived cardiomyocytes (hPSC-CMs) were detectable by measuring miR-302b-3p expression, with a detection sensitivity of 0.01%. Collectively, we demonstrate that our method of seamlessly monitoring specific miRNAs secreted into the supernatant is non-destructive and effective for the quality evaluation of hPSC-CMs., Competing Interests: Declaration of interests O.S., S.K., K.M., Y.A., K.F., and S.T. have a patent pending related to this work. K.F. is a co-founder and CEO of Heartseed, Inc. S.T. is an advisor to Heartseed Inc. S.K. is an employee of Heartseed Inc. M.K. and Y.A. are employees of Sysmex Corporation. S.T., H.K., and K.F. own equity in Heartseed, Inc. The remaining authors have no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Decreased muscle strength often occurs after anterior cruciate ligament (ACL) reconstruction; this can include muscle atrophy, neuromuscular dysfunction, and reduced force generation efficiency. Hybrid assistive limb (HAL) technology, which integrates an interactive biofeedback system connecting the musculoskeletal system to the brain and spinal motor nerves, offers a potential intervention. Our study, conducted from March 2018 to August 2023 using knee HAL single-joint technology, was a prospective non-randomized controlled trial involving 27 patients who had undergone arthroscopic ACL reconstruction. They were split into two groups: HAL (18 patients) and control (nine patients). Beginning 18 weeks after their surgery, the HAL group participated in three weekly sessions of knee HAL-assisted exercises. Both the HAL and control groups underwent isokinetic muscle strength tests at postoperative weeks 17 and 21. Testing utilized an isokinetic dynamometer at 60°/s, 180°/s, and 300°/s. The Limb Symmetry Index (LSI) was employed to measure side-to-side differences. The HAL group showed significant LSI improvements in peak extension torque across all testing velocities and for peak flexion torque at 60°/s and 300°/s. The rate of change in LSI for peak flexion torque at 300°/s was significantly higher post-measurements ( p = 0.036; effect size = 1.089). The change rate for LSI in peak extension torque at 300°/s and all peak flexion torques showed medium to large effect sizes in Cohen's d. In conclusion, knee HAL single-joint training positively influenced muscle strength recovery and efficiency. The HAL training group exhibited superior muscle strength at various isokinetic testing velocities compared to the control group.

Bioprocess optimization using mathematical models is prevalent, yet the discrepancy between model predictions and actual processes, known as process-model mismatch (PMM), remains a significant challenge. This study proposes a novel hybrid control system called the hybrid in silico/in-cell controller (HISICC) to address PMM by combining model-based optimization (in silico feedforward controller) with feedback controllers utilizing synthetic genetic circuits integrated into cells (in-cell feedback controller). We demonstrated the efficacy of HISICC using two engineered Escherichia coli strains, TA1415 and TA2445, previously developed for isopropanol (IPA) production. TA1415 contains a metabolic toggle switch (MTS) to manage the competition between cell growth and IPA production for intracellular acetyl-CoA by responding to external input of isopropyl β-D-1-thiogalactopyranoside (IPTG). TA2445, in addition to the MTS, has a genetic circuit that detects cell density to autonomously activate MTS. The combination of TA2445 with an in silico controller exemplifies HISICC implementation. We constructed mathematical models to optimize IPTG input values for both strains based on the two-compartment model and validated these models using experimental data of the IPA production process. Using these models, we evaluated the robustness of HISICC against PMM by comparing IPA yields with two strains in simulations assuming various magnitudes of PMM in cell growth rates. The results indicate that the in-cell feedback controller in TA2445 effectively compensates for PMM by modifying MTS activation timing. In conclusion, the HISICC system presents a promising solution to the PMM problem in bioprocess engineering, paving the way for more efficient and reliable optimization of microbial bioprocesses., (© 2023. Springer Nature Limited.)

Although the extracellular matrix (ECM) plays essential roles in heart tissue engineering, the optimal ECM components for heart tissue organization have not previously been elucidated. Here, we focused on the main ECM component, fibrillar collagen, and analyzed the effects of collagens on heart tissue engineering, by comparing the use of porcine heart-derived collagen and other organ-derived collagens in generating engineered heart tissue (EHT). We demonstrate that heart-derived collagen induces better contraction and relaxation of human induced pluripotent stem cell-derived EHT (hiPSC-EHT) and that hiPSC-EHT with heart-derived collagen exhibit more mature profiles than those with collagens from other organs. Further, we found that collagen fibril formation and gel stiffness influence the contraction, relaxation, and maturation of hiPSC-EHT, suggesting the importance of collagen types III and type V, which are relatively abundant in the heart. Thus, we demonstrate the effectiveness of organ-specific collagens in tissue engineering and drug discovery., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.T. is an advisor of Heartseed, Inc. K.F. is a co-founder and CEO of Heartseed, Inc. H.K., J.F., K.F., and S.T. own equity in Heartseed Inc. The remaining authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Peripheral nerve disorder of the lower extremities causes drop foot and disturbs the daily living activities of patients. The ankle joint hybrid assistive limb (HAL) provides voluntary ankle joint training using surface bioelectrical signals from the muscles of the lower extremities. We investigated the neurological effects of ankle joint HAL training in three patients. Sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs) were analyzed for the peroneal and tibial nerves prior to the first ankle joint HAL training session. Integrated surface electromyography EMG signals were recorded before and after the HAL training sessions to evaluate the effects of training for neuromuscular disorders. The patients were hospitalized to receive rehabilitation with HAL training for 2 weeks. The HAL training was performed daily with two 60 min sessions. All cases demonstrated severe neuromuscular impairment according to the result of the CMAP. All integrated EMG measurements of antagonistic muscle activities decreased after the ankle joint HAL training. The manual muscle testing (MMT) scores of each muscle were slightly increased after the HAL intervention for Case 2(tibialis anterior, from 2 to 2+; gastrocnemius muscles, from 2- to 2; extensor digitorum longus, and extensor hallucis longus, from 1 to 3). The MMT scores were also slightly increased except for gastrocnemius muscle for Case 3 (tibialis anterior, extensor digitorum longus, and extensor hallucis longus, from 2- to 2). These two patients demonstrated voluntary muscle contractions and nerve signals in the CMAP before the HAL training. Even though the amplitude of CMAPs was low, the HAL training may provide voluntary ankle joint movements by reducing the antagonistic muscle contraction via computer processing. The HAL training may enhance muscle movement and coordination through motor learning feedback.

Background: The effectiveness of peer learning has been recognized and discussed by many scholars, and implemented in the formal curriculums of medical schools internationally. However, there is a general dearth of studies in measuring the objective outcomes in learning., Methods: We investigated the objective effect of near-peer learning on tutee's emotions and its equivalence within the formal curriculum of a clinical reasoning Problem Based Learning session in a Japanese medical school. Fourth-year medical students were assigned to the group tutored by 6 th -year students or by faculties. The positive activating emotion, positive deactivating emotion, negative activating emotion, negative deactivating emotion, Neutral emotion were measured using the Japanese version of the Medical Emotion Scale (J-MES), and self-efficacy scores were also assessed. We calculated the mean differences of these variables between the faculty and the peer tutor groups and were statistically analyzed the equivalence of these scores. The equivalence margin was defined as a score of 0.4 for J-MES and 10.0 for the self-efficacy score, respectively., Results: Of the 143 eligible participant students, 90 were allocated to the peer tutor group and 53 were allocated to the faculty group. There was no significant difference between the groups. The 95% confidence interval of the mean score difference for positive activating emotions (-0.22 to 0.15), positive deactivating emotions (-0.35 to 0.18), negative activating emotions (-0.20 to 0.22), negative deactivating emotions (-0.20 to 0.23), and self-efficacy (-6.83 to 5.04) were withing the predetermined equivalence margins for emotion scores, meaning that equivalence was confirmed for these variables., Conclusions: Emotional outcomes were equivalent between near-peer PBL sessions and faculty-led sessions. This comparative measurement of the emotional outcomes in near-peer learning contributes to understanding PBL in the field of medical education., (© 2023. The Author(s).)

Energy transfer to ground state triplet molecular oxygen results in the generation of singlet molecular oxygen ( 1 O 2 ), which has potent oxidizing ability. Irradiation of light, notably ultraviolet A, to a photosensitizing molecule results in the generation of 1 O 2 , which is thought to play a role in causing skin damage and aging. It should also be noted that 1 O 2 is a dominant tumoricidal component that is generated during the photodynamic therapy (PDT). While type II photodynamic action generates not only 1 O 2 but also other reactive species, endoperoxides release pure 1 O 2 upon mild exposure to heat and, hence, are considered to be beneficial compounds for research purposes. Concerning target molecules, 1 O 2 preferentially reacts with unsaturated fatty acids to produce lipid peroxidation. Enzymes that contain a reactive cysteine group at the catalytic center are vulnerable to 1 O 2 exposure. Guanine base in nucleic acids is also susceptible to oxidative modification, and cells carrying DNA with oxidized guanine units may experience mutations. Since 1 O 2 is produced in various physiological reactions in addition to photodynamic reactions, overcoming technical challenges related to its detection and methods used for its generation would allow its potential functions in biological systems to be better understood.

γ-Glutamyl moiety that is attached to the cysteine (Cys) residue in glutathione (GSH) protects it from peptidase-mediated degradation. The sulfhydryl group of the Cys residue represents most of the functions of GSH, which include electron donation to peroxidases, protection of reactive sulfhydryl in proteins via glutaredoxin, and glutathione conjugation of xenobiotics, whereas Cys-derived sulfur is also a pivotal component of some redox-responsive molecules. The amount of Cys that is available tends to restrict the capacity of GSH synthesis. In in vitro systems, cystine is the major form in the extracellular milieu, and a specific cystine transporter, xCT, is essential for survival in most lines of cells and in many primary cultivated cells as well. A reduction in the supply of Cys causes GPX4 to be inhibited due to insufficient GSH synthesis, which leads to iron-dependent necrotic cell death, ferroptosis. Cells generally cannot take up GSH without the removal of γ-glutamyl moiety by γ-glutamyl transferase (GGT) on the cell surface. Meanwhile, the Cys-GSH axis is essentially common to certain types of cells; primarily, neuronal cells that contain a unique metabolic system for intercellular communication concerning γ-glutamyl peptides. After a general description of metabolic processes concerning the Cys-GSH axis, we provide an overview and discuss the significance of GSH-related compounds in the nervous system.

Heart transplantation (HT) is the only definitive treatment available for patients with end-stage heart failure who are refractory to medical and device therapies. However, HT as a therapeutic option, is limited by a significant shortage of donors. To overcome this shortage, regenerative medicine using human pluripotent stem cells (hPSCs), such as human embryonic stem cells and human-induced pluripotent stem cells (hiPSCs), has been considered an alternative to HT. Several issues, including the methods of large-scale culture and production of hPSCs and cardiomyocytes, the prevention of tumorigenesis secondary to contamination of undifferentiated stem cells and non-cardiomyocytes, and the establishment of an effective transplantation strategy in large-animal models, need to be addressed to fulfill this unmet need. Although post-transplantation arrhythmia and immune rejection remain problems, the ongoing rapid technological advances in hPSC research have been directed toward the clinical application of this technology. Cell therapy using hPSC-derived cardiomyocytes is expected to serve as an integral component of realistic medicine in the near future and is being potentially viewed as a treatment that would revolutionize the management of patients with severe heart failure., Competing Interests: Disclosures KF is a cofounder and CEO of Heartseed, Inc. ST is an advisor of Heartseed, Inc. ST, HK and KF own equity in Heartseed, 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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Oxaliplatin is an anticancer therapy for pancreatic, gastric, and colorectal cancers. It is also used in patients with carcinomas of unknown primary sites. Oxaliplatin is associated with less frequent renal dysfunction than other conventional platinum-based drugs such as cisplatin. Albeit, there have been several reports of acute kidney injury with frequent use. In all cases, renal dysfunction was temporary and did not require maintenance dialysis. There have been no previous reports of irreversible renal dysfunction after a single dose of oxaliplatin., Case Presentation: Previous reports of oxaliplatin-induced renal injury occurred after patients received multiples doses. In this study, a 75-year-old male with unknown primary cancer and underlying chronic kidney disease developed acute renal failure after receiving the first dose of oxaliplatin. Suspected of having drug-induced renal failure through an immunological mechanism, the patient was treated with steroids; however, treatment was ineffective. Renal biopsy ruled out interstitial nephritis and revealed acute tubular necrosis. Renal failure was irreversible, and the patient subsequently required maintenance hemodialysis., Conclusions: We provide the first report of pathology-confirmed acute tubular necrosis after the first dose of oxaliplatin which led to irreversible renal dysfunction and maintenance dialysis., (© 2023. The Author(s).)

The COVID-19 pandemic has greatly changed medical education, and medical trainees' self-regulation has become more emphasized. In Japan, the concept of self-regulated learning has not been fully applied in health profession education due to a lack of effective measurement tools. We aimed to validate the translated Japanese version of the Motivated Strategies for Learning Questionnaire in the context of Problem-Based Learning (J-MSLQ-PBL). The questionnaire employs a seven-point Likert-type scale with 81 items and is categorized into two sections: motivation and learning strategies. An exploratory factor analysis (EFA) was conducted by using Promax rotation to examine the factor structure of the scale, using the collected data from 112 Japanese medical students. Factor extraction was based on a scree plot investigation, and an item was accepted when the factor loading was ≥0.40. In the motivation section, the extracted factors from the EFA were well aligned with the subscales of the original MSLQ, including "Self-Efficacy for Learning and Performance", "Task Value", "Self-Efficacy for Learning and Performance", "Test Anxiety", "Extrinsic Goal Orientation", and "Intrinsic Goal Orientation". In the learning strategies, the extracted factors poorly matched the structure of the original subscales. This discrepancy could be explained by insufficient translation, the limited sample size from a single medical school, or cross-cultural differences in learning strategies between Western and Japanese medical students. Only the motivation part of the J-MSLQ-PBL should be implemented to measure the competency elements of self-regulated learning in Japan.

We prospectively investigated the association between acceptable travel distances (i.e., walking and cycling) and the incidence of functional disability and mortality among older Japanese adults. A baseline survey was conducted in 2013 among 7618 individuals aged ≥65 years in Kasama City, Japan, and they were tracked through the city's database until 2021. Acceptable travel distances were assessed using a questionnaire. Outcomes (i.e., functional disability and mortality) were gathered as binary (incident or not) with survival time. A multivariable-adjusted Cox proportional-hazards model indicated that shorter acceptable walking and cycling distances were markedly linked with higher risks of functional disability and mortality. In conclusion, acceptable distances of ≤500 m for walking and ≤1 km for cycling were associated with higher risks of functional disability and mortality among older adults., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

During voluntary muscle contraction, sensory information induced by electrostimulation of the nerves supplying the contracting muscle is inhibited and the amplitude of the corresponding somatosensory evoked potential (SEP) decreases. This phenomenon is called "gating." The reduction of the SEP amplitude is reportedly significantly larger when task performance is high. However, the relationship between dexterous movement skills and gating remains unclear. In this study, we investigated through a ball rotation (BR) task how dexterous movement skills affect the SEP amplitudes. Thirty healthy subjects performed the BR task comprising the rotation of two wooden balls as quickly as possible. We estimated the median number of ball rotations for each participant and classified the participants into two (fast and slow) groups based on the results. Moreover, we recorded SEPs, while the subjects performed BR tasks or rested. SEP amplitude reduction (P45) was significantly larger in the fast than in the slow group. We also observed that the P45 amplitude during the BR task was attenuated even more so in the case of the participants with better dexterous movement skills. Our results suggest that the participants with better dexterous movement skills might display stronger somatosensory information suppression because of increasing the motor cortex activity and the afferent input during the BR task., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pre-column fluorescent derivatization has been used for the fast quantification of amino acids using high-performance liquid chromatography (HPLC) systems. However, it generally requires an offline in-vial derivatization process with multiple derivatization reagents. The offline derivatization requires the same number of reaction vials as the number of sample vials for use as a reaction chamber for the derivatization reaction in an autosampler. Therefore, the number of samples analyzed per batch using the pre-column derivatization method is halved. To benefit from the pre-column derivatization method, we transformed the derivatization process from an offline chamber process to an online in-needle process (in-needle Pre-column Derivatization for Amino acids Quantification; iPDAQ). Fluorescent derivatization in the injection needle obviated the need for vacant vials as reaction chambers. Consequently, the throughput per batch improved up to two times, and the consumption of derivatization reagents was reduced to less than one-tenth of that in the conventional vial method. We demonstrated to separate and quantify the amino acids in various biological samples. Herein, we presented a novel HPLC-based amino acid quantification method that enables the continuous analysis of a large number of samples. The iPDAQ facilitates accurate amino acid quantification due to the automation of derivatization and achieves improvement in the throughput and reduction of analysis labor.

Objectives: To achieve better outcomes, neuromuscular and biomechanical factors should be considered in rehabilitation after anterior cruciate ligament reconstruction. In this study, we investigated the feasibility and safety of a wearable exoskeleton robot suit [known as the single-joint hybrid assistive limb (HAL-SJ)] and whether knee training using this device could improve functional outcomes after anterior cruciate ligament reconstruction., Methods: HAL-SJ-assisted knee extension and flexion exercises were commenced in 11 patients 18 weeks after reconstruction; exercises were performed once a week for three weeks at a frequency of five sets of ten repetitions. Patients were monitored for HAL-SJ-related adverse events. Physical evaluations were conducted before and after HAL-SJ training. Surface electromyography of the quadriceps and hamstring muscles was performed in 4 of the 11 patients during each session and the muscle co-contraction index was calculated., Results: The peak muscle torque was higher at all velocities after HAL-SJ training. The active range of motion significantly increased in both extension and flexion, and the range of motion in passive flexion significantly increased. The Tegner Activity Scale and Lysholm Knee Questionnaire scores also significantly increased after knee HAL training. The muscle co-contraction index during extension tended to be lower after HAL-SJ training. No adverse events were observed., Conclusions: The findings of this study indicate the feasibility and safety of HAL-SJ training as a neuromuscular rehabilitation tool after anterior cruciate ligament reconstruction. The knee HAL-SJ training may have contributed to these results from a neurophysiological perspective by lowering the co-contraction of knee muscles, which would correct impairment of the antagonistic or synergistic muscles., Competing Interests: CONFLICTS OF INTEREST: The authors report that there are no conflicts of interest., (2022 The Japanese Association of Rehabilitation Medicine.)

Background: In response to globalism, many East-Asian countries now include a Medical English course in their undergraduate medical education syllabus. The purpose of this study was to explore the relationship between the related attribute factors of students' motivation to learn medical English through an online modality. Methods: Of 134 eligible fourth-year medical students who participated in an Online Medical English course at a Japanese medical school, 105 were enrolled in this single cohort study. The participants completed pre- and post-course surveys regarding their motivation during the course, including perceived academic control and task value, and their assignment scores. A structural equation model was used to examine the hypothesized relationship of constructs, based on control-value theory. Results: The model showed a good fit for the data (χ 2 [df=7] = 1.821, p=0.969, CFI = 1.000, RMSEA < 0.001, SRMR < 0.05, GFI = 0.993, AGFI = 0.980). The latent variables of the perceived course achievement related to the observed variables of academic control and task value scale scores, and negatively predicted willingness for self-study after course completion. In addition, the preference of English as the course language negatively predicted willingness for self-study of medical English. Conclusion: Choice of English as the language of instruction and perceived high course achievement negatively predicted students' motivation for further English self-study after the class. The importance of incorporating the perspective of lifelong learning into the teaching of medical English was recognized., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Azuma M et al.)

Engineered heart tissues (EHTs) that are fabricated using human induced pluripotent stem cells (hiPSCs) have been considered as potential cardiac tissue substitutes in case of heart failure. In the present study, we have created hiPSC-derived cardiac organoids (hiPSC-COs) comprised of hiPSC-derived cardiomyocytes, human umbilical vein endothelial cells, and human fibroblasts. To produce a beating conduit for patients suffering from congenital heart diseases, we constructed scaffold-free tubular EHTs (T-EHTs) using hiPSC-COs and bio-3D printing with needle arrays. The bio-3D printed T-EHTs were cut open and transplanted around the abdominal aorta as well as the inferior vena cava (IVC) of NOG mice. The transplanted T-EHTs were covered with the omentum, and the abdomen was closed after completion of the procedure. Additionally, to compare the functionality of hiPSC-COs with that of T-EHTs, we transplanted the former around the aorta and IVC as well as injecting them into the subcutaneous tissue on the back of the mice. After 1 m of the transplantation procedures, we observed the beating of the T-EHTs in the mice. In histological analysis, the T-EHTs showed clear striation of the myocardium and vascularization compared to hiPSC-COs transplanted around the aorta or in subcutaneous tissue. Based on these results, bio-3D-printed T-EHTs exhibited a better maturation in vivo as compared to the hiPSC-COs. Therefore, these beating T-EHTs may form conduits for congenital heart disease patients, and T-EHT transplantation can form a treatment option in such cases., Competing Interests: KF is a co-founder and CEO of Heartseed Inc. ST and HS is an advisor of Heartseed, Inc. ST, HS, and KF own equity in Heartseed, Inc. KN is a co-founder and shareholder of Cyfuse Biomedical KK and an inventor/developer designated on the patent for the Bio-3D printer. 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., (Copyright © 2022 Kawai, Tohyama, Arai, Tamura, Soma, Fukuda, Shimizu, Nakayama and Kobayashi.)

Some hemodialysis patients are not suitable for creation of an arteriovenous fistula (AVF) or arteriovenous graft (AVG). However, they can receive a tunneled cuffed central venous catheter (tcCVC), but this carries risks of infection and mortality. We aimed to evaluate the safety and effectiveness of brachial artery transposition (BAT) versus those of tcCVC. This retrospective study evaluated hemodialysis patients who underwent BAT or tcCVC placement because of severe heart failure, hand ischemia, central venous stenosis or occlusion, inadequate vessels for creating standard arteriovenous access, or limited life expectancy. The primary outcome was whole access circuit patency. Thirty-eight patients who underwent BAT and 25 who underwent tcCVC placement were included. One-year patency rates for the whole access circuit were 84.6% and 44.9% in the BAT and tcCVC groups, respectively. The BAT group was more likely to maintain patency (unadjusted hazard ratio: 0.17, 95% confidence interval: 0.05-0.60, p = 0.006). The two groups did not have significantly different overall survival (log-rank p = 0.146), although severe complications were less common in the BAT group (3% vs. 28%, p = 0.005). Relative to tcCVC placement, BAT is safe and effective with acceptable patency in hemodialysis patients not suitable for AVF or AVG creation., (© 2022. The Author(s).)

Pyruvate is a key intermediate that is involved in various synthetic metabolic pathways for microbial chemical and fuel production. It is widely used in the food, chemical, and pharmaceutical industries. However, the microbial production of pyruvate and its derivatives compete with microbial cell growth, as pyruvate is an important metabolic intermediate that serves as a hub for various endogenous metabolic pathways, including gluconeogenesis, amino acid synthesis, TCA cycle, and fatty acid biosynthesis. To achieve a more efficient bioprocess for the production of pyruvate and its derivatives, it is necessary to reduce the metabolic imbalance between cell growth and target chemical production. For this purpose, we devised a dynamic metabolic engineering strategy within an Escherichia coli model, in which a metabolic toggle switch (MTS) was employed to redirect metabolic flux from the endogenous pathway toward the target synthetic pathway. Through a combination of TCA cycle interruption through MTS and reduction of pyruvate consumption in endogenous pathways, we achieved a drastic improvement (163 mM, 26-fold) in pyruvate production. In addition, we demonstrated the redirection of metabolic flux from excess pyruvate toward isobutanol production. The final isobutanol production titer of the strain harboring MTS was 26% improved compared with that of the control strain., (Copyright © 2021 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

The production of chemicals and fuels from renewable resources using engineered microbes is an attractive alternative for current fossil-dependent industries. Metabolic engineering has contributed to pathway engineering for the production of chemicals and fuels by various microorganisms. Recently, dynamic metabolic engineering harnessing synthetic biological tools has become a next-generation strategy in this field. The dynamic regulation of metabolic flux during fermentation optimizes metabolic states according to each fermentation stage such as cell growth phase and compound production phase. However, it is necessary to repeat the evaluation and redesign of the dynamic regulation system to achieve the practical use of engineered microbes. In this study, we performed quantitative metabolome analysis to investigate the effects of dynamic metabolic flux regulation on engineered Escherichia coli for γ-amino butyrate (GABA) fermentation. We prepared a stable isotope-labeled internal standard mixture (SILIS) for the stable isotope dilution method (SIDM), a mass spectrometry-based quantitative metabolome analysis method. We found multiple candidate bottlenecks for GABA production. Some metabolic reactions in the GABA production pathway should be engineered for further improvement in the direct GABA fermentation with dynamic metabolic engineering strategy., (Copyright © 2021 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

The number of patients with heart failure (HF) is increasing with aging in our society worldwide. Patients with HF who are resistant to medication and device therapy are candidates for heart transplantation (HT). However, the shortage of donor hearts is a serious issue. As an alternative to HT, cardiac regenerative therapy using human pluripotent stem cells (hPSCs), such as human embryonic stem cells and induced pluripotent stem cells, is expected to be realized. Differentiation of hPSCs into cardiomyocytes (CMs) is facilitated by mimicking normal heart development. To prevent tumorigenesis after transplantation, it is important to eliminate non-CMs, including residual hPSCs, and select only CMs. Among many CM selection systems, metabolic selection based on the differences in metabolism between CMs and non-CMs is favorable in terms of cost and efficacy. Large-scale culture systems have been developed because a large number of hPSC-derived CMs (hPSC-CMs) are required for transplantation in clinical settings. In large animal models, hPSC-CMs transplanted into the myocardium improved cardiac function in a myocardial infarction model. Although post-transplantation arrhythmia and immune rejection remain problems, their mechanisms and solutions are under investigation. In this manner, the problems of cardiac regenerative therapy are being solved individually. Thus, cardiac regenerative therapy with hPSC-CMs is expected to become a safe and effective treatment for HF in the near future. In this review, we describe previous studies related to hPSC-CMs and discuss the future perspectives of cardiac regenerative therapy using hPSC-CMs., Competing Interests: KF is a co-founder and CEO of Heartseed, Inc. ST was an advisor of Heartseed, Inc. ST, HK, and KF owned equity in Heartseed, 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., (Copyright © 2021 Soma, Morita, Kishino, Kanazawa, Fukuda and Tohyama.)

This study aimed to examine the factors related to participation in volunteer-managed preventive care exercises by focusing on the distance to exercise facilities and interpersonal social networks. A postal mail survey was conducted in 2013 in Kasama City in a rural region of Japan. Older adults (aged ≥ 65 years) who were living independently ( n = 16,870) were targeted. Potential participants who were aware of silver-rehabili taisou exercise (SRTE) and/or square-stepping exercise (SSE) were included in the analysis ( n = 4005). A multiple logistic regression analysis revealed that social and environmental factors were associated with participation in SRTE and SSE. After adjusting for confounding variables, exercise participation was negatively associated with an extensive distance from an exercise facility in both sexes for SRTE and SSE. Among women, participation in SRTE was negatively associated with weak interpersonal social networks (odds ratio (OR) = 0.57), and participation in SRTE and SSE was negatively associated with being a car passenger (SRTE, OR = 0.76; SSE, OR = 0.60). However, there were no significant interactions between sex and social and environmental factors. Our findings suggest the importance of considering location and transportation to promote participation in preventive care exercise.

Background: Size of reference population is a crucial factor affecting the accuracy of prediction of the genomic estimated breeding value (GEBV). There are few studies in beef cattle that have compared accuracies achieved using real data to that achieved with simulated data and deterministic predictions. Thus, extent to which traits of interest affect accuracy of genomic prediction in Japanese Black cattle remains obscure. This study aimed to explore the size of reference population for expected accuracy of genomic prediction for simulated and carcass traits in Japanese Black cattle using a large amount of samples., Results: A simulation analysis showed that heritability and size of reference population substantially impacted the accuracy of GEBV, whereas the number of quantitative trait loci did not. The estimated numbers of independent chromosome segments (M e ) and the related weighting factor (w) derived from simulation results and a maximum likelihood (ML) approach were 1900-3900 and 1, respectively. The expected accuracy for trait with heritability of 0.1-0.5 fitted well with empirical values when the reference population comprised > 5000 animals. The heritability for carcass traits was estimated to be 0.29-0.41 and the accuracy of GEBVs was relatively consistent with simulation results. When the reference population comprised 7000-11,000 animals, the accuracy of GEBV for carcass traits can range 0.73-0.79, which is comparable to estimated breeding value obtained in the progeny test., Conclusion: Our simulation analysis demonstrated that the expected accuracy of GEBV for a polygenic trait with low-to-moderate heritability could be practical in Japanese Black cattle population. For carcass traits, a total of 7000-11,000 animals can be a sufficient size of reference population for genomic prediction., (© 2021. The Author(s).)