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The identity of the nitric oxide synthase (NOS) isoform expressed in freshly dispersed rabbit gastric smooth muscle cells and in cultured rabbit gastric, human intestinal and guinea pig taenia coli smooth muscle cells was determined. Findings indicate the presence of a constitutive NOS in smooth muscle cells of the intestines in various species, except for guinea pig taenia coli.

Background: ABO-mismatched transfusions caused by human error are among the most serious problems in transfusion therapy. The major cause is misidentification of a recipient or a blood component at the bedside.Study Design and Methods: A network computer-assisted transfusion-management system has been developed with bar coding as a fail-safe/fool-proof system for accurate component-recipient identification at the bedside, which allows us to monitor the usage of blood components in real time. The efficacy of this system was evaluated to prevent human errors by monitoring the transfusion process via the network and analyzing voluntary and mandatory reports with regard to transfusion errors over a 3-year period. The crossmatch-to-transfusion ratio for operations and outdate rate of RBCs were calculated to assess economic benefit.Results: More than 60,000 blood components have been transfused perfectly to the intended recipients via the network, and one human error was prevented by the system. After establishment of the network system, the crossmatch-to-transfusion ratio for operations and outdate rate of RBCs have been gradually reduced from around 2.5 to 1.8 and from 3.9 to 0.32 percent, respectively.Conclusion: The network computer-assisted management system greatly contributes to safe and efficient transfusion therapy. [ABSTRACT FROM AUTHOR]

Purpose: Our aim was to develop practical training for laparoscopic surgery using Thielembalmed cadavers. Furthermore, in order to verbalize experts' motion characteristics and provide objective feedback to trainees, we initiated motion capture analyses of multiple surgical instruments simultaneously during the cadaveric trainings. In the present study, we report our preliminary results., Methods: Participants voluntarily joined the present cadaveric simulation trainings, and performed laparoscopic radical nephrectomy. After the trainings, scores for tissue similarity (face validity) and impression of educational merit (content validity) were collected from participants based on a 5-point Likert scale (tissue similarity: 5: very similar, 3: average, 1: very different; educational merit: 5: very high, 3: average, 1: very low). In addition, after the additional IRB approval, we started motion capture (Mocap) analyses of 6 surgical instruments (scissors, vessel sealing system, grasping forceps, clip applier, right-angled forceps, and suction), using an infrared trinocular camera (120-Hz location record). Mocap-metrics were compared according to the previous surgical experiences (experts: ≧50 laparoscopic surgeries, intermediates: 10-49, novices: 0-9), using the Kruskal-Wallis test., Results: A total of 9 experts, 19 intermediates, and 15 novices participated in the present study. In terms of face validity, the mean scores were higher than 3, other than for the Vena cava(mean score of 2.89). Participants agreed with the training value (usefulness for future skill improvement: mean score of 4.57). In terms of Mocap analysis, faster speed-related metrics (e.g., velocity, the distribution of tip velocity, acceleration, and jerk) in the scissors and vessel sealing system, a shorter path length of grasping forceps, and fewer dimensionless squared jerks, which indicated more purposeful motion of 4 surgical instruments (vessel sealing system, grasping forceps, clip applier and suction), were observed in the more experienced group., Conclusions: The Thiel-embalmed cadaver provides an excellent training opportunity for complex laparoscopic procedures with participants' high level of satisfaction, and may become a promising tool for a better objective understanding of surgical dexterity. In order to enrich formative feedback to trainees, we are now proceeding with Mocap analysis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study developed and validated a surgical instrument motion measurement system for skill evaluation during practical laparoscopic surgery training. Owing to the various advantages of laparoscopic surgery including minimal invasiveness, this technique has been widely used. However, expert surgeons have insufficient time for providing training to beginners due to the shortage of surgeons and limited working hours. Skill transfer efficiency has to be improved for which there is an urgent need to develop objective surgical skill evaluation methods. Therefore, a simple motion capture-based surgical instrument motion measurement system that could be easily installed in an operating room for skill assessment during practical surgical training was developed. The tip positions and orientations of the instruments were calculated based on the marker positions attached to the root of the instrument. Because the patterns of these markers are individual, this system can track multiple instruments simultaneously and detect exchanges. However due to the many obstacles in the operating room, the measurement data included noise and outliers. In this study, the effect of this decrease in measurement accuracy on feature calculation was determined. Accuracy verification experiments were conducted during wet-lab training to demonstrate the capability of this system to measure the motion of surgical instruments with practical accuracy. A surgical training experiment on a cadaver was conducted, and the motions of six surgical instruments were measured in 36 cases of laparoscopic radical nephrectomy. Outlier removal and smoothing methods were also developed and applied to remove the noise and outliers in the obtained data. The questionnaire survey conducted during the experiment confirmed that the measurement system did not interfere with the surgical operation. Thus, the proposed system was capable of making reliable measurements with minimal impact on surgery. The system will facilitate surgical education by enabling the evaluation of skill transfer of surgical skills., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ebina 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.)

In Japan, many workers are exposed to chronic stress, sleep deprivation, and nutritional imbalance. They tend still to go to work when ill, leading to decreased work performance and productivity, which has become a major social problem. We conducted a human entry study with the aim of finding a link between these two factors and proposing an optimized diet, believing that a review of diet may lead to an improvement in labor productivity. In this study, we used subjective accomplishment (SA) as a measure of productivity. First, we compared nutrient intake between groups with high and low SA using data from a health survey of 1564 healthy male and female adults. Significant differences were found in the intake of 13 nutrients in males and 15 nutrients in females, including potassium, vitamin A, insoluble fiber, and biotin. Recommended daily intake of these nutrients was determined from survey data. Next, we designed test meals containing sufficient amounts of 17 nutrients and conducted a single-arm intervention study (registration code UMIN000047054) in Kameyama City, Mie Prefecture, Japan. Healthy working adults (males and females aged 20-79 years) were recruited and supplied with test meals, which were eaten once a day 5 days a week for 8 weeks. SA was significantly higher and daytime sleepiness (DS) was significantly lower after lunch on workdays in younger participants (under 60 years) when they ate the test meals as breakfast or lunch. Our results suggest that SA and DS, which change daily, are strongly influenced by the meal eaten before work, and that taking the 17 nutrients may help prevent presenteeism and improve labor productivity.

Purpose: The ROCK inhibitor ripasudil hydrochloride hydrate was shown to have axonal protective effects in TNF-induced optic nerve degeneration. The α2-adrenoreceptor agonist brimonidine was also shown to exert axonal protection. The current study aimed to elucidate whether additive axonal protection was achieved by the simultaneous injection of ripasudil and brimonidine and examine the association with AMPK activation., Methods: Intravitreal administration was performed in the following groups: PBS, TNF, or TNF with ripasudil, with brimonidine, or with a combination of ripasudil and brimonidine. Axon numbers were counted to evaluate the effects against axon loss. Immunoblot analysis was performed to examine phosphorylated AMPK expression in optic nerves, and immunohistochemical analysis was performed to evaluate the expression levels of p-AMPK and neurofilament in the optic nerve., Results: Both ripasudil alone or brimonidine alone resulted in significant neuroprotection against TNF-induced axon loss. The combination of ripasudil and brimonidine showed additive protective effects. Combined ripasudil and brimonidine plus TNF significantly upregulated p-AMPK levels in the optic nerve compared with the TNF groups. Immunohistochemical analysis revealed that p-AMPK is present in axons and enhanced by combination therapy., Conclusion: The combination of ripasudil and brimonidine may have additive protective effects compared with single-agent treatment alone. These protective effects may be at least partially associated with AMPK activation., (© 2024. The Author(s).)

Skeletal muscle mass is critical for activities of daily living. Resistance training maintains or increases muscle mass, and various strategies maximize the training adaptation. Mesenchymal stem cells (MSCs) are multipotent cells with differential potency in skeletal muscle cells and the capacity to secrete growth factors. However, little is known regarding the effect of intramuscular injection of MSCs on basal muscle protein synthesis and catabolic systems after resistance training. Here, we measured changes in basal muscle protein synthesis, the ubiquitin-proteasome system, and autophagy-lysosome system-related factors after bouts of resistance exercise by intramuscular injection of MSCs. Mice performed three bouts of resistance exercise (each consisting of 50 maximal isometric contractions elicited by electrical stimulation) on the right gastrocnemius muscle every 48 h, and immediately after the first bout, mice were intramuscularly injected with either MSCs (2.0 × 10 6 cells) labeled with green fluorescence protein (GFP) or vehicle only placebo. Seventy-two hours after the third exercise bout, GFP was detected only in the muscle injected with MSCs with concomitant elevation of muscle protein synthesis. The injection of MSCs also increased protein ubiquitination. These results suggest that the intramuscular injection of MSCs augmented muscle protein turnover at the basal state after consecutive resistance exercise., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Purpose: Androgen deprivation therapy (ADT) is the mainstay approach for prostate cancer (PCa) management. However, the most commonly used ADT modality, gonadotropin-releasing hormone (GnRH) agonists, has been associated with an increased risk of cardiovascular disease (CVD)., Methods: The PCa Cardiovascular (PCCV) Expert Network, consisting of multinational urologists, cardiologists and oncologists with expertise in managing PCa, convened to discuss challenges to routine cardiovascular risk assessment in PCa management, as well as how to mitigate such risks in the current treatment landscape., Results: The experts identified several barriers, including lack of awareness, time constraints, challenges in implementing risk assessment tools and difficulties in establishing multidisciplinary teams that include cardiologists. The experts subsequently provided practical recommendations to improve cardio-oncology care for patients with PCa receiving ADT, such as simplifying cardiovascular risk assessment, individualising treatment based on CVD risk categories, establishing multidisciplinary teams and referral networks and fostering active patient engagement. A streamlined cardiovascular risk-stratification tool and a referral/management guide were developed for seamless integration into urologists' practices and presented herein. The PCCV Expert Network agreed that currently available evidence indicates that GnRH antagonists are associated with a lower risk of CVD than that of GnRH agonists and that GnRH antagonists are preferred for patients with PCa and a high CVD risk., Conclusion: In summary, this article provides insights and guidance to improve management for patients with PCa undergoing ADT., (© 2024. The Author(s).)

The optic nerve consists of the glia, vessels, and axons including myelin and axoplasm. Since axonal degeneration precedes retinal ganglion cell death in glaucoma, the preceding axonal degeneration model may be helpful for understanding the molecular mechanisms of optic nerve degeneration. Optic nerve samples from these models can provide information on several aspects of autophagy. Autophagosomes, the most typical organelles expressing autophagy, are found much more frequently inside axons than around the glia. Thus, immunoblot findings from the optic nerve can reflect the autophagy state in axons. Autophagic flux impairment may occur in degenerating optic nerve axons, as in other central nervous system neurodegenerative diseases. Several molecular candidates are involved in autophagy enhancement, leading to axonal protection. This concept is an attractive approach to the prevention of further retinal ganglion cell death. In this review, we describe the factors affecting autophagy, including nicotinamide riboside, p38, ULK, AMPK, ROCK, and SIRT1, in the optic nerve and propose potential methods of axonal protection via enhancement of autophagy., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A high-resolution haptic display that reproduces tactile distribution information on the contact surface between a finger and an object realizes the presentation of the softness of the object and the magnitude and direction of the applied force. In this article, we developed a 32-channel suction haptic display that can reproduce tactile distribution on fingertips with high resolution. The device is wearable, compact, and lightweight, thanks to the absence of actuators on the finger. A FE analysis of the skin deformation confirmed that the suction stimulus interfered less with adjacent stimuli in the skin than when pressing with positive pressure, thus allowing more precise control of local tactile stimuli. The optimal layout with the least error was selected from three configurations dividing 62 suction holes into 32 ports.The suction pressures were determined by calculating the pressure distribution by a real-time finite element simulation of the contact between the elastic object and the rigid finger. A discrimination experiment of softness with different Young's modulus and its JND investigation suggested that the higher resolution of the suction display improved the performance of the softness presentation compared to a 16-channel suction display previously developed by the authors.

Purpose: A relationship between p38 and autophagy remains debated. The aim of the current study is to investigate whether an inhibitor of p38 prevents axon loss induced by TNF and whether it affects autophagy., Methods: Rats were given intravitreal injection of TNF, TNF plus SB203580, a p38 inhibitor, or SB203580 alone. Immunoblot analysis was performed to examine p62 expression which is a marker of autophagic flux and LC3-II expression which is an autophagy marker in optic nerves 1 week after intravitreal injection. Morphometric analysis of axons was performed to evaluate the effects of SB203580 against TNF-induced optic nerve damage 2 weeks after intravitreal injection. Immunohistochemical analysis was performed to evaluate the expressions of LC3, neurofilament, phosphorylated p38 and p62 in the optic nerve., Results: Quantification of axon number showed that TNF-induced axon loss was significantly protected by SB203580. Immunoblot analysis showed that the increase of p62 induced by TNF was totally eliminated by SB203580, and the SB203580 alone injection decreased the expression of p62. The level of LC3-II was significantly upregulated in the TNF plus SB203580 group compared with the TNF alone group, and the SB203580 alone injection increased the expression of LC3-II. Immunohistochemical analysis showed that LC3 immunoreactivity was found in the neurofilament positive fibers and that these immunoreactivities were enhanced by SB203580. Some colocalizations of p-p38 and p62 were observed in the TNF-treated optic nerve., Conclusion: These results suggest that inhibition of p38 exerts axonal protection with upregulated autophagy in TNF-induced optic nerve damage., (© 2023. The Author(s).)

Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD + ), has been studied to support human health against metabolic stress, cardiovascular disease, and neurodegenerative disease. In the present study, we investigated the effects of oral NR on axonal damage in a rat ocular hypertension model. Intraocular pressure (IOP) elevation was induced by laser irradiation and then the rats received oral NR of 1000 mg/kg/day daily. IOP elevation was seen 7, 14, and 21 days after laser irradiation compared with the controls. We confirmed that oral NR administration significantly increased NAD + levels in the retina. After 3-week oral administration of NR, morphometric analysis of optic nerve cross-sections showed that the number of axons was protected compared with that in the untreated ocular hypertension group. Oral NR administration significantly prevented retinal ganglion cell (RGC) fiber loss in retinal flat mounts, as shown by neurofilament immunostaining. Immunoblotting samples from the optic nerves showed that oral NR administration augmented the phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) level in rats with and without ocular hypertension induction. Immunohistochemical analysis showed that some p-AMPK-immunopositive fibers were colocalized with neurofilament immunoreactivity in the control group, and oral NR administration enhanced p-AMPK immunopositivity. Our findings suggest that oral NR administration protects against glaucomatous RGC axonal degeneration with the possible upregulation of p-AMPK.

Aims: To elucidate the long-term cardiovascular benefit of lowering postprandial hyperglycemia (PPG) in early-stage T2DM patients., Methods: This 10-year post-trial follow-up study included 243 patients from the DIANA (DIAbetes and diffuse coronary Narrowing) study, a multi-center randomized controlled trial which compared the efficacy of one-year life-style and pharmacological (voglibose/nateglinide) intervention lowering PPG on coronary atherosclerosis in 302 early-stage T2DM subjects [impaired glucose tolerance (IGT) or newly-diagnosed T2DM] (UMIN-CTRID#0000107). MACE (all-cause death, non-fatal MI or unplanned coronary revascularization) were compared in (1) three assigned therapies (life-style intervention/vogliose/nateglinide) and (2) patients with and without improvement of PPG (reversion from IGT to NGT or from DM to IGT/NGT on 75 g oral glucose tolerance test)., Results: During the 10-year post-trial observational period, voglibose (HR = 1.07, 95%CI: 0.69-1.66, p = 0.74) or nateglinide (HR = 0.99, 95%CI: 0.64-1.55, p = 0.99) did not reduce MACE. Similarly, achieving the improvement of PPG was not associated with a reduction of MACE (HR = 0.78, 95%CI: 0.51-1.18, p = 0.25). However, in IGT subjects (n = 143), this glycemic management significantly reduced the occurrence of MACE (HR = 0.44, 95%CI: 0.23-0.86, p = 0.01), especially unplanned coronary revascularization (HR = 0.46, 95%CI: 0.22-0.94, p = 0.03)., Conclusions: The early improvement of PPG significantly reduced MACE and unplanned coronary revascularization in IGT subjects during the post-trial 10-year period., Competing Interests: Declaration of competing interest Yu Kataoka has received research support from Nipro and Abbott, and honoraria from Nipro, Abbott, Kowa, Amgen, Sanofi, Astellas, Takeda and Daiichi-Sankyo. Other authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) improve clinical outcomes in various cancers, but sometimes induce autoimmune adverse effects, including myocarditis, which is the most serious complication. There are many reports on ICI-induced myocarditis; however, only a few prospective surveillance reports exist. Therefore, we developed a prospective screening protocol and performed monitoring clinically suspected myocarditis in every patient treated with ICIs., Methods: We prospectively enrolled 126 consecutive patients treated with ICIs in this cohort. Outcomes of patients were determined and analyzed between April 2017 and May 2020. We evaluated vital signs, biomarkers, electrocardiograms, chest radiographs, and echocardiographs before and at 7 ± 3, 14 ± 3, 21 ± 3, and 60 ± 7 days after ICI initiation., Results: Eighteen (14.3 %) presented troponin I elevation and 13 of them presented signs of clinically suspected myocarditis (10.3 %). Among the 13 patients, ICI was discontinued in four cases (3.2 %) without fatal events. Myocarditis appeared at an early stage of ICI treatment, regardless of severity (median, 44 days)., Conclusions: We observed the frequency of patients with myocarditis or myocardial damage through a prospective screening program in the real world. Although the frequency was higher than expected, most cases were mild and ICI treatment could be continued under careful observation., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The purpose of this study was to characterize the motion features of surgical devices associated with laparoscopic surgical competency and build an automatic skill-credential system in porcine cadaver organ simulation training. Participants performed tissue dissection around the aorta, dividing vascular pedicles after applying Hem-o-lok (tissue dissection task) and parenchymal closure of the kidney (suturing task). Movements of surgical devices were tracked by a motion capture (Mocap) system, and Mocap-metrics were compared according to the level of surgical experience (experts: ≥50 laparoscopic surgeries, intermediates: 10-49, novices: 0-9), using the Kruskal-Wallis test and principal component analysis (PCA). Three machine-learning algorithms: support vector machine (SVM), PCA-SVM, and gradient boosting decision tree (GBDT), were utilized for discrimination of the surgical experience level. The accuracy of each model was evaluated by nested and repeated k-fold cross-validation. A total of 32 experts, 18 intermediates, and 20 novices participated in the present study. PCA revealed that efficiency-related metrics (e.g., path length) significantly contributed to PC 1 in both tasks. Regarding PC 2, speed-related metrics (e.g., velocity, acceleration, jerk) of right-hand devices largely contributed to the tissue dissection task, while those of left-hand devices did in the suturing task. Regarding the three-group discrimination, in the tissue dissection task, the GBDT method was superior to the other methods (median accuracy: 68.6%). In the suturing task, SVM and PCA-SVM methods were superior to the GBDT method (57.4 and 58.4%, respectively). Regarding the two-group discrimination (experts vs. intermediates/novices), the GBDT method resulted in a median accuracy of 72.9% in the tissue dissection task, and, in the suturing task, the PCA-SVM method resulted in a median accuracy of 69.2%. Overall, the mocap-based credential system using machine-learning classifiers provides a correct judgment rate of around 70% (two-group discrimination). Together with motion analysis and wet-lab training, simulation training could be a practical method for objectively assessing the surgical competence of trainees., Competing Interests: The authors have declared that no competing interests exist.

Substantial evidence suggests an important role of liver function in brain health. Liver function is clinically assessed by measuring the activity of hepatic enzymes in the peripheral blood. Brain-derived neurotrophic factor (BDNF) is an important regulator of brain function. Therefore, we hypothesized that blood BDNF levels are associated with liver function and fibrosis. To test this hypothesis, in this cross-sectional study, we investigated whether serum BDNF concentration is associated with liver enzyme activity, aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ratio, and fibrosis-4 (FIB-4) index in middle-aged and older women. We found that serum BDNF level showed a significant positive association with ALT and γ-glutamyltranspeptidase (GGT) activity and negative association with FIB-4 index, and a trend of negative association with the AST/ALT ratio after adjustment for age. Additionally, these associations remained statistically significant even after adjustment for body mass index (BMI) and fasting blood glucose level. These results demonstrate associations of serum BDNF levels with liver enzymes and hepatic fibrosis-related indices, which may underlie liver-brain interactions., Competing Interests: The authors have declared that no competing interests exist.

Objective: Adjuvant chemotherapy with trastuzumab improves the postoperative life expectancy of women with early-stage breast cancer. Although trastuzumab is reportedly cardiotoxic, quantification based on real-world evidence is lacking. Therefore, in this study, we aimed to analyse trastuzumab cardiotoxicity using a nationwide claim-based database., Methods: In this retrospective study, we used data from a nationwide claims database (Japan Medical Data Center, Tokyo, Japan) under the universal healthcare system. Women with breast cancer who underwent initial surgery were included. Patients with recurrent or advanced-stage breast cancer, with a history of heart failure, receiving neoadjuvant chemotherapy or a preoperative history of less than 6 months were excluded. Propensity score (PS) was calculated using logistic regression based on age, cardiovascular risk factors, radiotherapy and concomitant anthracyclines (AC)., Results: We identified 12 060 eligible patients (mean age 50.8±8.56 years) between January 2010 and December 2019. After 1:2 PS matching (trastuzumab users, TZ, n=1005; non-users, NT, n=2010), Cox proportional hazards model analysis showed that the rate of heart failure development within 18 months postoperative was significantly higher in the TZ group than in the NT group (adjusted HR 2.28, 95% CI 1.38 to 3.77). Baseline cardiac evaluation in the combined AC/TZ cases was 27.2% preoperative, 66.0% pre-AC and 86.6% pre-TZ, respectively., Conclusion: Trastuzumab cardiotoxicity remained relevant in the claim-based analysis adjusted for AC effects. Further collaborative studies in cardio-oncology with real-world data are warranted to improve the rate of baseline cardiovascular risk assessment in patients with cancer scheduled for cardiotoxic cancer treatment., Competing Interests: Competing interests: AS received lecture fees from Chugai and Eli-Lilly and received research grant from Chugai, AstraZeneca, Daiichi Sankyo, Eisai and Taiho. NY is an employee and a shareholder of Pfizer. SU received grants from Kowa, Bayer, Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, and Takeda and received lecture fees from Eisai, Novartis, MSD, and Boelinger Ingelheim. CS received research grant from Eli-Lilly. KS received lecture fees from Daiichi Sankyo. All of the above are unrelated to the submitted work. All other authors have no conflicts with any industry., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Our aim was to build a skill assessment system, providing objective feedback to trainees based on the motion metrics of laparoscopic surgical instruments., Methods: Participants performed tissue dissection around the aorta (tissue dissection task) and renal parenchymal closure (parenchymal-suturing task), using swine organs in a box trainer under a motion capture (Mocap) system. Two experts assessed the recorded movies, according to the formula of global operative assessment of laparoscopic skills (GOALS: score range, 5-25), and the mean scores were utilized as objective variables in the regression analyses. The correlations between mean GOALS scores and Mocap metrics were evaluated, and potential Mocap metrics with a Spearman's rank correlation coefficient value exceeding 0.4 were selected for each GOALS item estimation. Four regression algorithms, support vector regression (SVR), principal component analysis (PCA)-SVR, ridge regression, and partial least squares regression, were utilized for automatic GOALS estimation. Model validation was conducted by nested and repeated k-fold cross validation, and the mean absolute error (MAE) was calculated to evaluate the accuracy of each regression model., Results: Forty-five urologic, 9 gastroenterological, and 3 gynecologic surgeons, 4 junior residents, and 9 medical students participated in the training. In both tasks, a positive correlation was observed between the speed-related parameters (e.g., velocity, velocity range, acceleration, jerk) and mean GOALS scores, with a negative correlation between the efficiency-related parameters (e.g., task time, path length, number of opening/closing operations) and mean GOALS scores. Among the 4 algorithms, SVR showed the highest accuracy in the tissue dissection task ([Formula: see text]), and PCA-SVR in the parenchymal-suturing task ([Formula: see text]), based on 100 iterations of the validation process of automatic GOALS estimation., Conclusion: We developed a machine learning-based GOALS scoring system in wet lab training, with an error of approximately 1-2 points for the total score, and motion metrics that were explainable to trainees. Our future challenges are the further improvement of onsite GOALS feedback, exploring the educational benefit of our model and building an efficient training program., (© 2022. The Author(s).)

Background: Depression during pregnancy is relatively undertreated; however, the relationship between prenatal exposure to antidepressants and neonatal outcomes remains controversial., Methods: This retrospective cohort study used a Japanese nationwide claims database. Data of 114,359 singletons born between January 2005 and November 2019 were used to evaluate the relationship between prenatal exposure to antidepressants and neonatal morbidity., Results: Of 2892 mothers with a history of depression before delivery, 352 (12.1%) received prescriptions within three months before delivery (MP3), and 2540 did not (non-MP3). The participants were propensity score matched (PSM) in a ratio of 1:3 using logistic regression (MP3_PSM [n = 351] vs non-MP3_PSM [n = 1052]), and maternal prescriptions of antidepressants within three months before delivery were associated with neonatal morbidity indicators, including admission to the neonatal intensive care unit (NICU) (15.7 vs. 9.1%, odds ratio (OR) 1.9 [95% confidence interval (CI): 1.3-2.6]), poor neonatal adaptation syndrome (6.0 vs 1.0%, OR 6.6 [95% CI: 3.1-14.2]), transient tachycardia (15.7 vs. 6.7%, OR 2.6 [95% CI: 1.8-3.8]), and meconium aspiration syndrome (3.1 vs 0.7%, OR 4.8 [95% CI, 1.9-12.5]). There were no significant differences in the long-term duration of stay at the NICU (>15 days)., Limitations: Confounding factors may remain even after the propensity matching., Conclusion: Maternal prescription of antidepressants within three months before delivery was associated with increased admission to the NICU. However, the absolute risk of severe neonatal morbidity was low. Therefore, collaborative care for prenatal depression and the neonatal intensive care is warranted., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: Endovascular aortic repair (EVAR) evolved through competition with open aortic repair (OAR) as a safe and effective treatment option for appropriately selected patients with abdominal aortic aneurysm (AAA). Although endoleaks are the most common reason for post-EVAR reintervention, compliance with lifelong regular follow-up imaging remains a challenge., Design: Retrospective data analysis., Setting: The Japan Medical Data Center (JMDC), a claims database with anonymous data linkage across hospitals, consists of corporate employees and their families of ≤75 years of age., Participants: The analysis included participants in the JMDC who underwent EVAR or OAR for intact (iAAA) or ruptured (rAAA) AAA. Patients with less than 6 months of records before the aortic repair were excluded., Main Outcome Measures: Overall survival and reintervention rates., Results: We identified 986 cases (837 iAAA and 149 rAAA) from JMDC with first aortic repairs between January 2015 and December 2020. The number of patients, median age (years (IQR)), follow-up (months) and post-procedure CT scan (times per year) were as follows: iAAA (OAR: n=593, 62.0 (57.0-67.0), 26.0, 1.6, EVAR: n=244, 65.0 (31.0-69.0), 17.0, 2.2), rAAA (OAR: n=110, 59.0 (53.0-59.0), 16.0, 2.1, EVAR: n=39, 62.0 (31.0-67.0), 18.0, 2.4). Reintervention rate was significantly higher among EVAR than OAR in rAAA (15.4% vs 8.2%, p=0.04). In iAAA, there were no group difference after 5 years (7.8% vs 11.0%, p=0.28), even though EVAR had initial advantage. There were no differences in mortality rate between EVAR and OAR for either rAAA or iAAA., Conclusions: Claims-based analysis in Japan showed no statistically significant difference in 5-year survival rates of the OAR and EVAR groups. However, the reintervention rate of EVAR in rAAA was significantly higher, suggesting the need for regular post-EVAR follow-up with imaging. Therefore, international collaborations for long-term outcome studies with real-world data are warranted., Competing Interests: Competing interests: YK received a fee from the Pharmaceuticals and Medical Devices Agency. HO received a consultant fee from EPS International, outside the submission work. NY is an employee and shareholder of Pfizer. KS has received lecture fees from Diichi Sankyo, Novartis, Pfizer, and Bristol-Myers Squibb, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To evaluate the effectuality and safety of cataract surgery combined with either ab interno trabeculotomy by the microhook (µLOT) or a single iStent ® trabecular bypass implantation (iStent) in eyes with cataract and mild-to-moderate glaucoma., Methods: This study enrolled subjects with mild-to-moderate open angle glaucoma with visually significant cataract who used two or more ophthalmic antiglaucoma agents between 60 and 90y of age. Patients underwent cataract surgery cooperated with either implantation of an iStent (iStent-phaco) or excisional goniotomy with the µLOT (µLOT-phaco). Patients underwent µLOT-phaco in the eye with lower the mean deviation, according to the Humphrey field analyzer, while iStent-phaco was carried out on the other eye. Intraocular pressure (IOP) pre- and post-surgery, alterations in anterior chamber flare (ACF), and corneal endothelial cell density (ECD) were estimated., Results: Twenty subjects were enrolled (mean age: 73.6±7.3y). The mean medicated preoperative IOP was 16.7 mm Hg in the µLOT and 16.2 mm Hg in the iStent eyes. The mean final IOP at 12mo was 13.6 mm Hg in the µLOT eyes and 13.6 mm Hg in the iStent eyes, representing a 17.8% and 17.2% reduction, respectively. The preoperative ACF in the µLOT eyes was 9.5 pc/ms and it returned to normal in 30d postoperatively, with a value of 11.4 pc/ms. In the iStent eyes, ACF was 9.6 pc/ms preoperatively and it returned to normal by 7d postoperatively (11.2 pc/ms at day 7), demonstrating that postoperative inflammation was less in the iStent eyes. The corneal ECD in both groups was not significantly decreased., Conclusion: In this study, iStent and µLOT are both effective through 12mo of follow-up. Safety is more favorable in the iStent eyes, based on early anterior chamber inflammation., (International Journal of Ophthalmology Press.)

Purpose: Netarsudil, a Rho kinase inhibitor with norepinephrine transport inhibitory effect, lowers intraocular pressure, however, its effect on axon damage remains to be elucidated. The aim of the current study was to investigate the effect of netarsudil on TNF-induced axon loss and to examine whether it affects phosphorylated-AMP-activated kinase (p-AMPK) and autophagy in the optic nerve., Methods: Intravitreal administration of TNF or TNF with netarsudil was carried out on rats and quantification of axon number was determined. Electron microscopy determined autophagosome numbers. Localization of p-AMPK expression was examined by immunohistochemistry. The changes in p62, LC3-II, and p-AMPK levels were estimated in the optic nerve by immunoblot analysis. The effect of an AMPK activator A769662 or an AMPK inhibitor dorsomorphin on axon number was evaluated., Results: Morphometric analysis revealed apparent protection by netarsudil against TNF-induced axon degeneration. Netarsudil increased autophagosome numbers inside axons. Netarsudil treatment significantly upregulated optic nerve LC3-II levels in both the TNF-treated eyes and the control eyes. Increased p62 protein level induced by TNF was significantly ameliorated by netarsudil. The netarsudil administration alone lessened p62 levels. Netarsudil significantly upregulated the optic nerve p-AMPK levels. A769662 exhibited obvious axonal protection against TNF-induced damage. A769662 treatment upregulated LC3-II levels and the increment of p62 level induced by TNF was significantly ameliorated by A769662. Immunohistochemical analysis revealed that p-AMPK is present in axons. Netarsudil-mediated axonal protection was significantly suppressed by dorsomorphin administration., Conclusions: Netarsudil upregulated p-AMPK and autophagy. Netarsudil-mediated axonal protection may be associated with upregulated p-AMPK.

Skeletal muscle mass is critical for good quality of life. Mesenchymal stem cells (MSCs) are multipotent stem cells distributed across various tissues. They are characterized by the capacity to secrete growth factors and differentiate into skeletal muscle cells. These capabilities suggest that MSCs might be beneficial for muscle growth. Nevertheless, little is known regarding the effects on muscle protein anabolic and catabolic systems of intramuscular injection of MSCs into skeletal muscle. Therefore, in the present study, we measured changes in mechanistic target of rapamycin complex 1 (mTORC1) signaling, the ubiquitin-proteasome system, and autophagy-lysosome system-related factors after a single intramuscular injection of MSCs with green fluorescence protein (GFP) into mouse muscles. The intramuscularly-injected MSCs were retained in the gastrocnemius muscle for 7 days after the injection, indicated by detection of GFP and expression of platelet-derived growth factor receptor-alpha. The injection of MSCs increased the expression of satellite cell-related genes, activated mTORC1 signaling and muscle protein synthesis, and increased protein ubiquitination and autophagosome formation (indicated by the expression of microtubule-associated protein 1 light chain 3-II). These results suggest that the intramuscular injection of MSCs activated muscle anabolic and catabolic systems and accelerated muscle protein turnover., (© 2021. The Author(s).)

Background: Our aim was to characterize the motions of multiple laparoscopic surgical instruments among participants with different levels of surgical experience in a series of wet-lab training drills, in which participants need to perform a range of surgical procedures including grasping tissue, tissue traction and dissection, applying a Hem-o-lok clip, and suturing/knotting, and digitize the level of surgical competency., Methods: Participants performed tissue dissection around the aorta, dividing encountered vessels after applying a Hem-o-lok (Task 1), and renal parenchymal closure (Task 2: suturing, Task 3: suturing and knot-tying), using swine cadaveric organs placed in a box trainer under a motion capture (Mocap) system. Motion-related metrics were compared according to participants' level of surgical experience (experts: 50 ≤ laparoscopic surgeries, intermediates: 10-49, novices: 0-9), using the Kruskal-Wallis test, and significant metrics were subjected to principal component analysis (PCA)., Results: A total of 15 experts, 12 intermediates, and 18 novices participated in the training. In Task 1, a shorter path length and faster velocity/acceleration/jerk were observed using both scissors and a Hem-o-lok applier in the experts, and Hem-o-lok-related metrics markedly contributed to the 1st principal component on PCA analysis, followed by scissors-related metrics. Higher-level skills including a shorter path length and faster velocity were observed in both hands of the experts also in tasks 2 and 3. Sub-analysis showed that, in experts with 100 ≤  cases, scissors moved more frequently in the "close zone (0  ≤ to < 2.0 cm from aorta)" than those with 50-99 cases., Conclusion: Our novel Mocap system recognized significant differences in several metrics in multiple instruments according to the level of surgical experience. "Applying a Hem-o-lok clip on a pedicle" strongly reflected the level of surgical experience, and zone-metrics may be a promising tool to assess surgical expertise. Our next challenge is to give completely objective feedback to trainees on-site in the wet-lab.

Clinical studies intended for regulatory approval must demonstrate the clinical benefits of the drug in a target population. Clinical development of a drug proceeds by stepwise clinical studies; after safety and pharmacokinetics are evaluated and the recommended dosage and administration are determined, efficacy and safety are evaluated in an exploratory manner, and finally clinical benefits are compared with conventional standard therapies. Guidelines for the clinical evaluation of anti-cancer drugs in Japan were established in 1991 and amended in 2006 after molecular-targeted drugs were introduced. Recent progress in the development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti-cancer drugs. It is often difficult to conduct a confirmatory randomized controlled study using overall survival as the primary endpoint in rare molecular subtypes, and the primary evaluation of the efficacy of some drugs and subsequent approval is based on the tumor response. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study. However, this requires robust monitoring to detect possible ethnic differences in pharmacokinetics and drug efficacy. Development using the conditional approval system for drugs enforced in 2020 may be considered, when clinical utility is evaluated based on surrogate endpoints. Because of these changes, we have revised the guidelines for the clinical evaluation of anti-cancer drugs in Japan. To promote global development of anti-cancer drugs involving Japan, the guidelines have been translated into English., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)