Serum autotaxin is a prognostic indicator of liver-related events in patients with non-alcoholic fatty liver disease.

BACKGROUND: Circulating autotaxin (ATX) levels have been reported to correlate with liver inflammation activity and liver fibrosis severity in patients with non-alcoholic fatty liver disease (NAFLD). The objective of this study is to investigate whether serum ATX could predict liver-related events (LRE) in NAFLD patients. METHODS: This retrospective investigation includes 309 biopsy-proven NAFLD patients registered at Shinshu University Hospital. All patients are followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, hepatic encephalopathy, ascites, and esophagogastric varices, is investigated in relation to ATX levels at the time of liver biopsy. RESULTS: During the median follow-up period of 7.0 years, LRE are observed in 20 patients (6.5%). The area under the receiver operating characteristic curve and cut-off value of serum ATX for predicting LRE are 0.81 and 1.227 mg/l, respectively. Multivariate Cox proportional hazards models for LRE determine ATX and advanced fibrosis as independently associated factors. Furthermore, in a competing risk analysis that considered non-liver-related death as a competing event, ATX (HR 2.29, 95% CI 1.22-4.30, p = 0.010) is identified as an independent factor associated with LRE, along with advanced fibrosis (HR 8.01, 95% CI 2.10-30.60, p = 0.002). The predictive utility of ATX for LRE is validated in an independent cohort. CONCLUSIONS: Serum ATX may serve as a predictive marker for LRE in patients with NAFLD.

In non-alcoholic fatty liver disease (NAFLD), fat accumulates and can cause damage within the liver. The disease is becoming increasingly common worldwide. It is therefore important to identify individuals with NAFLD who are at higher risk of developing severe liver complications. In this study, we found that NAFLD patients with elevated levels of a substance called autotaxin (ATX) in their blood were more prone to liver-related issues. Thus, it is crucial for doctors to give special attention to NAFLD patients exhibiting high ATX levels. Through close ATX monitoring and appropriate treatment, doctors can potentially enhance their health outcomes and prevent the onset of more severe liver complications.

EGFR signaling and pharmacology in oncology revealed with innovative BRET-based biosensors.

Mutations of receptor tyrosine kinases (RTKs) are associated with the development of many cancers by modifying receptor signaling and contributing to drug resistance in clinical settings. We present enhanced bystander bioluminescence resonance energy transfer-based biosensors providing new insights into RTK biology and pharmacology critical for the development of more effective RTK-targeting drugs. Distinct SH2-specific effector biosensors allow for real-time and spatiotemporal monitoring of signal transduction pathways engaged upon RTK activation. Using EGFR as a model, we demonstrate the capacity of these biosensors to differentiate unique signaling signatures, with EGF and Epiregulin ligands displaying differences in efficacy, potency, and responses within different cellular compartments. We further demonstrate that EGFR single point mutations found in Glioblastoma or non-small cell lung cancer, impact the constitutive activity of EGFR and response to tyrosine kinase inhibitor. The BRET-based biosensors are compatible with microscopy, and more importantly characterize the next generation of therapeutics directed against RTKs.

Efficacy of surgical staple line reinforcement in Glissonean stapling: A single-center pilot study.

Vascular staplers are routinely used in laparoscopic liver resection, which has become a standard procedure in advanced medical facilities. Although previous reports have outlined the benefits of staple line reinforcement (SLR), its application in Glissonean pedicle transection during hepatic resection remains poorly studied. This study investigated surgical SLR as a tool to enhance staple line strength and improve perioperative hemostasis. Here, 10 patients who underwent laparoscopic liver resection using the Tri-StapleTM2.0 Reinforced Reload were included. Patient characteristics, surgical details, and outcomes were assessed. The results demonstrated successful outcomes with no complications related to bile leakage or injuries during staple insertion. Overall, our findings suggest that SLR can be safely utilized in Glissonean pedicle transection during laparoscopic liver resections. Further studies are required to comprehensively evaluate its benefits compared with conventional surgical staplers.

Suppressive effect of Yokukansan on glutamate released from canine keratinocytes.

Background: Canine atopic dermatitis (CAD) is caused by skin barrier dysfunction due to allergen exposure. Excessive glutamate release in the skin is associated with delayed skin barrier function recovery and epidermal thickening and lichenification. Treatment with Yokukansan (YKS), a traditional Japanese medicine, reduces dermatitis severity and scratching behavior in NC/Nga mice by decreasing epidermal glutamate levels. However, the association between canine keratinocytes and glutamate and the mechanism by which YKS inhibits glutamate release from keratinocytes remains unknown. Aim: We aimed to investigate glutamate release from canine progenitor epidermal keratinocytes (CPEKs) and the inhibitory effect of YKS on this release. We also explored the underlying mechanism of YKS to enable its application in CAD treatment. Methods: Glutamate produced from CPEKs in the medium at 24 hours was measured. The measurement conditions varied in terms of cell density and YKS concentration. CPEKs were treated with a glutamate receptor antagonist (MK-801), a glutamate transporter antagonist (THA), and a glutamate dehydrogenase inhibitor (epigallocatechin gallate; EGCG), and the inhibitory effect of YKS, YKS + THA, MK-801, and EGCG on this release was determined. MK-801 and glutamate dehydrogenase inhibitor were tested alone, and THA was tested in combination with YKS. Finally, glutamine incorporated into CPEKs at 24 hours was measured using radioisotope labeling. Results: CPEKs released glutamate in a cell density-dependent manner, inhibited by YKS in a concentration-dependent manner. Moreover, YKS reduced the intracellular uptake of radioisotope-labeled glutamine in a concentration-dependent manner. No involvement of glutamate receptor antagonism or activation of glutamate transporters was found, as suggested by previous studies. In addition, EGCG could inhibit glutamate release from CPEKs. Conclusion: Our findings indicated that glutamate release from CPEKs could be effectively inhibited by YKS, suggesting the utility of YKS in maintaining skin barrier function during CAD. In addition, CPEKs are appropriate for analyzing the mechanism of YKS. However, we found that the mechanism of action of YKS differs from that reported in previous studies, suggesting that it may have had a similar effect to EGCG in this study. Further research is warranted to understand the exact mechanism and clinical efficacy in treating CAD.

Distribution of internal medicine rotations among resident physicians in Japan: a nationwide, multicenter, cross-sectional study.

BACKGROUND: In Japan, postgraduate clinical training encompasses a 2-year residency program, including at least 24 weeks of internal medicine (IM) rotations. However, the fragmented structure of these rotations can compromise the training's quality and depth. For example, a resident might spend only a few weeks in cardiology before moving to endocrinology, without sufficient time to deepen their understanding or have clinical experience. This study examined current patterns and lengths of IM rotations within the Japanese postgraduate medical system. It scrutinized the piecemeal approach-whereby residents may engage in multiple short-term stints across various subspecialties without an overarching, integrated experience-and explored potential consequences for their clinical education. METHODS: This nationwide, multicenter, cross-sectional study used data from self-reported questionnaires completed by participants in the 2022 General Medicine In-Training Examination (GM-ITE). Data of 1,393 postgraduate year (PGY) one and two resident physicians who participated in the GM-ITE were included. We examined the IM rotation duration and number of IM subspecialties chosen by resident physicians during a 2-year rotation. RESULTS: Approximately half of the participants chose IM rotation periods of 32-40 weeks. A significant proportion of participants rotated in 5-7 internal medicine departments throughout the observation period. Notable variations in the distribution of rotations were observed, characterized by a common pattern where resident physicians typically spend 4 weeks in each department before moving to the next. This 4-week rotation is incrementally repeated across different subspecialties without a longer, continuous period in any single area. Notably, 39.7% of participants did not undertake general internal medicine rotations. These results suggest a narrowed exposure to medical conditions and patient care practices. CONCLUSIONS: Our study highlights the need to address the fragmented structure of IM rotations in Japan. We suggest that short, specialized learning periods may limit the opportunity to gain broad in-depth knowledge and practical experience. To improve the efficacy of postgraduate clinical education, we recommend fostering more sustained and comprehensive learning experiences.

Development of a Clinical Simulation Video to Evaluate Multiple Domains of Clinical Competence: Cross-Sectional Study.

BACKGROUND: Medical students in Japan undergo a 2-year postgraduate residency program to acquire clinical knowledge and general medical skills. The General Medicine In-Training Examination (GM-ITE) assesses postgraduate residents' clinical knowledge. A clinical simulation video (CSV) may assess learners' interpersonal abilities. OBJECTIVE: This study aimed to evaluate the relationship between GM-ITE scores and resident physicians' diagnostic skills by having them watch a CSV and to explore resident physicians' perceptions of the CSV's realism, educational value, and impact on their motivation to learn. METHODS: The participants included 56 postgraduate medical residents who took the GM-ITE between January 21 and January 28, 2021; watched the CSV; and then provided a diagnosis. The CSV and GM-ITE scores were compared, and the validity of the simulations was examined using discrimination indices, wherein ≥0.20 indicated high discriminatory power and >0.40 indicated a very good measure of the subject's qualifications. Additionally, we administered an anonymous questionnaire to ascertain participants' views on the realism and educational value of the CSV and its impact on their motivation to learn. RESULTS: Of the 56 participants, 6 (11%) provided the correct diagnosis, and all were from the second postgraduate year. All domains indicated high discriminatory power. The (anonymous) follow-up responses indicated that the CSV format was more suitable than the conventional GM-ITE for assessing clinical competence. The anonymous survey revealed that 12 (52%) participants found the CSV format more suitable than the GM-ITE for assessing clinical competence, 18 (78%) affirmed the realism of the video simulation, and 17 (74%) indicated that the experience increased their motivation to learn. CONCLUSIONS: The findings indicated that CSV modules simulating real-world clinical examinations were successful in assessing examinees' clinical competence across multiple domains. The study demonstrated that the CSV not only augmented the assessment of diagnostic skills but also positively impacted learners' motivation, suggesting a multifaceted role for simulation in medical education.

High-risk Features for Recurrence in Patients With Stage III Colorectal Cancer: A Retrospective Cohort Study.

BACKGROUND/AIM: Risk classification for recurrence in stage III colorectal cancer (CRC) is not as well established as it is for stage II. This study aimed to identify high-risk factors for stage III colorectal cancer and to investigate their clinical significance. PATIENTS AND METHODS: We retrospectively analyzed data from 120 patients with stage III CRC who had undergone curative colectomy at our institution between 2014 and 2020. We used logistic regression analysis to identify risk factors for recurrence and subsequently explored their clinical significance. RESULTS: We identified three high-risk factors in stage III CRC: preoperative bowel obstruction [odds ratio (OR)=5.39; 95% confidence interval (CI)=1.61-18.03; p=0.007], N2 disease (OR=3.12; 95%CI=1.05-9.29; p=0.041), and having fewer than 17 examined lymph nodes (OR=3.17; 95%CI=1.11-8.99; p=0.031). The prognosis of patients was clearly stratified by the number of these risk factors, and furthermore, the effectiveness of adjuvant therapy depended on their number. CONCLUSION: Tumor obstruction, N-stage, and the number of lymph nodes examined are important high-risk features for recurrence. This study provides clinicians with valuable insights to predict and stratify patient outcomes in stage III CRC.

Optimal cutoff value of the dry eye-related quality-of-life score for diagnosing dry eye disease.

This retrospective study aimed to determine the optimal cutoff values of the Dry Eye-Related Quality-of-Life Score (DEQS) questionnaire for diagnosing dry eye disease (DED) and classifying DED severities. Participants completed the DEQS questionnaire, the Japanese version of the Ocular Surface Disease Index (J-OSDI) questionnaire, and DED examinations. DED was diagnosed according to the 2016 Asia Dry Eye Society diagnostic criteria based on DED symptoms (J-OSDI ≥ 13 points) and tear film breakup time ≤ 5 s. Receiver operating characteristic (ROC) analysis was used to calculate the optimal cutoff values of the DEQS summary score for detecting DED and grading its severity. Among 427 patients, 296 (69.3%) and 131 (30.7%) were diagnosed with DED and non-DED, respectively. ROC analysis determined an optimal cutoff value of 15.0 points for DED diagnosis, with 83.5% sensitivity, 87.0% specificity, and an area under the curve of 0.915. The positive and negative predictive values for DEQS ≥ 15.0 points were 93.6% and 69.9%, respectively. DEQS cutoff values of 15.0, 20.0, and 26.8 points could be accepted for severity classification of DED subjective symptoms in clinical use and represent mild, moderate, and severe DED, respectively. Conclusively, the optimal cutoff values of DEQS enable DED detection and subjective symptom severity classification.

The Impact of 5-Aminolevulinic Acid Supplementation on Redox Balance and Aerobic Capacity.

We examined the impact of 5-aminolevulinic acid (5-ALA) and sodium-ferrous-citrate supplementation on aerobic capacity and redox balance through a placebo-controlled, double-blind trial. Fourteen healthy volunteers were randomly assigned to Pla + ALA (4-week placebo followed by 4-week 5-ALA supplementation) or ALA + Pla (4-week 5-ALA supplement followed by a 4-week placebo) group and administered 5-ALA (25 mg/day) or placebo once daily. The participants underwent submaximal incremental cycling tests at weeks 0, 2, 4, 6, and 8. In the cycling test at week 0, individual load-intensity stages required for blood lactate levels >2 mmol/L (lactate threshold, LT) and 4 mmol/L (onset of blood lactate accumulation, OBLA) were determined. The heart rate (HR), blood lactate (La), and oxidative stress markers (diacron reactive oxygen metabolite, d-ROMs; biological antioxidant potential, BAP) were measured at resting, LT, and OBLA states in each cycling test. Marker values were not significantly different between the groups. HR, La, and d-ROMs at resting, LT, and OBLA states were not significantly different among the conditions. BAP and BAP/d-ROMs ratios were significantly different in the OBLA state at week 4 of the 5-ALA group compared with that of the placebo group (p < 0.05). In conclusion, 5-ALA supplementation might improve redox balance during high-intensity aerobic exercise.

A surgical case of anti-coagulant ileus mimicking small-bowel tumors: a case report.

BACKGROUND: Anti-coagulant ileus, characterized by intramural hematoma due to excessive anti-coagulant therapy, presents a diagnostic challenge. Although previously considered uncommon, recently, reporting cases of anti-coagulant ileus have become more frequent. Herein, we report a rare surgical case of anti-coagulant ileus mimicking small-bowel tumors. CASE PRESENTATION: A 79-year-old man was admitted to our hospital for fatigue. He had been administered warfarin for 5 months for atrial fibrillation. On admission, the patient exhibited mild epigastric tenderness. Laboratory test results revealed anemia (hemoglobin, 8.4 g/dL); unmeasurably prolonged prothrombin time (PT) with international normalized ratio (INR) > 8; and elevated soluble interleukin 2 receptor (sIL-2R) levels (849 IU/mL; normal range, 122-496 IU/mL). Abdominal plain computed tomography (CT) showed a circumferentially thickened intestinal wall at one site in the jejunum and two in the ileum. After hospitalization, bowel obstruction did not improve with conservative treatment. Suspecting small-bowel tumors such as lymphoma, the patient subsequently underwent open surgery on day 3 after admission. No obvious tumor mass was observed intra-operatively. However, only thickened and hemorrhagic segments were identified at the suspected sites. We performed partial jejunal and ileal resections of 12 and 27 cm, respectively. Histopathology confirmed submucosal congestion, edema, and hemorrhage in each area without tumor components, leading to the final diagnosis of intramural hematoma. The postoperative course was uneventful, and he was discharged on postoperative day 9. No recurrence occurred during the 5-year follow-up period. CONCLUSIONS: We encountered a surgical case of anti-coagulant ileus, which was difficult to differentiate from malignant lymphoma based on CT findings and high sIL-2R levels. The possibility of anti-coagulant ileus should always be considered in patients on long-term anticoagulation medication and bowel obstruction with high PT-INR values.

Association of sleep quality with duty hours, mental health, and medical errors among Japanese postgraduate residents: a cross-sectional study.

Long duty hours (DH) impair sleep and negatively affect residents' health and medical safety. This cross-sectional study investigated the association among residents' DH, sleep duration, insomnia, sleep impairment, depressive symptoms, and self-reported medical errors among 5579 residents in Japan who completed the General Medicine In-Training Examination (2021) and participated in the training-environment survey. Weekly DH was classified under seven categories. Sleep duration and insomnia symptoms, from the Athens Insomnia Scale, were analysed to determine sleep impairment; depressive symptoms and medical errors were self-reported. Among 5095 residents, 15.5% slept < 5 h/day, and 26.7% had insomnia. In multivariable analysis, compared with ≥ 60 and < 70, DH ≥ 90 h/week associated with shorter sleep duration and worsen insomnia symptoms. Shorter durations of sleep and more intense symptoms of insomnia were associated with increased depressive symptoms. Medical errors increased only among residents with insomnia, but were not associated with sleep duration. DH > 90 h/week could lead to shorter sleep duration, worsen insomnia symptoms, and negatively impact well-being and medical safety. There was no significant association between sleep duration and medical errors; however, insomnia conferred an increased risk of medical errors. Limiting DH for residents to avoid excessive workload can help improve resident sleep, enhance resident well-being, and potentially reduce insomnia-associated medical errors.

Effectiveness of warm-up and dynamic balance training in preventing anterior cruciate ligament injuries in college gymnasts: a 3-year prospective study for one team.

BACKGROUND: The effect of trunk stability and dynamic balance warm-up exercises on physical functional improvement remains unelucidated. This study examined whether exercises could prevent anterior cruciate ligament (ACL) injury and improve trunk muscle activation and dynamic balance in gymnasts. METHODS: This comparison study, involving gymnastics practice sessions, included 31 university gymnasts and was conducted in two periods: 1 year of observation followed by 2 years of intervention. Participants performed a trunk and dynamic balance warm-up exercise program during the intervention. The effect of exercise on the incidence of ACL injury was evaluated. In addition, the paired t-test was used to compare the Y-balance distance and the changes in muscle thickness associated with trunk muscle activation at rest and during plank. RESULTS: ACL injury risk during the intervention was significantly lower, with a relative risk of 0.23 (P=0.02, 95% CI: 0.06-0.88). Changes in muscle thickness with activation of the transversus abdominis (P<0.01, mean difference 4.1, 95% CI: 9.97-28.07, Cohen's d=0.52), internal oblique (P<0.01, mean difference 5.2, 95% CI: 9.72-21.55, Cohen's d=0.65), and external oblique (P<0.01, mean difference 5.5, 95% CI: 20.44-39.09, Cohen's d=0.71) muscles were significantly higher during the intervention. The Y-balance distance was also significantly greater in the posterior medial reach (P<0.01, mean difference 3.3, 95% CI: 1.56-6.26, Cohen's d=0.46) during the intervention. CONCLUSIONS: Exercise-based warm-up programs may decrease ACL injuries. It can improve physical functions, such as the rate of change in trunk muscle thickness and the posterior medial distance during Y balance.

Effect of lower-extremity muscle power training on muscle strength, balance function and walking ability in older adults with heart failure: a randomized controlled trial.

PURPOSE: This study investigated the combined effect of lower-extremity muscle power training and regular cardiac rehabilitation on muscle strength, balance function, and walking ability of older adults with heart failure. METHODS: Thirty-one patients, comprising 17 males and 14 females, aged between 66 and 89 years and diagnosed with non-severe heart failure, were randomly assigned to either the intervention group (n = 15) or control group (n = 16). Both groups participated in a 12-week regular rehabilitation program, with the intervention group receiving additional lower-extremity muscle power training. Various outcome measures, including muscle strength (the five-times-sit-to-stand test and knee extensor peak torque), balance function (Berg balance scale and functional reach test), and walking ability (4-m walk and Timed Up-and-Go tests) were assessed at baseline and 12 weeks after the intervention. RESULTS: Of the 31 participants, 27 completed the study protocol. The intervention group demonstrated significantly greater improvement in the five-times-sit-to-stand test time, indicating enhanced lower-extremity muscle power compared to the control group. Both groups showed significant differences in the Berg balance scale, functional reach test, 4-m walk test, and Timed Up-and-Go test between baseline and 12 weeks. However, the effect sizes for the changes during the study period were larger in the intervention group (d = 0.74-1.19) than the control group (d = 0.57-0.96). CONCLUSION: Combining lower-extremity muscle power training with regular cardiac rehabilitation may lead to additional improvements in muscle function for older adults with heart failure, resulting in enhanced dynamic balance and walking ability. TRIAL REGISTRATION NUMBER/DATE OF REGISTRATION: UMIN000032087/April 4, 2018.

Prognostic Significance of C-Reactive Protein in Lenvatinib-Treated Unresectable Hepatocellular Carcinoma: A Multi-Institutional Study.

BACKGROUND: Serum C-reactive protein (CRP) is an established biomarker for acute inflammation and has been identified as a prognostic indicator for hepatocellular carcinoma (HCC). However, the significance of the serum CRP level, specifically in HCC patients treated with lenvatinib, remains unclear. METHODS: We retrospectively analyzed 125 HCC patients who received lenvatinib treatment at six centers. Clinical characteristics were assessed to identify clinical associations between serum CRP and HCC prognosis. RESULTS: The median overall serum CRP level was 0.29 mg/dL. The cohort was divided into two groups: the low-CRP group with a serum CRP < 0.5 mg/dL and the high-CRP group with a serum CRP ≥ 0.5 mg/dL. The low-CRP group exhibited significantly longer overall survival (OS) than the high-CRP group (22.9 vs. 7.8 months, p < 0.001). No significant difference was observed for progression-free survival (PFS) between the high- and low-CRP groups (9.8 vs. 8.4 months, p = 0.411), while time-to-treatment failure (TTF) was significantly longer in the low-CRP group (8.5 vs. 4.4 months, p = 0.007). The discontinuation rate due to poor performance status was significantly higher in the high-CRP group (p < 0.001). CONCLUSION: A baseline serum CRP level exceeding 0.5 mg/dL was identified as an unfavorable prognostic factor in HCC patients receiving lenvatinib treatment.

The effects of resident work hours on well-being, performance, and education: A review from a Japanese perspective.

This article examines the impact of working-hour restrictions on the well-being, performance, and education of medical residents in Japan. Despite Japan's plan to introduce new regulations for resident working hours by 2024, there is still an ongoing debate regarding their appropriateness. This review provides a comprehensive overview of the current regulations of resident working hours worldwide, with a specific focus on weekly hours. The varying regulations are highlighted, including the 80-hour-per-week regulation in the United States and the 48-h-per-week regulation in the European Union influencing other regions. The article also discusses the effectiveness of working-hour restrictions on residents' mental health, with shorter working hours having potentially greater benefits. However, the impacts on medical safety and resident education are mixed, and further reduction in working hours must be carefully considered to avoid adverse effects. The planned changes to working-hour limits for residents in Japan offer a unique opportunity to gain new evidence on the impact of such regulations, which will be of interest to policymakers and researchers worldwide.

Shoseiryuto Promotes the Formation of a Tight-Junction Barrier in Cultured Human Bronchial Epithelial Cells.

Shoseiryuto (SST) (Xiao-Qing-Long-Tang in Chinese) is an effective treatment for respiratory diseases, such as bronchial asthma and allergic rhinitis, but its effects on the bronchial tight-junction (TJ) barrier have not been clarified. This study aimed to evaluate the effect of SST on TJ-barrier function in human bronchial epithelial (16HBE) cells. The 16HBE cells were cultured in a culture medium without (control) and with SST in the absence and presence of bacterial endotoxin lipopolysaccharide (LPS) in transwell chambers. Transepithelial electrical resistance (TEER) and sodium fluorescein (Na-F) permeability of the cultured-cell monolayer were measured as TJ integrity markers. In addition, immunofluorescence staining and quantitative real-time polymerase chain reaction analysis were used to measure the expression of the TJ protein, occludin. SST increased TEER and decreased Na-F permeability of the 16HBE cell monolayers. Furthermore, SST increased both occludin mRNA and immunostained protein expressions, suggesting that SST has the effect of directly promoting epithelial TJ-barrier function. LPS decreased TEER, increased Na-F permeability, and decreased both occludin mRNA and protein expression. LPS-induced barrier dysfunction was completely blocked by pre/co- and posttreatment with SST. These results suggest that SST has protective and therapeutic effects against LPS-induced TJ-barrier damage. To our knowledge, these are the first results to demonstrate the protective and therapeutic effects conferred by TJ-barrier promoting, which may be a novel mechanism contributing to the efficacy of SST for respiratory diseases.